Actin is a family of globular multi-functional proteins that form microfilaments. It is found in essentially all eukaryotic cells (the only known exception being nematode sperm), where it may be present at a concentration of over 100 M. An actin protein's mass is roughly 42-kDa, with a diameter of 4 to 7nm, and it is the monomeric subunit of two types of filaments in cells: microfilaments, one of the three major components of the cytoskeleton, and thin filaments, part of the contractile apparatus in muscle cells. It can be present as either a free monomer called G-actin (globular) or as part of a linear polymer microfilament called F-actin (filamentous), both of which are essential for such important cellular functions as the mobility and contraction of cells during cell division.

Actin participates in many important cellular processes, including muscle contraction, cell motility, cell division and cytokinesis, vesicle and organelle movement, cell signaling, and the establishment and maintenance of cell junctions and cell shape. Many of these processes are mediated by extensive and intimate interactions of actin with cellular membranes.[2] In vertebrates, three main groups of actin isoforms, alpha, beta, and gamma have been identified. The alpha actins, found in muscle tissues, are a major constituent of the contractile apparatus. The beta and gamma actins coexist in most cell types as components of the cytoskeleton, and as mediators of internal cell motility. It is believed that the diverse range of structures formed by actin enabling it to fulfill such a large range of functions is regulated through the binding of tropomyosin along the filaments.[3]

A cells ability to dynamically form microfilaments provides the scaffolding that allows it to rapidly remodel itself in response to its environment or to the organisms internal signals, for example, to increase cell membrane absorption or increase cell adhesion in order to form cell tissue. Other enzymes or organelles such as cilia can be anchored to this scaffolding in order to control the deformation of the external cell membrane, which allows endocytosis and cytokinesis. It can also produce movement either by itself or with the help of molecular motors. Actin therefore contributes to processes such as the intracellular transport of vesicles and organelles as well as muscular contraction and cellular migration. It therefore plays an important role in embryogenesis, the healing of wounds and the invasivity of cancer cells. The evolutionary origin of actin can be traced to prokaryotic cells, which have equivalent proteins.[4] Actin homologs from prokaryotes and archaea polymerize into different helical or linear filaments consisting of one or multiple strands. However the in-strand contacts and nucleotide binding sites are preserved in prokaryotes and in archaea.[5] Lastly, actin plays an important role in the control of gene expression.

A large number of illnesses and diseases are caused by mutations in alleles of the genes that regulate the production of actin or of its associated proteins. The production of actin is also key to the process of infection by some pathogenic microorganisms. Mutations in the different genes that regulate actin production in humans can cause muscular diseases, variations in the size and function of the heart as well as deafness. The make-up of the cytoskeleton is also related to the pathogenicity of intracellular bacteria and viruses, particularly in the processes related to evading the actions of the immune system.[6]

Actin was first observed experimentally in 1887 by W.D. Halliburton, who extracted a protein from muscle that 'coagulated' preparations of myosin that he called "myosin-ferment".[7] However, Halliburton was unable to further refine his findings, and the discovery of actin is credited instead to Brun Ferenc Straub, a young biochemist working in Albert Szent-Gyrgyi's laboratory at the Institute of Medical Chemistry at the University of Szeged, Hungary.

In 1942, Straub developed a novel technique for extracting muscle protein that allowed him to isolate substantial amounts of relatively pure actin. Straub's method is essentially the same as that used in laboratories today. Szent-Gyorgyi had previously described the more viscous form of myosin produced by slow muscle extractions as 'activated' myosin, and, since Straub's protein produced the activating effect, it was dubbed actin. Adding ATP to a mixture of both proteins (called actomyosin) causes a decrease in viscosity. The hostilities of World War II meant Szent-Gyorgyi and Straub were unable to publish the work in Western scientific journals. Actin therefore only became well known in the West in 1945, when their paper was published as a supplement to the Acta Physiologica Scandinavica.[8] Straub continued to work on actin, and in 1950 reported that actin contains bound ATP[9] and that, during polymerization of the protein into microfilaments, the nucleotide is hydrolyzed to ADP and inorganic phosphate (which remain bound to the microfilament). Straub suggested that the transformation of ATP-bound actin to ADP-bound actin played a role in muscular contraction. In fact, this is true only in smooth muscle, and was not supported through experimentation until 2001.[9][10]

The amino acid sequencing of actin was completed by M. Elzinga and co-workers in 1973.[11] The crystal structure of G-actin was solved in 1990 by Kabsch and colleagues.[12] In the same year, a model for F-actin was proposed by Holmes and colleagues following experiments using co-crystallization with different proteins.[13] The procedure of co-crystallization with different proteins was used repeatedly during the following years, until in 2001 the isolated protein was crystallized along with ADP. However, there is still no high-resolution X-ray structure of F-actin. The crystallization of F-actin was possible due to the use of a rhodamine conjugate that impedes polymerization by blocking the amino acid cys-374.[1] Christine Oriol-Audit died in the same year that actin was first crystallized but she was the researcher that in 1977 first crystallized actin in the absence of Actin Binding Proteins (ABPs). However, the resulting crystals were too small for the available technology of the time.[14]

Although no high-resolution model of actins filamentous form currently exists, in 2008 Sawayas team were able to produce a more exact model of its structure based on multiple crystals of actin dimers that bind in different places.[15] This model has subsequently been further refined by Sawaya and Lorenz. Other approaches such as the use of cryo-electron microscopy and synchrotron radiation have recently allowed increasing resolution and better understanding of the nature of the interactions and conformational changes implicated in the formation of actin filaments.[16][17][18]

Its amino acid sequence is also one of the most highly conserved of the proteins as it has changed little over the course of evolution, differing by no more than 20% in species as diverse as algae and humans. It is therefore considered to have an optimised structure.[4] It has two distinguishing features: it is an enzyme that slowly hydrolizes ATP, the "universal energy currency" of biological processes. However, the ATP is required in order to maintain its structural integrity. Its efficient structure is formed by an almost unique folding process. In addition, it is able to carry out more interactions than any other protein, which allows it to perform a wider variety of functions than other proteins at almost every level of cellular life.[4]Myosin is an example of a protein that bonds with actin. Another example is villin, which can weave actin into bundles or cut the filaments depending on the concentration of calcium cations in the surrounding medium.[19]

Actin is one of the most abundant proteins in eukaryotes, where it is found throughout the cytoplasm.[19] In fact, in muscle fibres it comprises 20% of total cellular protein by weight and between 1% and 5% in other cells. However, there is not only one type of actin, the genes that code for actin are defined as a gene family (a family that in plants contains more than 60 elements, including genes and pseudogenes and in humans more than 30 elements).[4][20] This means that the genetic information of each individual contains instructions that generate actin variants (called isoforms) that possess slightly different functions. This, in turn, means that eukaryotic organisms express different genes that give rise to: -actin, which is found in contractile structures; -actin, found at the expanding edge of cells that use the projection of their cellular structures as their means of mobility; and -actin, which is found in the filaments of stress fibres.[21] In addition to the similarities that exist between an organisms isoforms there is also an evolutionary conservation in the structure and function even between organisms contained in different eukaryotic domains: in bacteria the actin homologue MreB has been identified, which is a protein that is capable of polymerizing into microfilaments;[4][17] and in archaea the homologue Ta0583 is even more similar to the eukaryotic actins.[22]

Cellular actin has two forms: monomeric globules called G-actin and polymeric filaments called F-actin (that is, as filaments made up of many G-actin monomers). F-actin can also be described as a microfilament. Two parallel F-actin strands must rotate 166 degrees to lie correctly on top of each other. This creates the double helix structure of the microfilaments found in the cytoskeleton. Microfilaments measure approximately 7 nm in diameter with the helix repeating every 37nm. Each molecule of actin is bound to a molecule of adenosine triphosphate (ATP) or adenosine diphosphate (ADP) that is associated with a Mg2+ cation. The most commonly found forms of actin, compared to all the possible combinations, are ATP-G-Actin and ADP-F-actin.[23][24]

Scanning electron microscope images indicate that G-actin has a globular structure; however, X-ray crystallography shows that each of these globules consists of two lobes separated by a cleft. This structure represents the ATPase fold, which is a centre of enzymatic catalysis that binds ATP and Mg2+ and hydrolyzes the former to ADP plus phosphate. This fold is a conserved structural motif that is also found in other proteins that interact with triphosphate nucleotides such as hexokinase (an enzyme used in energy metabolism) or in Hsp70 proteins (a protein family that play an important part in protein folding).[25] G-actin is only functional when it contains either ADP or ATP in its cleft but the form that is bound to ATP predominates in cells when actin is present in its free state.[23]

The X-ray crystallography model of actin that was produced by Kabsch from the striated muscle tissue of rabbits is the most commonly used in structural studies as it was the first to be purified. The G-actin crystallized by Kabsch is approximately 67 x 40 x 37 in size, has a molecular mass of 41,785 Da and an estimated isoelectric point of 4.8. Its net charge at pH = 7 is -7.[11][26]

Elzinga and co-workers first determined the complete peptide sequence for this type of actin in 1973, with later work by the same author adding further detail to the model. It contains 374 amino acid residues. Its N-terminus is highly acidic and starts with an acetyled aspartate in its amino group. While its C-terminus is alkaline and is formed by a phenylalanine preceded by a cysteine, which has a degree of functional importance. Both extremes are in close proximity within the I-subdomain. An anomalous N-methylhistidine is located at position 73.[26]

The tertiary structure is formed by two domains known as the large and the small, which are separated by a cleft centred around the location of the bond with ATP-ADP+Pi. Below this there is a deeper notch called a groove. In the native state, despite their names, both have a comparable depth.[11]

The normal convention in topological studies means that a protein is shown with the biggest domain on the left-hand side and the smallest domain on the right-hand side. In this position the smaller domain is in turn divided into two: subdomain I (lower position, residues 1-32, 70-144 and 338-374) and subdomain II (upper position, residues 33-69). The larger domain is also divided in two: subdomain III (lower, residues 145-180 and 270-337) and subdomain IV (higher, residues 181-269). The exposed areas of subdomains I and III are referred to as the barbed ends, while the exposed areas of domains II and IV are termed the pointed" ends. This nomenclature refers to the fact that, due to the small mass of subdomain II actin is polar; the importance of this will be discussed below in the discussion on assembly dynamics. Some authors call the subdomains Ia, Ib, IIa and IIb, respectively.[27]

The most notable supersecondary structure is a five chain beta sheet that is composed of a -meander and a -- clockwise unit. It is present in both domains suggesting that the protein arose from gene duplication.[12]

The classical description of F-actin states that it has a filamentous structure that can be considered to be a single stranded levorotatory helix with a rotation of 166 around the helical axis and an axial translation of 27.5 , or a single stranded dextrorotatory helix with a cross over spacing of 350-380 , with each actin surrounded by four more.[29] The symmetry of the actin polymer at 2.17 subunits per turn of a helix is incompatible with the formation of crystals, which is only possible with a symmetry of exactly 2, 3, 4 or 6 subunits per turn. Therefore, models have to be constructed that explain these anomalies using data from electron microscopy, cryo-electron microscopy, crystallization of dimers in different positions and diffraction of X-rays.[17][18] It should be pointed out that it is not correct to talk of a structure for a molecule as dynamic as the actin filament. In reality we talk of distinct structural states, in these the measurement of axial translation remains constant at 27.5 while the subunit rotation data shows considerable variability, with displacements of up to 10% from its optimum position commonly seen. Some proteins, such as cofilin appear to increase the angle of turn, but again this could be interpreted as the establishment of different "structural states". These could be important in the polymerization process.[30]

There is less agreement regarding measurements of the turn radius and filament thickness: while the first models assigned a longitude of 25 , current X-ray diffraction data, backed up by cryo-electron microscopy suggests a longitude of 23.7 . These studies have shown the precise contact points between monomers. Some are formed with units of the same chain, between the "barbed" end on one monomer and the "pointed" end of the next one. While the monomers in adjacent chains make lateral contact through projections from subdomain IV, with the most important projections being those formed by the C-terminus and the hydrophobic link formed by three bodies involving residues 39-42, 201-203 and 286. This model suggests that a filament is formed by monomers in a "sheet" formation, in which the subdomains turn about themselves, this form is also found in the bacterial actin homologue MreB.[17]

The F-actin polymer is considered to have structural polarity due to the fact that all the microfilaments subunits point towards the same end. This gives rise to a naming convention: the end that possesses an actin subunit that has its ATP binding site exposed is called the "(-) end", while the opposite end where the cleft is directed at a different adjacent monomer is called the "(+) end".[21] The terms "pointed" and "barbed" referring to the two ends of the microfilaments derive from their appearance under transmission electron microscopy when samples are examined following a preparation technique called "decoration". This method consists of the addition of myosin S1 fragments to tissue that has been fixed with tannic acid. This myosin forms polar bonds with actin monomers, giving rise to a configuration that looks like arrows with feather fletchings along its shaft, where the shaft is the actin and the fletchings are the myosin. Following this logic, the end of the microfilament that does not have any protruding myosin is called the point of the arrow (- end) and the other end is called the barbed end (+ end).[31] A S1 fragment is composed of the head and neck domains of myosin II. Under physiological conditions, G-actin (the monomer form) is transformed to F-actin (the polymer form) by ATP, where the role of ATP is essential.[32]

The helical F-actin filament found in muscles also contains a tropomyosin molecule, which is a 40 nanometre long protein that is wrapped around the F-actin helix.[18] During the resting phase the tropomyosin covers the actins active sites so that the actin-myosin interaction cannot take place and produce muscular contraction. There are other protein molecules bound to the tropomyosin thread, these are the troponins that have three polymers: troponin I, troponin T and troponin C.[33]

Actin can spontaneously acquire a large part of its tertiary structure.[35] However, the way it acquires its fully functional form from its newly synthesized native form is special and almost unique in protein chemistry. The reason for this special route could be the need to avoid the presence of incorrectly folded actin monomers, which could be toxic as they can act as inefficient polymerization terminators. Nevertheless, it is key to establishing the stability of the cytoskeleton, and additionally, it is an essential process for coordinating the cell cycle.[36][37]

CCT is required in order to ensure that folding takes place correctly. CCT is a group II cytosolic molecular chaperone (or chaperonin, a protein that assists in the folding of other macromolecular structures). CCT is formed of a double ring of eight different subunits (hetero-octameric) and it differs from other molecular chaperones, particularly from its homologue GroEL which is found in the Archaea, as it does not require a co-chaperone to act as a lid over the central catalytic cavity. Substrates bind to CCT through specific domains. It was initially thought that it only bound with actin and tubulin, although recent immunoprecipitation studies have shown that it interacts with a large number of polypeptides, which possibly function as substrates. It acts through ATP-dependent conformational changes that on occasion require several rounds of liberation and catalysis in order to complete a reaction.[38]

In order to successfully complete their folding, both actin and tubulin need to interact with another protein called prefoldin, which is a heterohexameric complex (formed by six distinct subunits), in an interaction that is so specific that the molecules have coevolved[citation needed]. Actin complexes with prefoldin while it is still being formed, when it is approximately 145 amino acids long, specifically those at the N-terminal.[39]

Different recognition sub-units are used for actin or tubulin although there is some overlap. In actin the subunits that bind with prefoldin are probably PFD3 and PFD4, which bind in two places one between residues 60-79 and the other between residues 170-198. The actin is recognized, loaded and delivered to the cytosolic chaperonin (CCT) in an open conformation by the inner end of prefoldins "tentacles (see the image and note).[35] The contact when actin is delivered is so brief that a tertiary complex is not formed, immediately freeing the prefoldin.[34]

The CCT then causes actin's sequential folding by forming bonds with its subunits rather than simply enclosing it in its cavity.[40] This is why it possesses specific recognition areas in its apical -domain. The first stage in the folding consists of the recognition of residues 245-249. Next, other determinants establish contact.[41] Both actin and tubulin bind to CCT in open conformations in the absence of ATP. In actins case, two subunits are bound during each conformational change, whereas for tubulin binding takes place with four subunits. Actin has specific binding sequences, which interact with the and -CCT subunits or with -CCT and -CCT. After AMP-PNP is bound to CCT the substrates move within the chaperonins cavity. It also seems that in the case of actin, the CAP protein is required as a possible cofactor in actin's final folding states.[37]

The exact manner by which this process is regulated is still not fully understood, but it is known that the protein PhLP3 (a protein similar to phosducin) inhibits its activity through the formation of a tertiary complex.[38]

Actin is an ATPase, which means that it is an enzyme that hydrolyzes ATP. This group of enzymes is characterised by their slow reaction rates. It is known that this ATPase is active, that is, its speed increases by some 40,000 times when the actin forms part of a filament.[30] A reference value for this rate of hydrolysis under ideal conditions is around 0.3 s1. Then, the Pi remains bound to the actin next to the ADP for a long time, until it is liberated next to the end of the filament.[42]

The exact molecular details of the catalytic mechanism are still not fully understood. Although there is much debate on this issue, it seems certain that a "closed" conformation is required for the hydrolysis of ATP, and it is thought that the residues that are involved in the process move to the appropriate distance.[30] The glutamic acid Glu137 is one of the key residues, which is located in subdomain 1. Its function is to bind the water molecule that produces a nucleophilic attack on the ATPs -phosphate bond, while the nucleotide is strongly bound to subdomains 3 and 4. The slowness of the catalytic process is due to the large distance and skewed position of the water molecule in relation to the reactant. It is highly likely that the conformational change produced by the rotation of the domains between actins G and F forms moves the Glu137 closer allowing its hydrolysis. This model suggests that the polymerization and ATPases function would be decoupled straight away.[17][18]

Principal interactions of structural proteins are at cadherin-based adherens junction. Actin filaments are linked to -actinin and to the membrane through vinculin. The head domain of vinculin associates to E-cadherin via -catenin, -catenin, and -catenin. The tail domain of vinculin binds to membrane lipids and to actin filaments.

Actin has been one of the most highly conserved proteins throughout evolution because it interacts with a large number of other proteins. It has 80.2% sequence conservation at the gene level between Homo sapiens and Saccharomyces cerevisiae (a species of yeast), and 95% conservation of the primary structure of the protein product.[4]

Although most yeasts have only a single actin gene, higher eukaryotes, in general, express several isoforms of actin encoded by a family of related genes. Mammals have at least six actin isoforms coded by separate genes,[43] which are divided into three classes (alpha, beta and gamma) according to their isoelectric points. In general, alpha actins are found in muscle (-skeletal, -aortic smooth, -cardiac, and 2-enteric smooth), whereas beta and gamma isoforms are prominent in non-muscle cells (- and 1-cytoplasmic). Although the amino acid sequences and in vitro properties of the isoforms are highly similar, these isoforms cannot completely substitute for one another in vivo.[44]

The typical actin gene has an approximately 100-nucleotide 5' UTR, a 1200-nucleotide translated region, and a 200-nucleotide 3' UTR. The majority of actin genes are interrupted by introns, with up to six introns in any of 19 well-characterised locations. The high conservation of the family makes actin the favoured model for studies comparing the introns-early and introns-late models of intron evolution.

All non-spherical prokaryotes appear to possess genes such as MreB, which encode homologues of actin; these genes are required for the cell's shape to be maintained. The plasmid-derived gene ParM encodes an actin-like protein whose polymerized form is dynamically unstable, and appears to partition the plasmid DNA into its daughter cells during cell division by a mechanism analogous to that employed by microtubules in eukaryotic mitosis.[45] Actin is found in both smooth and rough endoplasmic reticulums.

Actin polymerization and depolymerization is necessary in chemotaxis and cytokinesis. Nucleating factors are necessary to stimulate actin polymerization. One such nucleating factor is the Arp2/3 complex, which mimics a G-actin dimer in order to stimulate the nucleation (or formation of the first trimer) of monomeric G-actin. The Arp2/3 complex binds to actin filaments at 70 degrees to form new actin branches off existing actin filaments. Also, actin filaments themselves bind ATP, and hydrolysis of this ATP stimulates destabilization of the polymer.

The growth of actin filaments can be regulated by thymosin and profilin. Thymosin binds to G-actin to buffer the polymerizing process, while profilin binds to G-actin to exchange ADP for ATP, promoting the monomeric addition to the barbed, plus end of F-actin filaments.

F-actin is both strong and dynamic. Unlike other polymers, such as DNA, whose constituent elements are bound together with covalent bonds, the monomers of actin filaments are assembled by weaker bonds. The lateral bonds with neighbouring monomers resolve this anomaly, which in theory should weaken the structure as they can be broken by thermal agitation. In addition, the weak bonds give the advantage that the filament ends can easily release or incorporate monomers. This means that the filaments can be rapidly remodelled and can change cellular structure in response to an environmental stimulus. Which, along with the biochemical mechanism by which it is brought about is known as the "assembly dynamic".[6]

Studies focusing on the accumulation and loss of subunits by microfilaments are carried out in vitro (that is, in the laboratory and not on cellular systems) as the polymerization of the resulting actin gives rise to the same F-actin as produced in vivo. The in vivo process is controlled by a multitude of proteins in order to make it responsive to cellular demands, this makes it difficult to observe its basic conditions.[46]

In vitro production takes place in a sequential manner: first, there is the "activation phase", when the bonding and exchange of divalent cations occurs in specific places on the G-actin, which is bound to ATP. This produces a conformational change, sometimes called G*-actin or F-actin monomer as it is very similar to the units that are located on the filament.[27] This prepares it for the "nucleation phase", in which the G-actin gives rise to small unstable fragments of F-actin that are able to polymerize. Unstable dimers and trimers are initially formed. The "elongation phase" begins when there are a sufficiently large number of these short polymers. In this phase the filament forms and rapidly grows through the reversible addition of new monomers at both extremes.[47] Finally, a "stationary equilibrium" is achieved where the G-actin monomers are exchanged at both ends of the microfilament without any change to its total length.[19] In this last phase the "critical concentration Cc" is defined as the ratio between the assembly constant and the dissociation constant for G-actin, where the dynamic for the addition and elimination of dimers and trimers does not produce a change in the microfilament's length. Under normal in vitro conditions Cc is 0.1 M,[48] which means that at higher values polymerization occurs and at lower values depolymerization occurs.[49]

As indicated above, although actin hydrolyzes ATP, everything points to the fact that ATP is not required for actin to be assembled, given that, on one hand, the hydrolysis mainly takes place inside the filament, and on the other hand the ADP could also instigate polymerization. This poses the question of understanding which thermodynamically unfavourable process requires such a prodigious expenditure of energy. The so-called actin cycle, which couples ATP hydrolysis to actin polymerization, consists of the preferential addition of G-actin-ATP monomers to a filaments barbed end, and the simultaneous disassembly of F-actin-ADP monomers at the pointed end where the ADP is subsequently changed into ATP, thereby closing the cycle, this aspect of actin filament formation is known as treadmilling.

ATP is hydrolysed relatively rapidly just after the addition of a G-actin monomer to the filament. There are two hypotheses regarding how this occurs; the stochastic, which suggests that hydrolysis randomly occurs in a manner that is in some way influenced by the neighbouring molecules; and the vectoral, which suggests that hydrolysis only occurs adjacent to other molecules whose ATP has already been hydrolysed. In either case, the resulting Pi is not released, it remains for some time noncovalently bound to actins ADP, in this way there are three species of actin in a filament: ATP-Actin, ADP+Pi-Actin and ADP-Actin.[42][50] The amount of each one of these species present in a filament depends on its length and state: as elongation commences the filament has an approximately equal amount of actin monomers bound with ATP and ADP+Pi and a small amount of ADP-Actin at the (-) end. As the stationary state is reached the situation reverses, with ADP present along the majority of the filament and only the area nearest the (+) end containing ADP+Pi and with ATP only present at the tip.[51]

If we compare the filaments that only contain ADP-Actin with those that include ATP, in the former the critical constants are similar at both ends, while Cc for the other two nucleotides is different: At the (+) end Cc+=0.1 M, while at the (-) end Cc=0.8 M, which gives rise to the following situations:[21]

It is therefore possible to deduce that the energy produced by hydrolysis is used to create a true stationary state, that is a flux, instead of a simple equilibrium, one that is dynamic, polar and attached to the filament. This justifies the expenditure of energy as it promotes essential biological functions.[42] In addition, the configuration of the different monomer types is detected by actin binding proteins, which also control this dynamism, as will be described in the following section.

Microfilament formation by treadmilling has been found to be atypical in stereocilia. In this case the control of the structure's size is totally apical and it is controlled in some way by gene expression, that is, by the total quantity of protein monomer synthesized in any given moment.[52]

The actin cytoskeleton in vivo is not exclusively composed of actin, other proteins are required for its formation, continuance and function. These proteins are called actin-binding proteins (ABP) and they are involved in actins polymerization, depolymerization, stability, organisation in bundles or networks, fragmentation and destruction.[19] The diversity of these proteins is such that actin is thought to be the protein that takes part in the greatest number of protein-protein interactions.[54] For example, G-actin sequestering elements exist that impede its incorporation into microfilaments. There are also proteins that stimulate its polymerization or that give complexity to the synthesizing networks.[21]

Other proteins that bind to actin regulate the length of the microfilaments by cutting them, which gives rise to new active ends for polymerization. For example, if a microfilament with two ends is cut twice, there will be three new microfilaments with six ends. This new situation favors the dynamics of assembly and disassembly. The most notable of these proteins are gelsolin and cofilin. These proteins first achieve a cut by binding to an actin monomer located in the polymer they then change the actin monomers conformation while remaining bound to the newly generated (+) end. This has the effect of impeding the addition or exchange of new G-actin subunits. Depolymerization is encouraged as the (-) ends are not linked to any other molecule.[60]

Other proteins that bind with actin cover the ends of F-actin in order to stabilize them, but they are unable to break them. Examples of this type of protein are CapZ (that binds the (+) ends depending on a cells levels of Ca2+/calmodulin. These levels depend on the cells internal and external signals and are involved in the regulation of its biological functions).[61] Another example is tropomodulin (that binds to the (-) end). Tropomodulin basically acts to stabilize the F-actin present in the myofibrils present in muscle sarcomeres, which are structures characterized by their great stability.[62]

The Arp2/3 complex is widely found in all eukaryotic organisms.[64] It is composed of seven subunits, some of which possess a topology that is clearly related to their biological function: two of the subunits, "ARP2 and "ARP3, have a structure similar to that of actin monomers. This homology allows both units to act as nucleation agents in the polymerization of G-actin and F-actin. This complex is also required in more complicated processes such as in establishing dendritic structures and also in anastomosis (the reconnection of two branching structures that had previously been joined, such as in blood vessels).[65]

There are a number of toxins that interfere with actins dynamics, either by preventing it from polymerizing (latrunculin and cytochalasin D) or by stabilizing it (phalloidin):

Actin forms filaments ('F-actin' or microfilaments) that are essential elements of the eukaryotic cytoskeleton, able to undergo very fast polymerization and depolymerization dynamics. In most cells actin filaments form larger-scale networks which are essential for many key functions in cells:[69]

The actin protein is found in both the cytoplasm and the cell nucleus.[70] Its location is regulated by cell membrane signal transduction pathways that integrate the stimuli that a cell receives stimulating the restructuring of the actin networks in response. In Dictyostelium, phospholipase D has been found to intervene in inositol phosphate pathways.[71] Actin filaments are particularly stable and abundant in muscle fibres. Within the sarcomere (the basic morphological and physiological unit of muscle fibres) actin is present in both the I and A bands; myosin is also present in the latter.[72]

Microfilaments are involved in the movement of all mobile cells, including non-muscular types, and drugs that disrupt F-actin organization (such as the cytochalasins) affect the activity of these cells. Actin comprises 2% of the total amount of proteins in hepatocytes, 10% in fibroblasts, 15% in amoebas and up to 50-80% in activated platelets.[73] There are a number of different types of actin with slightly different structures and functions. This means that -actin is found exclusively in muscle fibres, while types and are found in other cells. In addition, as the latter types have a high turnover rate the majority of them are found outside permanent structures. This means that the microfilaments found in cells other than muscle cells are present in two forms:[74]

Actins cytoskeleton is key to the processes of endocytosis, cytokinesis, determination of cell polarity and morphogenesis in yeasts. In addition to relying on actin these processes involve 20 or 30 associated proteins, which all have a high degree of evolutionary conservation, along with many signalling molecules. Together these elements allow a spatially and temporally modulated assembly that defines a cells response to both internal and external stimuli.[76]

Yeasts contain three main elements that are associated with actin: patches, cables and rings that, despite being present for long, are subject to a dynamic equilibrium due to continual polymerization and depolymerization. They possess a number of accessory proteins including ADF/cofilin, which has a molecular weight of 16kDa and is coded for by a single gene, called COF1; Aip1, a cofilin cofactor that promotes the disassembly of microfilaments; Srv2/CAP, a process regulator related to adenylate cyclase proteins; a profilin with a molecular weight of approximately 14 kDa that is associated with actin monomers; and twinfilin, a 40 kDa protein involved in the organization of patches.[76]

Plant genome studies have revealed the existence of protein isovariants within the actin family of genes. Within Arabidopsis thaliana, a dicotyledon used as a model organism, there are ten types of actin, nine types of -tubulins, six -tubulins, six profilins and dozens of myosins. This diversity is explained by the evolutionary necessity of possessing variants that slightly differ in their temporal and spatial expression.[4] The majority of these proteins were jointly expressed in the tissue analysed. Actin networks are distributed throughout the cytoplasm of cells that have been cultivated in vitro. There is a concentration of the network around the nucleus that is connected via spokes to the cellular cortex, this network is highly dynamic, with a continuous polymerization and depolymerization.[77]

Even though the majority of plant cells have a cell wall that defines their morphology and impedes their movement, their microfilaments can generate sufficient force to achieve a number of cellular activities, such as, the cytoplasmic currents generated by the microfilaments and myosin. Actin is also involved in the movement of organelles and in cellular morphogenesis, which involve cell division as well as the elongation and differentiation of the cell.[79]

The most notable proteins associated with the actin cytoskeleton in plants include:[79]villin, which belongs to the same family as gelsolin/severin and is able to cut microfilaments and bind actin monomers in the presence of calcium cations; fimbrin, which is able to recognize and unite actin monomers and which is involved in the formation of networks (by a different regulation process from that of animals and yeasts);[80]formins, which are able to act as an F-actin polymerization nucleating agent; myosin, a typical molecular motor that is specific to eukaryotes and which in Arabidopsis thaliana is coded for by 17 genes in two distinct classes; CHUP1, which can bind actin and is implicated in the spatial distribution of chloroplasts in the cell; KAM1/MUR3 that define the morphology of the Golgi apparatus as well as the composition of xyloglucans in the cell wall; NtWLIM1, which facilitates the emergence of actin cell structures; and ERD10, which is involved in the association of organelles within membranes and microfilaments and which seems to play a role that is involved in an organisms reaction to stress.

Nuclear actin was first noticed and described in 1977 by Clark and Merriam.[81] Authors describe a protein present in the nuclear fraction, obtained from Xenopus laevis oocytes, which shows the same features such skeletal muscle actin. Since that time there have been many scientific reports about the structure and functions of actin in the nucleus (for review see: Hofmann 2009.[82]) The controlled level of actin in the nucleus, its interaction with actin-binding proteins (ABP) and the presence of different isoforms allows actin to play an important role in many important nuclear processes.

The actin sequence does not contain a nuclear localization signal. The small size of actin (about 43 kDa) allows it to enter the nucleus by passive diffusion.[83] Actin however shuttles between cytoplasm and nucleus quite quickly, which indicates the existence of active transport. The import of actin into the nucleus (probably in a complex with cofilin) is facilitated by the import protein importin 9.[84]

Low level of actin in the nucleus seems to be very important, because actin has two nuclear export signals (NES) into its sequence. Microinjected actin is quickly removed from the nucleus to the cytoplasm. Actin is exported at least in two ways, through exportin 1 (EXP1) and exportin 6 (Exp6).[85][86]

Specific modifications, such as SUMOylation, allows for nuclear actin retention. It was demonstrated that a mutation preventing SUMOylation causes rapid export of beta actin from the nucleus.[87]

Based on the experimental results a general mechanism of nuclear actin transport can be proposed:[87][88]

Nuclear actin exists mainly as a monomer, but can also form dynamic oligomers and short polymers.[89][90][91] Nuclear actin organization varies in different cell types. For example, in Xenopus oocytes (with higher nuclear actin level in comparison to somatic cells) actin forms filaments, which stabilize nucleus architecture. These filaments can be observed under the microscope thanks to fluorophore-conjugated phalloidin staining.[81][83]

In somatic cell nucleus however we cannot observe any actin filaments using this technique.[92] The DNase I inhibition assay, so far the only test which allows the quantification of the polymerized actin directly in biological samples, have revealed that endogenous nuclear actin occurs indeed mainly in a monomeric form.[91]

Precisely controlled level of actin in the cell nucleus, lower than in the cytoplasm, prevents the formation of filaments. The polymerization is also reduced by the limited access to actin monomers, which are bound in complexes with ABPs, mainly cofilin.[88]

Little attention is paid to actin isoforms, however it has been shown that different isoforms of actin are present in the cell nucleus. Actin isoforms, despite of their high sequence similarity, have different biochemical properties such as polymerization and depolymerization kinetic.[93] They also shows different localization and functions.

The level of actin isoforms, both in the cytoplasm and the nucleus, may change for example in response to stimulation of cell growth or arrest of proliferation and transcriptional activity.[94]

Research concerns on nuclear actin are usually focused on isoform beta.[95][96][97][98] However the use of antibodies directed against different actin isoforms allows identifying not only the cytoplasmic beta in the cell nucleus, but also:

The presence of different isoforms of actin may have a significant effect on its function in nuclear processes, especially because the level of individual isoforms can be controlled independently.[91]

Functions of actin in the nucleus are associated with its ability to polymerization, interaction with variety of ABPs and with structural elements of the nucleus. Nuclear actin is involved in:

Due to its ability to conformational changes and interaction with many proteins actin acts as a regulator of formation and activity of protein complexes such as transcriptional complex.[105]

In muscle cells, actomyosin myofibrils makeup much of the cytoplasmic material. These myofibrils are made of thin filaments of actin (typically around 7nm in diameter), and thick filaments of the motor-protein myosin (typically around 15nm in diameter).[121] These myofibrils use energy derived from ATP to create movements of cells, such as muscle contraction.[121] Using the hydrolysis of ATP for energy, myosin heads undergo a cycle during which they attach to thin filaments, exert a tension, and then, depending on the load, perform a power stroke that causes the thin filaments to slide past, shortening the muscle.

In contractile bundles, the actin-bundling protein alpha-actinin separates each thin filament by ~35nm. This increase in distance allows thick filaments to fit in between and interact, enabling deformation or contraction. In deformation, one end of myosin is bound to the plasma membrane, while the other end "walks" toward the plus end of the actin filament. This pulls the membrane into a different shape relative to the cell cortex. For contraction, the myosin molecule is usually bound to two separate filaments and both ends simultaneously "walk" toward their filament's plus end, sliding the actin filaments closer to each other. This results in the shortening, or contraction, of the actin bundle (but not the filament). This mechanism is responsible for muscle contraction and cytokinesis, the division of one cell into two.

The helical F-actin filament found in muscles also contains a tropomyosin molecule, a 40-nanometre protein that is wrapped around the F-actin helix. During the resting phase the tropomyosin covers the actins active sites so that the actin-myosin interaction cannot take place and produce muscular contraction (the interaction gives rise to a movement between the two proteins that, because it is repeated many times, produces a contraction). There are other protein molecules bound to the tropomyosin thread, these include the troponins that have three polymers: troponin I, troponin T, and troponin C.[33] Tropomyosins regulatory function depends on its interaction with troponin in the presence of Ca2+ ions.[122]

Both actin and myosin are involved in muscle contraction and relaxation and they make up 90% of muscle protein.[123] The overall process is initiated by an external signal, typically through an action potential stimulating the muscle, which contains specialized cells whose interiors are rich in actin and myosin filaments. The contraction-relaxation cycle comprises the following steps:[72]

The traditional image of actins function relates it to the maintenance of the cytoskeleton and, therefore, the organization and movement of organelles, as well as the determination of a cells shape.[74] However, actin has a wider role in eukaryotic cell physiology, in addition to similar functions in prokaryotes.

The majority of mammals possess six different actin genes. Of these, two code for the cytoskeleton (ACTB and ACTG1) while the other four are involved in skeletal striated muscle (ACTA1), smooth muscle tissue (ACTA2), intestinal muscles (ACTG2) and cardiac muscle (ACTC1). The actin in the cytoskeleton is involved in the pathogenic mechanisms of many infectious agents, including HIV. The vast majority of the mutations that affect actin are point mutations that have a dominant effect, with the exception of six mutations involved in nemaline myopathy. This is because in many cases the mutant of the actin monomer acts as a cap by preventing the elongation of F-actin.[27]

ACTA1 is the gene that codes for the -isoform of actin that is predominant in human skeletal striated muscles, although it is also expressed in heart muscle and in the thyroid gland.[141] Its DNA sequence consists of seven exons that produce five known transcripts.[142] The majority of these consist of point mutations causing substitution of amino acids. The mutations are in many cases associated with a phenotype that determines the severity and the course of the affliction.[27][142]

The mutation alters the structure and function of skeletal muscles producing one of three forms of myopathy: type 3 nemaline myopathy, congenital myopathy with an excess of thin myofilaments (CM) and Congenital myopathy with fibre type disproportion (CMFTD). Mutations have also been found that produce core myopathies).[144] Although their phenotypes are similar, in addition to typical nemaline myopathy some specialists distinguish another type of myopathy called actinic nemaline myopathy. In the former, clumps of actin form instead of the typical rods. It is important to state that a patient can show more than one of these phenotypes in a biopsy.[145] The most common symptoms consist of a typical facial morphology (myopathic faces), muscular weakness, a delay in motor development and respiratory difficulties. The course of the illness, its gravity and the age at which it appears are all variable and overlapping forms of myopathy are also found. A symptom of nemalinic myopathy is that Nemaline rods appear in differing places in Type 1 muscle fibres. These rods are non-pathognomonic structures that have a similar composition to the Z disks found in the sarcomere.[146]

The pathogenesis of this myopathy is very varied. Many mutations occur in the region of actins indentation near to its nucleotide binding sites, while others occur in Domain 2, or in the areas where interaction occurs with associated proteins. This goes some way to explain the great variety of clumps that form in these cases, such as Nemaline or Intranuclear Bodies or Zebra Bodies.[27] Changes in actins folding occur in nemaline myopathy as well as changes in its aggregation and there are also changes in the expression of other associated proteins. In some variants where intranuclear bodies are found the changes in the folding masks the nucleuss protein exportation signal so that the accumulation of actin's mutated form occurs in the cell nucleus.[147] On the other hand, it appears that mutations to ACTA1 that give rise to a CFTDM have a greater effect on sarcomeric function than on its structure.[148] Recent investigations have tried to understand this apparent paradox, which suggests there is no clear correlation between the number of rods and muscular weakness. It appears that some mutations are able to induce a greater apoptosis rate in type II muscular fibres.[36]

There are two isoforms that code for actins in the smooth muscle tissue:

ACTG2 codes for the largest actin isoform, which has nine exons, one of which, the one located at the 5' end, is not translated.[149] It is an -actin that is expressed in the enteric smooth muscle. No mutations to this gene have been found that correspond to pathologies, although microarrays have shown that this protein is more often expressed in cases that are resistant to chemotherapy using cisplatin.[150]

ACTA2 codes for an -actin located in the smooth muscle, and also in vascular smooth muscle. It has been noted that the MYH11 mutation could be responsible for at least 14% of hereditary thoracic aortic aneurisms particularly Type 6. This is because the mutated variant produces an incorrect filamentary assembly and a reduced capacity for vascular smooth muscle contraction. Degradation of the aortic media has been recorded in these individuals, with areas of disorganization and hyperplasia as well as stenosis of the aortas vasa vasorum.[151] The number of afflictions that the gene is implicated in is increasing. It has been related to Moyamoya disease and it seems likely that certain mutations in heterozygosis could confer a predisposition to many vascular pathologies, such as thoracic aortic aneurysm and ischaemic heart disease.[152] The -actin found in smooth muscles is also an interesting marker for evaluating the progress of liver cirrhosis.[153]

The ACTC1 gene codes for the -actin isoform present in heart muscle. It was first sequenced by Hamada and co-workers in 1982, when it was found that it is interrupted by five introns.[154] It was the first of the six genes where alleles were found that were implicated in pathological processes.[155]

A number of structural disorders associated with point mutations of this gene have been described that cause malfunctioning of the heart, such as Type 1R dilated cardiomyopathy and Type 11 hypertrophic cardiomyopathy. Certain defects of the atrial septum have been described recently that could also be related to these mutations.[157][158]

Two cases of dilated cardiomyopathy have been studied involving a substitution of highly conserved amino acids belonging to the protein domains that bind and intersperse with the Z discs. This has led to the theory that the dilation is produced by a defect in the transmission of contractile force in the myocytes.[29][155]

The mutations inACTC1 are responsible for at least 5% of hypertrophic cardiomyopathies.[159] The existence of a number of point mutations have also been found:[160]

Pathogenesis appears to involve a compensatory mechanism: the mutated proteins act like toxins with a dominant effect, decreasing the hearts ability to contract causing abnormal mechanical behaviour such that the hypertrophy, that is usually delayed, is a consequence of the cardiac muscles normal response to stress.[161]

Recent studies have discovered ACTC1 mutations that are implicated in two other pathological processes: Infantile idiopathic restrictive cardiomyopathy,[162] and noncompaction of the left ventricular myocardium.[163]

ACTB is a highly complex locus. A number of pseudogenes exist that are distributed throughout the genome, and its sequence contains six exons that can give rise to up to 21 different transcriptions by alternative splicing, which are known as the -actins. Consistent with this complexity, its products are also found in a number of locations and they form part of a wide variety of processes (cytoskeleton, NuA4 histone-acyltransferase complex, cell nucleus) and in addition they are associated with the mechanisms of a great number of pathological processes (carcinomas, juvenile dystonia, infection mechanisms, nervous system malformations and tumour invasion, among others).[164] A new form of actin has been discovered, kappa actin, which appears to substitute for -actin in processes relating to tumours.[165]

Three pathological processes have so far been discovered that are caused by a direct alteration in gene sequence:

The ACTG1 locus codes for the cytosolic -actin protein that is responsible for the formation of cytoskeletal microfilaments. It contains six exons, giving rise to 22 different mRNAs, which produce four complete isoforms whose form of expression is probably dependent on the type of tissue they are found in. It also has two different DNA promoters.[170] It has been noted that the sequences translated from this locus and from that of -actin are very similar to the predicted ones, suggesting a common ancestral sequence that suffered duplication and genetic conversion.[171]

In terms of pathology, it has been associated with processes such as amyloidosis, retinitis pigmentosa, infection mechanisms, kidney diseases and various types of congenital hearing loss.[170]

Six autosomal-dominant point mutations in the sequence have been found to cause various types of hearing loss, particularly sensorineural hearing loss linked to the DFNA 20/26 locus. It seems that they affect the stereocilia of the ciliated cells present in the inner ears Organ of Corti. -actin is the most abundant protein found in human tissue, but it is not very abundant in ciliated cells, which explains the location of the pathology. On the other hand, it appears that the majority of these mutations affect the areas involved in linking with other proteins, particularly actomyosin.[27] Some experiments have suggested that the pathological mechanism for this type of hearing loss relates to the F-actin in the mutations being more sensitive to cofilin than normal.[172]

However, although there is no record of any case, it is known that -actin is also expressed in skeletal muscles, and although it is present in small quantities, model organisms have shown that its absence can give rise to myopathies.[173]

Some infectious agents use actin, especially cytoplasmic actin, in their life cycle. Two basic forms are present in bacteria:

In addition to the previously cited example, actin polymerization is stimulated in the initial steps of the internalization of some viruses, notably HIV, by, for example, inactivating the cofilin complex.[178]

The role that actin plays in the invasion process of cancer cells has still not been determined.[179]

The eukaryotic cytoskeleton of organisms among all taxonomic groups have similar components to actin and tubulin. For example, the protein that is coded by the ACTG2 gene in humans is completely equivalent to the homologues present in rats and mice, even though at a nucleotide level the similarity decreases to 92%.[149] However, there are major differences with the equivalents in prokaryotes (FtsZ and MreB), where the similarity between nucleotide sequences is between 4050% among different bacteria and archaea species. Some authors suggest that the ancestral protein that gave rise to the model eukaryotic actin resembles the proteins present in modern bacterial cytoskeletons.[4][180]

Some authors point out that the behaviour of actin, tubulin and histone, a protein involved in the stabilization and regulation of DNA, are similar in their ability to bind nucleotides and in their ability of take advantage of Brownian motion. It has also been suggested that they all have a common ancestor.[181] Therefore, evolutionary processes resulted in the diversification of ancestral proteins into the varieties present today, conserving, among others, actins as efficient molecules that were able to tackle essential ancestral biological processes, such as endocytosis.[182]

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Skin Stem Cells Comments Off on Actin – Wikipedia | January 23rd, 2017

3D printing may seem a little unfathomable to some, especially when you apply biomedical engineering to 3D printing. In general, 3D printing involves taking a digital model or blueprint created via software, which is then printed in successive layers of materials like glass, metal, plastic, ceramic and assembled one layer at a time. Many major manufacturers use them to manufacture airplane parts or electrical appliances.

Some of the most incredible uses for 3D printing are developing within the medical field. Some of the following ways this futuristic technology is being developed for medical use might sound like a Michael Crichton novel, but are fast becoming reality.

Bioprinting is based on bio-ink, which is made of living cell structures. When a particular digital model is input, specific living tissue is printed and built up layer by cell layer. Bioprinting research is being developed to print different types of tissue, while 3D inkjet printing is being used to develop advanced medical devices and tools.

While an entire organ has yet to be successfully printed for practical surgical use, scientists and researchers have successfully printed kidney cells, sheets of cardiac tissue that beat like a real heart and the foundations of a human liver, among many other organ tissues. While printing out an entire human organ for transplant may still be at least a decade away, medical researchers and scientists are well on their way to making this a reality.

Stem cells have amazing regenerative properties already they can reproduce many different kinds of human tissue. Now, stem cells are being bioprinted in several university research labs, such as the Heriot-Watt University of Edinburgh. Stem cell printing was the precursor to printing other kinds of tissues, and could eventually lead to printing cells directly into parts of the body.

Imagine the uses that printing skin grafts could do for burn victims, skin cancer patients and other kinds of afflictions and diseases that affect the epidermis. Medical engineers in Germany have been developing skin cell bioprinting since 2010, and researcher James Yoo from Wake Forest Institute is developing skin graft printing that can be applied directly onto burn victims.

Hod Lipson, a Cornell engineer, prototyped tissue bioprinting for cartilage within the past few years. Though Lipson has yet to bioprint a meniscus that can withstand the kind of pressure and pounding that a real one can, he and other engineers are well on their way to understanding how to apply these properties. Additionally, the same group from Germany who bioprinted stem cells is also working toward the same results for bioprinting bone and others parts of the skeletal system.

Just six months ago, bioengineering students from the University of British Columbia won a prestigious award for their engineering and 3D printing of a new and extremely effective type of surgical smoke evacuator. Other surgical tools that have been 3D printed include forceps, hemostats, scalpel handles and clamps and best of all, they come out of the printer sterile and cost a tenth as much as the stainless steel equivalent.

In the same way that tissue and types of organ cells are being printed and studied, disease cells and cancer cells are also being bioprinted, in order to more effectively and systematically study how tumors grow and develop. Such medical engineering would allow for better drug testing, cancer cell analyzing and therapy development. With developments in 3D and bioprinting, it may even be a possibility within our lifetime that a cure for cancer is discovered.

Another German institute has created blood vessels using artificial biological cells, a 3D inkjet printer and a laser to mold them into shape. Likewise, researchers at the University of Rostock in Germany, Harvard Medical Institute and the University of Sydney are developing methods of heart repair, or types of a heart patch, made with 3D printed cells.

The human cell heart patches have gone through successful testing on rats, and have also included development of artificial cardiac tissues that successfully mimic the mechanical and biological properties of a real human heart.

There are plenty of other developments being made with 3D and bioprinting, but one of the biggest obstacles is finding software that is advanced or sophisticated enough to meet the challenge of creating the blueprint. While creating the blueprint for an ash tray, and subsequently producing it via 3D printing is a fairly simple and quick process, there is no equivalent for creating digital models of a liver or heart at this point.

However, with the quick developments and advancements researchers and biomedical engineers have made in a short few years, this obstacle will soon be one of many that are overcome on the way to successful complex bioprinting.

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Skin Stem Cells Comments Off on 7 Major Advancements 3D Printing Is Making in the Medical … | December 30th, 2016

This article is about skin in humans. For other animals, see skin.

The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs.[1] Human skin is similar to that of most other mammals. Though nearly all human skin is covered with hair follicles, it can appear hairless. There are two general types of skin, hairy and glabrous skin.[2] The adjective cutaneous literally means "of the skin" (from Latin cutis, skin).

Because it interfaces with the environment, skin plays an important immunity role in protecting the body against pathogens[3] and excessive water loss.[4] Its other functions are insulation, temperature regulation, sensation, synthesis of vitamin D, and the protection of vitamin B folates. Severely damaged skin will try to heal by forming scar tissue. This is often discolored and depigmented.

In humans, skin pigmentation varies among populations, and skin type can range from dry to oily. Such skin variety provides a rich and diverse habitat for bacteria that number roughly 1000 species from 19 phyla, present on the human skin.[5][6]

Skin has mesodermal cells, pigmentation, such as melanin provided by melanocytes, which absorb some of the potentially dangerous ultraviolet radiation (UV) in sunlight. It also contains DNA repair enzymes that help reverse UV damage, such that people lacking the genes for these enzymes suffer high rates of skin cancer. One form predominantly produced by UV light, malignant melanoma, is particularly invasive, causing it to spread quickly, and can often be deadly. Human skin pigmentation varies among populations in a striking manner. This has led to the classification of people(s) on the basis of skin color.[7]

The skin is the largest organ in the human body. For the average adult human, the skin has a surface area of between 1.5-2.0 square metres (16.1-21.5 sq ft.). The thickness of the skin varies considerably over all parts of the body, and between men and women and the young and the old. An example is the skin on the forearm which is on average 1.3mm in the male and 1.26mm in the female.[8] The average square inch (6.5cm) of skin holds 650 sweat glands, 20 blood vessels, 60,000 melanocytes, and more than 1,000 nerve endings.[9][bettersourceneeded] The average human skin cell is about 30 micrometers in diameter, but there are variants. A skin cell usually ranges from 25-40 micrometers (squared), depending on a variety of factors.

Skin is composed of three primary layers: the epidermis, the dermis and the hypodermis.[8]

Epidermis, "epi" coming from the Greek meaning "over" or "upon", is the outermost layer of the skin. It forms the waterproof, protective wrap over the body's surface which also serves as a barrier to infection and is made up of stratified squamous epithelium with an underlying basal lamina.

The epidermis contains no blood vessels, and cells in the deepest layers are nourished almost exclusively by diffused oxygen from the surrounding air[10] and to a far lesser degree by blood capillaries extending to the outer layers of the dermis. The main type of cells which make up the epidermis are Merkel cells, keratinocytes, with melanocytes and Langerhans cells also present. The epidermis can be further subdivided into the following strata (beginning with the outermost layer): corneum, lucidum (only in palms of hands and bottoms of feet), granulosum, spinosum, basale. Cells are formed through mitosis at the basale layer. The daughter cells (see cell division) move up the strata changing shape and composition as they die due to isolation from their blood source. The cytoplasm is released and the protein keratin is inserted. They eventually reach the corneum and slough off (desquamation). This process is called "keratinization". This keratinized layer of skin is responsible for keeping water in the body and keeping other harmful chemicals and pathogens out, making skin a natural barrier to infection.

The epidermis contains no blood vessels, and is nourished by diffusion from the dermis. The main type of cells which make up the epidermis are keratinocytes, melanocytes, Langerhans cells and Merkels cells. The epidermis helps the skin to regulate body temperature.

Epidermis is divided into several layers where cells are formed through mitosis at the innermost layers. They move up the strata changing shape and composition as they differentiate and become filled with keratin. They eventually reach the top layer called stratum corneum and are sloughed off, or desquamated. This process is called keratinization and takes place within weeks. The outermost layer of the epidermis consists of 25 to 30 layers of dead cells.

Epidermis is divided into the following 5 sublayers or strata:

Blood capillaries are found beneath the epidermis, and are linked to an arteriole and a venule. Arterial shunt vessels may bypass the network in ears, the nose and fingertips.

The dermis is the layer of skin beneath the epidermis that consists of epithelial tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many nerve endings that provide the sense of touch and heat. It contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels. The blood vessels in the dermis provide nourishment and waste removal from its own cells as well as from the Stratum basale of the epidermis.

The dermis is structurally divided into two areas: a superficial area adjacent to the epidermis, called the papillary region, and a deep thicker area known as the reticular region.

The papillary region is composed of loose areolar connective tissue. It is named for its fingerlike projections called papillae, that extend toward the epidermis. The papillae provide the dermis with a "bumpy" surface that interdigitates with the epidermis, strengthening the connection between the two layers of skin.

In the palms, fingers, soles, and toes, the influence of the papillae projecting into the epidermis forms contours in the skin's surface. These epidermal ridges occur in patterns (see: fingerprint) that are genetically and epigenetically determined and are therefore unique to the individual, making it possible to use fingerprints or footprints as a means of identification.

The reticular region lies deep in the papillary region and is usually much thicker. It is composed of dense irregular connective tissue, and receives its name from the dense concentration of collagenous, elastic, and reticular fibers that weave throughout it. These protein fibers give the dermis its properties of strength, extensibility, and elasticity.

Also located within the reticular region are the roots of the hair, sebaceous glands, sweat glands, receptors, nails, and blood vessels.

Tattoo ink is held in the dermis. Stretch marks from pregnancy are also located in the dermis.

The hypodermis is not part of the skin, and lies below the dermis. Its purpose is to attach the skin to underlying bone and muscle as well as supplying it with blood vessels and nerves. It consists of loose connective tissue, adipose tissue and elastin. The main cell types are fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of body fat). Fat serves as padding and insulation for the body.

Human skin shows high skin color variety from the darkest brown to the lightest pinkish-white hues. Human skin shows higher variation in color than any other single mammalian species and is the result of natural selection. Skin pigmentation in humans evolved to primarily regulate the amount of ultraviolet radiation (UVR) penetrating the skin, controlling its biochemical effects.[11]

The actual skin color of different humans is affected by many substances, although the single most important substance determining human skin color is the pigment melanin. Melanin is produced within the skin in cells called melanocytes and it is the main determinant of the skin color of darker-skinned humans. The skin color of people with light skin is determined mainly by the bluish-white connective tissue under the dermis and by the hemoglobin circulating in the veins of the dermis. The red color underlying the skin becomes more visible, especially in the face, when, as consequence of physical exercise or the stimulation of the nervous system (anger, fear), arterioles dilate.[12]

There are at least five different pigments that determine the color of the skin.[13][14] These pigments are present at different levels and places.

There is a correlation between the geographic distribution of UV radiation (UVR) and the distribution of indigenous skin pigmentation around the world. Areas that highlight higher amounts of UVR reflect darker-skinned populations, generally located nearer towards the equator. Areas that are far from the tropics and closer to the poles have lower concentration of UVR, which is reflected in lighter-skinned populations.[15]

In the same population it has been observed that adult human females are considerably lighter in skin pigmentation than males. Females need more calcium during pregnancy and lactation and vitamin D which is synthesized from sunlight helps in absorbing calcium. For this reason it is thought that females may have evolved to have lighter skin in order to help their bodies absorb more calcium.[16]

The Fitzpatrick scale[17][18] is a numerical classification schema for human skin color developed in 1975 as a way to classify the typical response of different types of skin to ultraviolet (UV) light:

As skin ages, it becomes thinner and more easily damaged. Intensifying this effect is the decreasing ability of skin to heal itself as a person ages.

Among other things, skin aging is noted by a decrease in volume and elasticity. There are many internal and external causes to skin aging. For example, aging skin receives less blood flow and lower glandular activity.

A validated comprehensive grading scale has categorized the clinical findings of skin aging as laxity (sagging), rhytids (wrinkles), and the various facets of photoaging, including erythema (redness), and telangiectasia, dyspigmentation (brown discoloration), solar elastosis (yellowing), keratoses (abnormal growths) and poor texture.[19]

Cortisol causes degradation of collagen,[20] accelerating skin aging.[21]

Anti-aging supplements are used to treat skin aging.

Photoaging has two main concerns: an increased risk for skin cancer and the appearance of damaged skin. In younger skin, sun damage will heal faster since the cells in the epidermis have a faster turnover rate, while in the older population the skin becomes thinner and the epidermis turnover rate for cell repair is lower which may result in the dermis layer being damaged.[22]

Skin performs the following functions:

The human skin is a rich environment for microbes.[5][6] Around 1000 species of bacteria from 19 bacterial phyla have been found. Most come from only four phyla: Actinobacteria (51.8%), Firmicutes (24.4%), Proteobacteria (16.5%), and Bacteroidetes (6.3%). Propionibacteria and Staphylococci species were the main species in sebaceous areas. There are three main ecological areas: moist, dry and sebaceous. In moist places on the body Corynebacteria together with Staphylococci dominate. In dry areas, there is a mixture of species but dominated by b-Proteobacteria and Flavobacteriales. Ecologically, sebaceous areas had greater species richness than moist and dry ones. The areas with least similarity between people in species were the spaces between fingers, the spaces between toes, axillae, and umbilical cord stump. Most similarly were beside the nostril, nares (inside the nostril), and on the back.

Reflecting upon the diversity of the human skin researchers on the human skin microbiome have observed: "hairy, moist underarms lie a short distance from smooth dry forearms, but these two niches are likely as ecologically dissimilar as rainforests are to deserts."[5]

The NIH has launched the Human Microbiome Project to characterize the human microbiota which includes that on the skin and the role of this microbiome in health and disease.[23]

Microorganisms like Staphylococcus epidermidis colonize the skin surface. The density of skin flora depends on region of the skin. The disinfected skin surface gets recolonized from bacteria residing in the deeper areas of the hair follicle, gut and urogenital openings.

Diseases of the skin include skin infections and skin neoplasms (including skin cancer).

Dermatology is the branch of medicine that deals with conditions of the skin.[2]

The skin supports its own ecosystems of microorganisms, including yeasts and bacteria, which cannot be removed by any amount of cleaning. Estimates place the number of individual bacteria on the surface of one square inch (6.5 square cm) of human skin at 50 million, though this figure varies greatly over the average 20 square feet (1.9m2) of human skin. Oily surfaces, such as the face, may contain over 500 million bacteria per square inch (6.5cm). Despite these vast quantities, all of the bacteria found on the skin's surface would fit into a volume the size of a pea.[24] In general, the microorganisms keep one another in check and are part of a healthy skin. When the balance is disturbed, there may be an overgrowth and infection, such as when antibiotics kill microbes, resulting in an overgrowth of yeast. The skin is continuous with the inner epithelial lining of the body at the orifices, each of which supports its own complement of microbes.

Cosmetics should be used carefully on the skin because these may cause allergic reactions. Each season requires suitable clothing in order to facilitate the evaporation of the sweat. Sunlight, water and air play an important role in keeping the skin healthy.

Oily skin is caused by over-active sebaceous glands, that produce a substance called sebum, a naturally healthy skin lubricant.[1] When the skin produces excessive sebum, it becomes heavy and thick in texture. Oily skin is typified by shininess, blemishes and pimples.[1] The oily-skin type is not necessarily bad, since such skin is less prone to wrinkling, or other signs of aging,[1] because the oil helps to keep needed moisture locked into the epidermis (outermost layer of skin).

The negative aspect of the oily-skin type is that oily complexions are especially susceptible to clogged pores, blackheads, and buildup of dead skin cells on the surface of the skin.[1] Oily skin can be sallow and rough in texture and tends to have large, clearly visible pores everywhere, except around the eyes and neck.[1]

Human skin has a low permeability; that is, most foreign substances are unable to penetrate and diffuse through the skin. Skin's outermost layer, the stratum corneum, is an effective barrier to most inorganic nanosized particles.[25][26] This protects the body from external particles such as toxins by not allowing them to come into contact with internal tissues. However, in some cases it is desirable to allow particles entry to the body through the skin. Potential medical applications of such particle transfer has prompted developments in nanomedicine and biology to increase skin permeability. One application of transcutaneous particle delivery could be to locate and treat cancer. Nanomedical researchers seek to target the epidermis and other layers of active cell division where nanoparticles can interact directly with cells that have lost their growth-control mechanisms (cancer cells). Such direct interaction could be used to more accurately diagnose properties of specific tumors or to treat them by delivering drugs with cellular specificity.

Nanoparticles 40nm in diameter and smaller have been successful in penetrating the skin.[27][28][29] Research confirms that nanoparticles larger than 40nm do not penetrate the skin past the stratum corneum.[27] Most particles that do penetrate will diffuse through skin cells, but some will travel down hair follicles and reach the dermis layer.

The permeability of skin relative to different shapes of nanoparticles has also been studied. Research has shown that spherical particles have a better ability to penetrate the skin compared to oblong (ellipsoidal) particles because spheres are symmetric in all three spatial dimensions.[29] One study compared the two shapes and recorded data that showed spherical particles located deep in the epidermis and dermis whereas ellipsoidal particles were mainly found in the stratum corneum and epidermal layers.[30]Nanorods are used in experiments because of their unique fluorescent properties but have shown mediocre penetration.

Nanoparticles of different materials have shown skins permeability limitations. In many experiments, gold nanoparticles 40nm in diameter or smaller are used and have shown to penetrate to the epidermis. Titanium oxide (TiO2), zinc oxide (ZnO), and silver nanoparticles are ineffective in penetrating the skin past the stratum corneum.[31][32]Cadmium selenide (CdSe) quantum dots have proven to penetrate very effectively when they have certain properties. Because CdSe is toxic to living organisms, the particle must be covered in a surface group. An experiment comparing the permeability of quantum dots coated in polyethylene glycol (PEG), PEG-amine, and carboxylic acid concluded the PEG and PEG-amine surface groups allowed for the greatest penetration of particles. The carboxylic acid coated particles did not penetrate past the stratum corneum.[30]

Scientists previously believed that the skin was an effective barrier to inorganic particles. Damage from mechanical stressors was believed to be the only way to increase its permeability.[33] Recently, however, simpler and more effective methods for increasing skin permeability have been developed. For example, ultraviolet radiation (UVR) has been used to slightly damage the surface of skin, causing a time-dependent defect allowing easier penetration of nanoparticles.[34] The UVRs high energy causes a restructuring of cells, weakening the boundary between the stratum corneum and the epidermal layer.[34][35] The damage of the skin is typically measured by the transepidermal water loss (TEWL), though it may take 35 days for the TEWL to reach its peak value. When the TEWL reaches its highest value, the maximum density of nanoparticles is able to permeate the skin. Studies confirm that UVR damaged skin significantly increases the permeability.[34][35] The effects of increased permeability after UVR exposure can lead to an increase in the number of particles that permeate the skin. However, the specific permeability of skin after UVR exposure relative to particles of different sizes and materials has not been determined.[34]

Other skin damaging methods used to increase nanoparticle penetration include tape stripping, skin abrasion, and chemical enhancement. Tape stripping is the process in which tape is applied to skin then lifted to remove the top layer of skin. Skin abrasion is done by shaving the top 5-10 micrometers off the surface of the skin. Chemical enhancement is the process in which chemicals such as polyvinylpyrrolidone (PVP), dimethyl sulfoxide (DMSO), and oleic acid are applied to the surface of the skin to increase permeability.[36][37]

Electroporation is the application of short pulses of electric fields on skin and has proven to increase skin permeability. The pulses are high voltage and on the order of milliseconds when applied. Charged molecules penetrate the skin more frequently than neutral molecules after the skin has been exposed to electric field pulses. Results have shown molecules on the order of 100 micrometers to easily permeate electroporated skin.[37]

A large area of interest in nanomedicine is the transdermal patch because of the possibility of a painless application of therapeutic agents with very few side effects. Transdermal patches have been limited to administer a small number of drugs, such as nicotine, because of the limitations in permeability of the skin. Development of techniques that increase skin permeability has led to more drugs that can be applied via transdermal patches and more options for patients.[37]

Increasing the permeability of skin allows nanoparticles to penetrate and target cancer cells. Nanoparticles along with multi-modal imaging techniques have been used as a way to diagnose cancer non-invasively. Skin with high permeability allowed quantum dots with an antibody attached to the surface for active targeting to successfully penetrate and identify cancerous tumors in mice. Tumor targeting is beneficial because the particles can be excited using fluorescence microscopy and emit light energy and heat that will destroy cancer cells.[38]

Sunblock and sunscreen are different important skin-care products though both offer full protection from the sun.[39][40]

SunblockSunblock is opaque and stronger than sunscreen, since it is able to block most of the UVA/UVB rays and radiation from the sun, and does not need to be reapplied several times in a day. Titanium dioxide and zinc oxide are two of the important ingredients in sunblock.[41]

SunscreenSunscreen is more transparent once applied to the skin and also has the ability to protect against UVA/UVB rays, although the sunscreen's ingredients have the ability to break down at a faster rate once exposed to sunlight, and some of the radiation is able to penetrate to the skin. In order for sunscreen to be more effective it is necessary to consistently reapply and use one with a higher sun protection factor.

Vitamin A, also known as retinoids, benefits the skin by normalizing keratinization, downregulating sebum production which contributes to acne, and reversing and treating photodamage, striae, and cellulite.

Vitamin D and analogs are used to downregulate the cutaneous immune system and epithelial proliferation while promoting differentiation.

Vitamin C is an antioxidant that regulates collagen synthesis, forms barrier lipids, regenerates vitamin E, and provides photoprotection.

Vitamin E is a membrane antioxidant that protects against oxidative damage and also provides protection against harmful UV rays. [42]

Several scientific studies confirmed that changes in baseline nutritional status affects skin condition. [43]

The Mayo Clinic lists foods they state help the skin: yellow, green, and orange fruits and vegetables; fat-free dairy products; whole-grain foods; fatty fish, nuts.[44]

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Human skin - Wikipedia

Skin Stem Cells Comments Off on Human skin – Wikipedia | November 30th, 2016

In August, 2011 an all natural rejuvenating serum that uses your own adult stem cells to decrease wrinkles and increase moisture retention and elasticity was launched in the United States, and subsequently in Australia. This is a mocha based fusion of the world's most restorative ingredients and a blend of six cytokines that stimulate the proliferation and migration of the skin's stem cells by more than 225%.

There are a number of stem cell based serums and skin care products that have appeared on the marketplace over the past few years, and they constitute a novel frontier in skin care. Although many of them are nothing more than simple skin care products with misleading or spurious stem cell claims, a few are legitimate products. The legitimate ones are all based on the use of compounds called cytokines, which are growth factors supporting the functions of stem cells in the skin. Some of them contain an extract from apple stem cells, whose effectiveness really remains to be proven there is an obvious difference between human skin and an apple! Others contained cytokines from human stem cells. The latter are obviously the premium products.

One of the questions the developers of this product asked was: Of all the natural compounds and herbal extracts known to benefit the skin, which do so by supporting the natural role of stem cells in the skin? Are there natural compounds that can support the intrinsic ability of the skin to renew itself? They studied a broad array of plants and herbal extracts for their effect on the proliferation and differentiation of human skin stem cells grown in vitro, and they discovered a handful of natural compounds that have an effect on the very stem cells of your skin. By supporting the natural role of your skins stem cells, you support the process of rejuvenation of your skin from within.......the way nature intended. These compounds include AFA, the same product from which stem cell nutrition is derived.

AFA alone increased the proliferation of skin stem cells by nearly 100% in the study. Other natural ingredients include: Aloe vera (which increased skin stem cell proliferation by 87%) and a proprietary fucoidan that increased proliferation by 55%. When blended together, the effect of these plants on skin stem cell proliferation was further synergistically increased by ingredients like vanilla, maqui berry, cacao, old mans weed and others. All these ingredients taken together constitute the Stem Cell Complex unique to this product with a Stem Cell Index exceeding 250%

Hyaluronic acid is part of the infrastructure (skeleton of the skin) and is one of the main components forming the matrix of the skin. One of the main roles of hyaluronic acid is to retain moisture in the skin. Good hydration is the hallmark of young skin, and it comes from the presence of hyaluronic acid. Recently a group of scientists discovered that as we age, although we continue to produce hyaluronic acid, its structure is less and less branched. The highly branched hyaluronic acid in young skin allows for greater retention of water in the skin. Since these branches are formed of a derivative of glucosamine, scientists discovered that the best results are obtained when this derivative of glucosamine is applied on the skin, instead of hyaluronic acid itself. This product is the first in the US to contain that very derivative of glucosamine, produced by fermentation.

An all-natural formula Of all the stem cell based skin care products, this is the only one that is truly natural ......even though many make the claim. In essence, all skin care products are oils blended with water extracts of various plants. Since oil and water do not mix, it is necessary to use compounds called emulsifiers that can dissolve in both water and in lipids, thereby helping to create an emulsion. There are very few natural emulsifiers and none that are known to be effective at making a cold emulsion which is essential to the preservation of all the delicate actives found in herbal extracts. This is the only skin care product made cold with an all-natural emulsification system. Products like glycerin are relatively natural and can be used as emulsifiers; however, they are known for their drying effect on the skin. There is no glycerin here. Once produced, natural skin care products are essentially food for bacteria, so they need to be preserved. And this is the biggest challenge, as there are virtually no natural preservatives commercially available. Although the best products claim to have none of the dangerous carcinogenic parabens, they have other compounds just as dangerous such as phenoxyethanol and various forms of benzoic acid, all known to be irritants to the skin. The developers asked the question, Where in nature can we find natural antibacterial compounds? They harvested several flowers known to grow in very moist areas while blooming for weeks, unaffected by bacterial or fungal growth, and they extracted their antibacterial power. To this they added a proprietary process called SoniPure that inactivates bacteria by the use of sound waves a breakthrough innovative process. So this skin serum is 100% stable without delivering harmful compounds to your skin.

The developers intention was to create a product to restructure the skin from within in order to increase water retention and skin elasticity, which in turn would naturally reduce wrinkles and fine lines and this is exactly what was demonstrated in an independent clinical trial. It was shown to increase water retention by 30% and skin elasticity by 10% and to reduce wrinkles by an average of 25% in 28 days. Some people saw significant benefits after only 7 days, while others report wrinkle reduction by as much as 75%. In all participants, wrinkle reduction was already statistically significant after 7 days. So you can easily see how both the developmental process and the resulting formula ensure that this product is undeniably second-to-none in stem cell based skin care.

In healthy individuals, skin youthfulness is maintained by epidermal stem cells which self-renew and generate daughter cells that become new skin. Therefore, part of skin aging is caused by impaired adult stem cell mobilization from the bone marrow and the reduced number of adult stem cells able to respond to repair signals. This means that, if we increase the number of circulating adult stem cells, we can affect the epidermal stem cells. Research also shows that topical application of cytokines stimulates the migration and proliferation of skin stem cells.

In much the same way as stem cell nutrition works with adult stem cells to deliver inner wellness, the rejuvenating skin serum applies the benefits of adult stem cell science to the bodys largest organ, the skin, to achieve and maintain outer vibrance! Taking care of this organ the skin, which exposed to the elements on a continual basis is essential. The rejuvenating skin serum assists in our daily process at the skin level, by a proprietary blend of over two dozen natural ingredients found during years of searching worldwide. Each natural ingredient has been selected for its nutrient-rich attributes that fight the appearance of aging, regenerating cells, decreasing fine lines and wrinkles, increasing moisture retention and increasing skin elasticity. In addition, some of the ingredients have natural sun-protecting components.

After using stem cell serum on one side of face only for only 10 days

Your skin's response to an increase in circulating adult stem cells. The most evident visual response in people's facial skin a few weeks after taking stem cell nutrition is that - it glows. People notice a smoothness and improvement in color of their skin. Skin may also show improvements in age related and hormonal pigmentation, decreased bruising and increased elasticity and tone.

Before and after using stem cell serum

This product is second to none, and early clinical tests have demonstrated the following dramatic results: Decreased fine line & coarse wrinkles 25% in 28 days Increased moisture retention 30% in 28 days Increased elasticity 10% in 28 days

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Rejuvenating Skin Serum - Stem Cell Nutrition

Skin Stem Cells Comments Off on Rejuvenating Skin Serum – Stem Cell Nutrition | November 27th, 2016

Persons using assistive technology might not be able to fully access information in this file. For assistance, please send e-mail to: mmwrq@cdc.gov. Type 508 Accommodation and the title of the report in the subject line of e-mail.

Please note: An erratum has been published for this article. To view the erratum, please click here.

Clare A. Dykewicz, M.D., M.P.H. Harold W. Jaffe, M.D., Director Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention

Clare A. Dykewicz, M.D., M.P.H., Chair Harold W. Jaffe, M.D. Thomas J. Spira, M.D. Division of AIDS, STD, and TB Laboratory Research

William R. Jarvis, M.D. Hospital Infections Program National Center for Infectious Diseases, CDC

Jonathan E. Kaplan, M.D. Division of AIDS, STD, and TB Laboratory Research National Center for Infectious Diseases Division of HIV/AIDS Prevention --- Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Brian R. Edlin, M.D. Division of HIV/AIDS Prevention---Surveillance and Epidemiology National Center for HIV, STD, and TB Prevention, CDC

Robert T. Chen, M.D., M.A. Beth Hibbs, R.N., M.P.H. Epidemiology and Surveillance Division National Immunization Program, CDC

Raleigh A. Bowden, M.D. Keith Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

David Emanuel, M.B.Ch.B. Indiana University Indianapolis, Indiana

David L. Longworth, M.D. Cleveland Clinic Foundation Cleveland, Ohio

Philip A. Rowlings, M.B.B.S., M.S. International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry Milwaukee, Wisconsin

Robert H. Rubin, M.D. Massachusetts General Hospital Boston, Massachusetts and Massachusetts Institute of Technology Cambridge, Massachusetts

Kent A. Sepkowitz, M.D. Memorial-Sloan Kettering Cancer Center New York, New York

John R. Wingard, M.D. University of Florida Gainesville, Florida

John F. Modlin, M.D. Dartmouth Medical School Hanover, New Hampshire

Donna M. Ambrosino, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Norman W. Baylor, Ph.D. Food and Drug Administration Rockville, Maryland

Albert D. Donnenberg, Ph.D. University of Pittsburgh Pittsburgh, Pennsylvania

Pierce Gardner, M.D. State University of New York at Stony Brook Stony Brook, New York

Roger H. Giller, M.D. University of Colorado Denver, Colorado

Neal A. Halsey, M.D. Johns Hopkins University Baltimore, Maryland

Chinh T. Le, M.D. Kaiser-Permanente Medical Center Santa Rosa, California

Deborah C. Molrine, M.D. Dana-Farber Cancer Institute Boston, Massachusetts

Keith M. Sullivan, M.D. Fred Hutchinson Cancer Research Center Seattle, Washington

CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation have cosponsored these guidelines for preventing opportunistic infections (OIs) among hematopoietic stem cell transplant (HSCT) recipients. The guidelines were drafted with the assistance of a working group of experts in infectious diseases, transplantation, and public health. For the purposes of this report, HSCT is defined as any transplantation of blood- or marrow-derived hematopoietic stem cells, regardless of transplant type (i.e., allogeneic or autologous) or cell source (i.e., bone marrow, peripheral blood, or placental or umbilical cord blood). Such OIs as bacterial, viral, fungal, protozoal, and helminth infections occur with increased frequency or severity among HSCT recipients. These evidence-based guidelines contain information regarding preventing OIs, hospital infection control, strategies for safe living after transplantation, vaccinations, and hematopoietic stem cell safety. The disease-specific sections address preventing exposure and disease for pediatric and adult and autologous and allogeneic HSCT recipients. The goal of these guidelines is twofold: to summarize current data and provide evidence-based recommendations regarding preventing OIs among HSCT patients. The guidelines were developed for use by HSCT recipients, their household and close contacts, transplant and infectious diseases physicians, HSCT center personnel, and public health professionals. For all recommendations, prevention strategies are rated by the strength of the recommendation and the quality of the evidence supporting the recommendation. Adhering to these guidelines should reduce the number and severity of OIs among HSCT recipients.

In 1992, the Institute of Medicine (1) recommended that CDC lead a global effort to detect and control emerging infectious agents. In response, CDC published a plan (2) that outlined national disease prevention priorities, including the development of guidelines for preventing opportunistic infections (OIs) among immunosuppressed persons. During 1995, CDC published guidelines for preventing OIs among persons infected with human immunodeficiency virus (HIV) and revised those guidelines during 1997 and 1999 (3--5). Because of the success of those guidelines, CDC sought to determine the need for expanding OI prevention activities to other immunosuppressed populations. An informal survey of hematology, oncology, and infectious disease specialists at transplant centers and a working group formed by CDC determined that guidelines were needed to help prevent OIs among hematopoietic stem cell transplant (HSCT)* recipients.

The working group defined OIs as infections that occur with increased frequency or severity among HSCT recipients, and they drafted evidence-based recommendations for preventing exposure to and disease caused by bacterial, fungal, viral, protozoal, or helminthic pathogens. During March 1997, the working group presented the first draft of these guidelines at a meeting of representatives from public and private health organizations. After review by that group and other experts, these guidelines were revised and made available during September 1999 for a 45-day public comment period after notification in the Federal Register. Public comments were added when feasible, and the report was approved by CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. The pediatric content of these guidelines has been endorsed also by the American Academy of Pediatrics. The hematopoietic stem cell safety section was endorsed by the International Society of Hematotherapy and Graft Engineering.

The first recommendations presented in this report are followed by recommendations for hospital infection control, strategies for safe living, vaccinations, and hematopoietic stem cell safety. Unless otherwise noted, these recommendations address allogeneic and autologous and pediatric and adult HSCT recipients. Additionally, these recommendations are intended for use by the recipients, their household and other close contacts, transplant and infectious diseases specialists, HSCT center personnel, and public health professionals.

For all recommendations, prevention strategies are rated by the strength of the recommendation (Table 1) and the quality of the evidence (Table 2) supporting the recommendation. The principles of this rating system were developed by the Infectious Disease Society of America and the U.S. Public Health Service for use in the guidelines for preventing OIs among HIV-infected persons (3--6). This rating system allows assessments of recommendations to which adherence is critical.

HSCT is the infusion of hematopoietic stem cells from a donor into a patient who has received chemotherapy, which is usually marrow-ablative. Increasingly, HSCT has been used to treat neoplastic diseases, hematologic disorders, immunodeficiency syndromes, congenital enzyme deficiencies, and autoimmune disorders (e.g., systemic lupus erythematosus or multiple sclerosis) (7--10). Moreover, HSCT has become standard treatment for selected conditions (7,11,12). Data from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry indicate that approximately 20,000 HSCTs were performed in North America during 1998 (Statistical Center of the International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry, unpublished data, 1998).

HSCTs are classified as either allogeneic or autologous on the basis of the source of the transplanted hematopoietic progenitor cells. Cells used in allogeneic HSCTs are harvested from a donor other than the transplant recipient. Such transplants are the most effective treatment for persons with severe aplastic anemia (13) and offer the only curative therapy for persons with chronic myelogenous leukemia (12). Allogeneic donors might be a blood relative or an unrelated donor. Allogeneic transplants are usually most successful when the donor is a human lymphocyte antigen (HLA)-identical twin or matched sibling. However, for allogeneic candidates who lack such a donor, registry organizations (e.g., the National Marrow Donor Program) maintain computerized databases that store information regarding HLA type from millions of volunteer donors (14--16). Another source of stem cells for allogeneic candidates without an HLA-matched sibling is a mismatched family member (17,18). However, persons who receive allogeneic grafts from donors who are not HLA-matched siblings are at a substantially greater risk for graft-versus-host disease (GVHD) (19). These persons are also at increased risk for suboptimal graft function and delayed immune system recovery (19). To reduce GVHD among allogeneic HSCTs, techniques have been developed to remove T-lymphocytes, the principal effectors of GVHD, from the donor graft. Although the recipients of T-lymphocyte--depleted marrow grafts generally have lower rates of GVHD, they also have greater rates of graft rejection, cytomegalovirus (CMV) infection, invasive fungal infection, and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (20).

The patient's own cells are used in an autologous HSCT. Similar to autologous transplants are syngeneic transplants, among whom the HLA-identical twin serves as the donor. Autologous HSCTs are preferred for patients who require high-level or marrow-ablative chemotherapy to eradicate an underlying malignancy but have healthy, undiseased bone marrows. Autologous HSCTs are also preferred when the immunologic antitumor effect of an allograft is not beneficial. Autologous HSCTs are used most frequently to treat breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease (21). Neither autologous nor syngeneic HSCTs confer a risk for chronic GVHD.

Recently, medical centers have begun to harvest hematopoietic stem cells from placental or umbilical cord blood (UCB) immediately after birth. These harvested cells are used primarily for allogeneic transplants among children. Early results demonstrate that greater degrees of histoincompatibility between donor and recipient might be tolerated without graft rejection or GVHD when UCB hematopoietic cells are used (22--24). However, immune system function after UCB transplants has not been well-studied.

HSCT is also evolving rapidly in other areas. For example, hematopoietic stem cells harvested from the patient's peripheral blood after treatment with hematopoietic colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF or filgastrim] or granulocyte-macrophage colony-stimulating factor [GM-CSF or sargramostim]) are being used increasingly among autologous recipients (25) and are under investigation for use among allogeneic HSCT. Peripheral blood has largely replaced bone marrow as a source of stem cells for autologous recipients. A benefit of harvesting such cells from the donor's peripheral blood instead of bone marrow is that it eliminates the need for general anesthesia associated with bone marrow aspiration.

GVHD is a condition in which the donated cells recognize the recipient's cells as nonself and attack them. Although the use of intravenous immunoglobulin (IVIG) in the routine management of allogeneic patients was common in the past as a means of producing immune modulation among patients with GVHD, this practice has declined because of cost factors (26) and because of the development of other strategies for GVHD prophylaxis (27). For example, use of cyclosporine GVHD prophylaxis has become commonplace since its introduction during the early 1980s. Most frequently, cyclosporine or tacrolimus (FK506) is administered in combination with other immunosuppressive agents (e.g., methotrexate or corticosteroids) (27). Although cyclosporine is effective in preventing GVHD, its use entails greater hazards for infectious complications and relapse of the underlying neoplastic disease for which the transplant was performed.

Although survival rates for certain autologous recipients have improved (28,29), infection remains a leading cause of death among allogeneic transplants and is a major cause of morbidity among autologous HSCTs (29). Researchers from the National Marrow Donor Program reported that, of 462 persons receiving unrelated allogeneic HSCTs during December 1987--November 1990, a total of 66% had died by 1991 (15). Among primary and secondary causes of death, the most common cause was infection, which occurred among 37% of 307 patients (15).**

Despite high morbidity and mortality after HSCT, recipients who survive long-term are likely to enjoy good health. A survey of 798 persons who had received an HSCT before 1985 and who had survived for >5 years after HSCT, determined that 93% were in good health and that 89% had returned to work or school full time (30). In another survey of 125 adults who had survived a mean of 10 years after HSCT, 88% responded that the benefits of transplantation outweighed the side effects (31).

During the first year after an HSCT, recipients typically follow a predictable pattern of immune system deficiency and recovery, which begins with the chemotherapy or radiation therapy (i.e., the conditioning regimen) administered just before the HSCT to treat the underlying disease. Unfortunately, this conditioning regimen also destroys normal hematopoiesis for neutrophils, monocytes, and macrophages and damages mucosal progenitor cells, causing a temporary loss of mucosal barrier integrity. The gastrointestinal tract, which normally contains bacteria, commensal fungi, and other bacteria-carrying sources (e.g., skin or mucosa) becomes a reservoir of potential pathogens. Virtually all HSCT recipients rapidly lose all T- and B-lymphocytes after conditioning, losing immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens, and vaccines. Because transfer of donor immunity to HSCT recipients is variable and influenced by the timing of antigen exposure among donor and recipient, passively acquired donor immunity cannot be relied upon to provide long-term immunity against infectious diseases among HSCT recipients.

During the first month after HSCT, the major host-defense deficits include impaired phagocytosis and damaged mucocutaneous barriers. Additionally, indwelling intravenous catheters are frequently placed and left in situ for weeks to administer parenteral medications, blood products, and nutritional supplements. These catheters serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (e.g., . coagulase-negative Staphylococci, Staphylococcus aureus, Candida species, and Enterococci) (32,33).

Engraftment for adults and children is defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of >500/mm3 and sustained platelet count of >20,000, lasting >3 consecutive days without transfusions. Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range: 6--84 days) (15). In the absence of corticosteroid use, engraftment is associated with the restoration of effective phagocytic function, which results in a decreased risk for bacterial and fungal infections. However, all HSCT recipients and particularly allogeneic recipients, experience an immune system dysfunction for months after engraftment. For example, although allogeneic recipients might have normal total lymphocyte counts within >2 months after HSCT, they have abnormal CD4/CD8 T-cell ratios, reflecting their decreased CD4 and increased CD8 T-cell counts (27). They might also have immunoglobulin G (IgG)2, IgG4, and immunoglobulin A (IgA) deficiencies for months after HSCT and have difficulty switching from immunoglobulin M (IgM) to IgG production after antigen exposure (32). Immune system recovery might be delayed further by CMV infection (34).

During the first >2 months after HSCT, recipients might experience acute GVHD that manifests as skin, gastrointestinal, and liver injury, and is graded on a scale of I--IV (32,35,36). Although autologous or syngeneic recipients might occasionally experience a mild, self-limited illness that is acute GVHD-like (19,37), GVHD occurs primarily among allogeneic recipients, particularly those receiving matched, unrelated donor transplants. GVHD is a substantial risk factor for infection among HSCT recipients because it is associated with a delayed immunologic recovery and prolonged immunodeficiency (19). Additionally, the immunosuppressive agents used for GVHD prophylaxis and treatment might make the HSCT recipient more vulnerable to opportunistic viral and fungal pathogens (38).

Certain patients, particularly adult allogeneic recipients, might also experience chronic GVHD, which is graded as either limited or extensive chronic GVHD (19,39). Chronic GVHD appears similar to autoimmune, connective-tissue disorders (e.g., scleroderma or systemic lupus erythematosus) (40) and is associated with cellular and humoral immunodeficiencies, including macrophage deficiency, impaired neutrophil chemotaxis (41), poor response to vaccination (42--44), and severe mucositis (19). Risk factors for chronic GVHD include increasing age, allogeneic HSCT (particularly those among whom the donor is unrelated or a non-HLA identical family member) (40), and a history of acute GVHD (24,45). Chronic GVHD was first described as occurring >100 days after HSCT but can occur 40 days after HSCT (19). Although allogeneic recipients with chronic GVHD have normal or high total serum immunoglobulin levels (41), they experience long-lasting IgA, IgG, and IgG subclass deficiencies (41,46,47) and poor opsonization and impaired reticuloendothelial function. Consequently, they are at even greater risk for infections (32,39), particularly life-threatening bacterial infections from encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis). After chronic GVHD resolves, which might take years, cell-mediated and humoral immunity function are gradually restored.

HSCT recipients experience certain infections at different times posttransplant, reflecting the predominant host-defense defect(s) (Figure). Immune system recovery for HSCT recipients takes place in three phases beginning at day 0, the day of transplant. Phase I is the preengraftment phase (<30 days after HSCT); phase II, the postengraftment phase (30--100 days after HSCT); and phase III, the late phase (>100 days after HSCT). Prevention strategies should be based on these three phases and the following information:

Preventing infections among HSCT recipients is preferable to treating infections. How ever, despite recent technologic advances, more research is needed to optimize health outcomes for HSCT recipients. Efforts to improve immune system reconstitution, particularly among allogeneic transplant recipients, and to prevent or resolve the immune dysregulation resulting from donor-recipient histoincompatibility and GVHD remain substantial challenges for preventing recurrent, persistent, or progressive infections among HSCT patients.

Preventing Exposure

Because bacteria are carried on the hands, health-care workers (HCWs) and others in contact with HSCT recipients should routinely follow appropriate hand-washing practices to avoid exposing recipients to bacterial pathogens (AIII).

Preventing Disease

Preventing Early Disease (0--100 Days After HSCT). Routine gut decontamination is not recommended for HSCT candidates (51--53) (DIII). Because of limited data, no recommendations can be made regarding the routine use of antibiotics for bacterial prophylaxis among afebrile, asymptomatic neutropenic recipients. Although studies have reported that using prophylactic antibiotics might reduce bacteremia rates after HSCT (51), infection-related fatality rates are not reduced (52). If physicians choose to use prophylactic antibiotics among asymptomatic, afebrile, neutropenic recipients, they should routinely review hospital and HSCT center antibiotic-susceptibility profiles, particularly when using a single antibiotic for antibacterial prophylaxis (BIII). The emergence of fluoquinolone-resistant coagulase-negative Staphylococci and Es. coli (51,52), vancomycin-intermediate Sta. aureus and vancomycin-resistant Enterococcus (VRE) are increasing concerns (54). Vancomycin should not be used as an agent for routine bacterial prophylaxis (DIII). Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT (55); however, no data were found that indicate whether growth factors effectively reduce the attack rate of invasive bacterial disease.

Physicians should not routinely administer IVIG products to HSCT recipients for bacterial infection prophylaxis (DII), although IVIG has been recommended for use in producing immune system modulation for GVHD prevention. Researchers have recommended routine IVIG*** use to prevent bacterial infections among the approximately 20%--25% of HSCT recipients with unrelated marrow grafts who experience severe hypogamma-globulinemia (e.g., IgG < 400 mg/dl) within the first 100 days after transplant (CIII). For example, recipients who are hypogammaglobulinemic might receive prophylactic IVIG to prevent bacterial sinopulmonary infections (e.g., from Stre. pneumoniae) (8) (CIII). For hypogammaglobulinemic allogeneic recipients, physicians can use a higher and more frequent dose of IVIG than is standard for non-HSCT recipients because the IVIG half-life among HSCT recipients (generally 1--10 days) is much shorter than the half-life among healthy adults (generally 18--23 days) (56--58). Additionally, infections might accelerate IgG catabolism; therefore, the IVIG dose for a hypogammaglobulinemic recipient should be individualized to maintain trough serum IgG concentrations >400--500 mg/dl (58) (BII). Consequently, physicians should monitor trough serum IgG concentrations among these patients approximately every 2 weeks and adjust IVIG doses as needed (BIII) (Appendix).

Preventing Late Disease (>100 Days After HSCT). Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic resistance patterns. In the absence of severe demonstrable hypogammaglobulinemia (e.g., IgG levels < 400 mg/dl, which might be associated with recurrent sinopulmonary infections), routine monthly IVIG administration to HSCT recipients >90 days after HSCT is not recommended (60) (DI) as a means of preventing bacterial infections.

Other Disease Prevention Recommendations. Routine use of IVIG among autologous recipients is not recommended (61) (DII). Recommendations for preventing bacterial infections are the same among pediatric or adult HSCT recipients.

Preventing Exposure

Appropriate care precautions should be taken with hospitalized patients infected with Stre. pneumoniae (62,63) (BIII) to prevent exposure among HSCT recipients.

Preventing Disease

Information regarding the currently available 23-valent pneumococcal polysaccharide vaccine indicates limited immunogenicity among HSCT recipients. However, because of its potential benefit to certain patients, it should be administered to HSCT recipients at 12 and 24 months after HSCT (64--66) (BIII). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, and Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Trimethoprim-sulfamethasaxole (TMP-SMZ) administered for Pneumocystis carinii pneumonia (PCP) prophylaxis will also provide protection against pneumococcal infections. However, no data were found to support using TMP-SMZ prophylaxis among HSCT recipients solely for the purpose of preventing Stre. pneumoniae disease. Certain strains of Stre. pneumoniae are resistant to TMP-SMZ and penicillin. Recommendations for preventing pneumococcal infections are the same for allogeneic or autologous recipients.

As with adults, pediatric HSCT recipients aged >2 years should be administered the current 23-valent pneumococcal polysaccharide vaccine because the vaccine can be effective (BIII). However, this vaccine should not be administered to children aged <2 years because it is not effective among that age population (DI). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among pediatric HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.

Preventing Exposure

Because Streptococci viridans colonize the oropharynx and gut, no effective method of preventing exposure is known.

Preventing Disease

Chemotherapy-induced oral mucositis is a potential source of Streptococci viridans bacteremia. Consequently, before conditioning starts, dental consults should be obtained for all HSCT candidates to assess their state of oral health and to perform any needed dental procedures to decrease the risk for oral infections after transplant (67) (AIII).

Generally, HSCT physicians should not use prophylactic antibiotics to prevent Streptococci viridans infections (DIII). No data were found that demonstrate efficacy of prophylactic antibiotics for this infection. Furthermore, such use might select antibiotic-resistant bacteria, and in fact, penicillin- and vancomycin-resistant strains of Streptococci viridans have been reported (68). However, when Streptococci viridans infections among HSCT recipients are virulent and associated with overwhelming sepsis and shock in an institution, prophylaxis might be evaluated (CIII). Decisions regarding the use of Streptococci viridans prophylaxis should be made only after consultation with the hospital epidemiologists or infection-control practitioners who monitor rates of nosocomial bacteremia and bacterial susceptibility (BIII).

HSCT physicians should be familiar with current antibiotic susceptibilities for patient isolates from their HSCT centers, including Streptococci viridans (BIII). Physicians should maintain a high index of suspicion for this infection among HSCT recipients with symptomatic mucositis because early diagnosis and aggressive therapy are currently the only potential means of preventing shock when severely neutropenic HSCT recipients experience Streptococci viridans bacteremia (69).

Preventing Exposure

Adults with Ha. influenzae type b (Hib) pneumonia require standard precautions (62) to prevent exposing the HSCT recipient to Hib. Adults and children who are in contact with the HSCT recipient and who have known or suspected invasive Hib disease, including meningitis, bacteremia, or epiglottitis, should be placed in droplet precautions until 24 hours after they begin appropriate antibiotic therapy, after which they can be switched to standard precautions. Household contacts exposed to persons with Hib disease and who also have contact with HSCT recipients should be administered rifampin prophylaxis according to published recommendations (70,71); prophylaxis for household contacts of a patient with Hib disease are necessary if all contacts aged <4 years are not fully vaccinated (BIII) (Appendix). This recommendation is critical because the risk for invasive Hib disease among unvaccinated household contacts aged <4 years is increased, and rifampin can be effective in eliminating Hib carriage and preventing invasive Hib disease (72--74). Pediatric household contacts should be up-to-date with Hib vaccinations to prevent possible Hib exposure to the HSCT recipient (AII).

Preventing Disease

Although no data regarding vaccine efficacy among HSCT recipients were found, Hib conjugate vaccine should be administered to HSCT recipients at 12, 14, and 24 months after HSCT (BII). This vaccine is recommended because the majority of HSCT recipients have low levels of Hib capsular polysaccharide antibodies >4 months after HSCT (75), and allogeneic recipients with chronic GVHD are at increased risk for infection from encapsulated organisms (e.g., Hib) (76,77). HSCT recipients who are exposed to persons with Hib disease should be offered rifampin prophylaxis according to published recommendations (70) (BIII) (Appendix).

Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59) (BIII). Antibiotic selection should be guided by local antibiotic-resistance patterns. Recommendations for preventing Hib infections are the same for allogeneic or autologous recipients. Recommendations for preventing Hib disease are the same for pediatric or adult HSCT recipients, except that any child infected with Hib pneumonia requires standard precautions with droplet precautions added for the first 24 hours after beginning appropriate antibiotic therapy (62,70) (BIII). Appropriate pediatric doses should be administered for Hib conjugate vaccine and for rifampin prophylaxis (71) (Appendix).

Preventing Exposure

HSCT candidates should be tested for the presence of serum anti-CMV IgG antibodies before transplantation to determine their risk for primary CMV infection and reactivation after HSCT (AIII). Only Food and Drug Administration (FDA) licensed or approved tests should be used. HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others, including family members, to decrease the risk for CMV exposure (BIII).

Sexually active patients who are not in long-term monogamous relationships should always use latex condoms during sexual contact to reduce their risk for exposure to CMV and other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for CMV infections. Therefore, during periods of immuno-compromise, sexually active HSCT recipients in monogamous relationships should ask partners to be tested for serum CMV IgG antibody, and discordant couples should use latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII).

After handling or changing diapers or after wiping oral and nasal secretions, HSCT candidates and recipients should practice regular hand washing to reduce the risk for CMV exposure (AII). CMV-seronegative recipients of allogeneic stem cell transplants from CMV-seronegative donors (i.e., R-negative or D-negative) should receive only leukocyte-reduced or CMV-seronegative red cells or leukocyte-reduced platelets (<1 x 106 leukocytes/unit) to prevent transfusion-associated CMV infection (78) (AI). However, insufficient data were found to recommend use of leukocyte-reduced or CMV-seronega tive red cells and platelets among CMV-seronegative recipients who have CMV-seropositive donors (i.e., R-negative or D-positive).

All HCWs should wear gloves when handling blood products or other potentially contaminated biologic materials (AII) to prevent transmission of CMV to HSCT recipients. HSCT patients who are known to excrete CMV should be placed under standard precautions (62) for the duration of CMV excretion to avoid possible transmission to CMV-seronegative HSCT recipients and candidates (AIII). Physicians are cautioned that CMV excretion can be episodic or prolonged.

Preventing Disease and Disease Recurrence

HSCT recipients at risk for CMV disease after HSCT (i.e., all CMV-seropositive HSCT recipients, and all CMV-seronegative recipients with a CMV-seropositive donor) should be placed on a CMV disease prevention program from the time of engraftment until 100 days after HSCT (i.e., phase II) (AI). Physicians should use either prophylaxis or preemptive treatment with ganciclovir for allogeneic recipients (AI). In selecting a CMV disease prevention strategy, physicians should assess the risks and benefits of each strategy, the needs and condition of the patient, and the hospital's virology laboratory support capability.

Prophylaxis strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients involves administering ganciclovir prophylaxis to all allogeneic recipients at risk throughout phase II (i.e., from engraftment to 100 days after HSCT). The induction course is usually started at engraftment (AI), although physicians can add a brief prophylactic course during HSCT preconditioning (CIII) (Appendix).

Preemptive strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients is preferred over prophylaxis for CMV-seronegative HSCT recipients of seropositive donor cells (i.e., D-positive or R-negative) because of the low attack rate of active CMV infection if screened or filtered blood product support is used (BII). Preemptive strategy restricts ganciclovir use for those patients who have evidence of CMV infection after HSCT. It requires the use of sensitive and specific laboratory tests to rapidly diagnose CMV infection after HSCT and to enable immediate administration of ganciclovir after CMV infection has been detected. Allogeneic recipients at risk should be screened >1 times/week from 10 days to 100 days after HSCT (i.e., phase II) for the presence of CMV viremia or antigenemia (AIII).

HSCT physicians should select one of two diagnostic tests to determine the need for preemptive treatment. Currently, the detection of CMV pp65 antigen in leukocytes (antigenemia) (79,80) is preferred for screening for preemptive treatment because it is more rapid and sensitive than culture and has good positive predictive value (79--81). Direct detection of CMV-DNA (deoxyribonucleic acid) by polymerase chain reaction (PCR) (82) is very sensitive but has a low positive predictive value (79). Although CMV-DNA PCR is less sensitive than whole blood or leukocyte PCR, plasma CMV-DNA PCR is useful during neutropenia, when the number of leukocytes/slide is too low to allow CMV pp65 antigenemia testing.

Virus culture of urine, saliva, blood, or bronchoalveolar washings by rapid shell-vial culture (83) or routine culture (84,85) can be used; however, viral culture techniques are less sensitive than CMV-DNA PCR or CMV pp65 antigenemia tests. Also, rapid shell-viral cultures require >48 hours and routine viral cultures can require weeks to obtain final results. Thus, viral culture techniques are less satisfactory than PCR or antigenemia tests. HSCT centers without access to PCR or antigenemia tests should use prophylaxis rather than preemptive therapy for CMV disease prevention (86) (BII). Physicians do use other diagnostic tests (e.g., hybrid capture CMV-DNA assay, Version 2.0 [87] or CMV pp67 viral RNA [ribonucleic acid] detection) (88); however, limited data were found regarding use among HSCT recipients, and therefore, no recommendation for use can be made.

Allogeneic recipients <100 days after HSCT (i.e., during phase II) should begin preemptive treatment with ganciclovir if CMV viremia or any antigenemia is detected or if the recipient has >2 consecutively positive CMV-DNA PCR tests (BIII). After preemptive treatment has been started, maintenance ganciclovir is usually continued until 100 days after HSCT or for a minimum of 3 weeks, whichever is longer (AI) (Appendix). Antigen or PCR tests should be negative when ganciclovir is stopped. Studies report that a shorter course of ganciclovir (e.g., for 3 weeks or until negative PCR or antigenemia occurs) (89--91) might provide adequate CMV prevention with less toxicity, but routine weekly screening by pp65 antigen or PCR test is necessary after stopping ganciclovir because CMV reactivation can occur (BIII).

Presently, only the intravenous formulation of ganciclovir has been approved for use in CMV prophylactic or preemptive strategies (BIII). No recommendation for oral ganciclovir use among HSCT recipients can be made because clinical trials evaluating its efficacy are still in progress. One group has used ganciclovir and foscarnet on alternate days for CMV prevention (92), but no recommendation can be made regarding this strategy because of limited data. Patients who are ganciclovir-intolerant should be administered foscarnet instead (93) (BII) (Appendix). HSCT recipients receiving ganciclovir should have ANCs checked >2 times/week (BIII). Researchers report managing ganciclovir-associated neutropenia by adding G-CSF (94) or temporarily stopping ganciclovir for >2 days if the patient's ANC is <1,000 (CIII). Ganciclovir can be restarted when the patient's ANC is >1,000 for 2 consecutive days. Alternatively, researchers report substituting foscarnet for ganciclovir if a) the HSCT recipient is still CMV viremic or antigenemic or b) the ANC remains <1,000 for >5 days after ganciclovir has been stopped (CIII) (Appendix). Because neutropenia accompanying ganciclovir administration is usually brief, such patients do not require antifungal or antibacterial prophylaxis (DIII).

Currently, no benefit has been reported from routinely administering ganciclovir prophylaxis to all HSCT recipients at >100 days after HSCT (i.e., during phase III). However, persons with high risk for late CMV disease should be routinely screened biweekly for evidence of CMV reactivation as long as substantial immunocompromise persists (BIII). Risk factors for late CMV disease include allogeneic HSCT accompanied by chronic GVHD, steroid use, low CD4 counts, delay in high avidity anti-CMV antibody, and recipients of matched unrelated or T-cell--depleted HSCTs who are at high risk (95--99). If CMV is still detectable by routine screening >100 days after HSCT, ganciclovir should be continued until CMV is no longer detectable (AI). If low-grade CMV antigenemia (<5 positive cells/slide) is detected on routine screening, the antigenemia test should be repeated in 3 days (BIII). If CMV antigenemia indicates >5 cells/slide, PCR is positive, or the shell-vial culture detects CMV viremia, a 3-week course of preemptive ganciclovir treatment should be administered (BIII) (Appendix). Ganciclovir should also be started if the patient has had >2 consecutively positive viremia or PCR tests (e.g., in a person receiving steroids for GVHD or who received ganciclovir or foscarnet at <100 days after HSCT). Current investigational strategies for preventing late CMV disease include the use of targeted prophylaxis with antiviral drugs and cellular immunotherapy for those with deficient or absent CMV-specific immune system function.

If viremia persists after 4 weeks of ganciclovir preemptive therapy or if the level of antigenemia continues to rise after 3 weeks of therapy, ganciclovir-resistant CMV should be suspected. If CMV viremia recurs during continuous treatment with ganciclovir, researchers report restarting ganciclovir induction (100) or stopping ganciclovir and starting foscarnet (CIII). Limited data were found regarding the use of foscarnet among HSCT recipients for either CMV prophylaxis or preemptive therapy (92,93).

Infusion of donor-derived CMV-specific clones of CD8+ T-cells into the transplant recipient is being evaluated under FDA Investigational New Drug authorization; therefore, no recommendation can be made. Although, in a substantial cooperative study, high-dose acyclovir has had certain efficacy for preventing CMV disease (101), its utility is limited in a setting where more potent anti-CMV agents (e.g., ganciclovir) are used (102). Acyclovir is not effective in preventing CMV disease after autologous HSCT (103) and is, therefore, not recommended for CMV preemptive therapy (DII). Consequently, valacyclovir, although under study for use among HSCT recipients, is presumed to be less effective than ganciclovir against CMV and is currently not recommended for CMV disease prevention (DII).

Although HSCT physicians continue to use IVIG for immune system modulation, IVIG is not recommended for CMV disease prophylaxis among HSCT recipients (DI). Cidofovir, a nucleoside analog, is approved by FDA for the treatment of AIDS-associated CMV retinitis. The drug's major disadvantage is nephrotoxicity. Cidofovir is currently in FDA phase 1 trial for use among HSCT recipients; therefore, recommendations for its use cannot be made.

Use of CMV-negative or leukocyte-reduced blood products is not routinely required for all autologous recipients because most have a substantially lower risk for CMV disease. However, CMV-negative or leukocyte-reduced blood products can be used for CMV-seronegative autologous recipients (CIII). Researchers report that CMV-seropositive autologous recipients be evaluated for preemptive therapy if they have underlying hematologic malignancies (e.g., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-chlorodeoxyadenosine (CDA) (CIII). This subpopulation of autologous recipients should be monitored weekly from time of engraftment until 60 days after HSCT for CMV reactivation, preferably with quantitative CMV pp65 antigen (80) or quantitative PCR (BII).

Autologous recipients at high risk who experience CMV antigenemia (i.e., blood levels of >5 positive cells/slide) should receive 3 weeks of preemptive treatment with ganciclovir or foscarnet (80), but CD34+-selected patients should be treated at any level of antigenemia (BII) (Appendix). Prophylactic approach to CMV disease prevention is not appropriate for CMV-seropositive autologous recipients. Indications for the use of CMV prophylaxis or preemptive treatment are the same for children or adults.

Preventing Exposure

All transplant candidates, particularly those who are EBV-seronegative, should be advised of behaviors that could decrease the likelihood of EBV exposure (AII). For example, HSCT recipients and candidates should follow safe hygiene practices (e.g., frequent hand washing [AIII] and avoiding the sharing of cups, glasses, and eating utensils with others) (104) (BIII), and they should avoid contact with potentially infected respiratory secretions and saliva (104) (AII).

Preventing Disease

Infusion of donor-derived, EBV-specific cytotoxic T-lymphocytes has demonstrated promise in the prophylaxis of EBV-lymphoma among recipients of T-cell--depleted unrelated or mismatched allogeneic recipients (105,106). However, insufficient data were found to recommend its use. Prophylaxis or preemptive therapy with acyclovir is not recommended because of lack of efficacy (107,108) (DII).

Preventing Exposure

HSCT candidates should be tested for serum anti-HSV IgG before transplant (AIII); however, type-specific anti-HSV IgG serology testing is not necessary. Only FDA-licensed or -approved tests should be used. All HSCT candidates, particularly those who are HSV-seronegative, should be informed of the importance of avoiding HSV infection while immunocompromised and should be advised of behaviors that will decrease the likelihood of HSV exposure (AII). HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others (BIII). Sexually active patients who are not in a long-term monogamous relationship should always use latex condoms during sexual contact to reduce the risk for exposure to HSV as well as other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for HSV infections. Therefore, during periods of immunocompromise, sexually active HSCT recipients in such relationships should ask partners to be tested for serum HSV IgG antibody. If the partners are discordant, they should consider using latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII). Any person with disseminated, primary, or severe mucocutaneous HSV disease should be placed under contact precautions for the duration of the illness (62) (AI) to prevent transmission of HSV to HSCT recipients.

Preventing Disease and Disease Recurrence

Acyclovir. Acyclovir prophylaxis should be offered to all HSV-seropositive allogeneic recipients to prevent HSV reactivation during the early posttransplant period (109--113) (AI). Standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and continue until engraftment occurs or until mucositis resolves, whichever is longer, or approximately 30 days after HSCT (BIII) (Appendix). Without supportive data from controlled studies, routine use of antiviral prophylaxis for >30 days after HSCT to prevent HSV is not recommended (DIII). Routine acyclovir prophylaxis is not indicated for HSV-seronegative HSCT recipients, even if the donors are HSV-seropositive (DIII). Researchers have proposed administration of ganciclovir prophylaxis alone (86) to HSCT recipients who required simultaneous prophylaxis for CMV and HSV after HSCT (CIII) because ganciclovir has in vitro activity against CMV and HSV 1 and 2 (114), although ganciclovir has not been approved for use against HSV.

Valacyclovir. Researchers have reported valacyclovir use for preventing HSV among HSCT recipients (CIII); however, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome among HSCT recipients (115). Controlled trial data among HSCT recipients are limited (115), and the FDA has not approved valacyclovir for use among recipients. Physicians wishing to use valacyclovir among recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix).

Foscarnet. Because of its substantial renal and infusion-related toxicity, foscarnet is not recommended for routine HSV prophylaxis among HSCT recipients (DIII).

Famciclovir. Presently, data regarding safety and efficacy of famciclovir among HSCT recipients are limited; therefore, no recommendations for HSV prophylaxis with famciclovir can be made.

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Guidelines for Preventing Opportunistic Infections Among ...

Skin Stem Cells Comments Off on Guidelines for Preventing Opportunistic Infections Among … | October 12th, 2016

Some cells are visible to the unaided eye

The smallest objects that the unaided human eye can see are about 0.1 mm long. That means that under the right conditions, you might be able to see an ameoba proteus, a human egg, and a paramecium without using magnification. A magnifying glass can help you to see them more clearly, but they will still look tiny.

Smaller cells are easily visible under a light microscope. It's even possible to make out structures within the cell, such as the nucleus, mitochondria and chloroplasts. Light microscopes use a system of lenses to magnify an image. The power of a light microscope is limited by the wavelength of visible light, which is about 500 nm. The most powerful light microscopes can resolve bacteria but not viruses.

To see anything smaller than 500 nm, you will need an electron microscope. Electron microscopes shoot a high-voltage beam of electrons onto or through an object, which deflects and absorbs some of the electrons. Resolution is still limited by the wavelength of the electron beam, but this wavelength is much smaller than that of visible light. The most powerful electron microscopes can resolve molecules and even individual atoms.

The label on the nucleotide is not quite accurate. Adenine refers to a portion of the molecule, the nitrogenous base. It would be more accurate to label the nucleotide deoxyadenosine monophosphate, as it includes the sugar deoxyribose and a phosphate group in addition to the nitrogenous base. However, the more familiar "adenine" label makes it easier for people to recognize it as one of the building blocks of DNA.

No, this isn't a mistake. First, there's less DNA in a sperm cell than there is in a non-reproductive cell such as a skin cell. Second, the DNA in a sperm cell is super-condensed and compacted into a highly dense form. Third, the head of a sperm cell is almost all nucleus. Most of the cytoplasm has been squeezed out in order to make the sperm an efficient torpedo-like swimming machine.

The X chromosome is shown here in a condensed state, as it would appear in a cell that's going through mitosis. It has also been duplicated, so there are actually two identical copies stuck together at their middles. A human sperm cell contains just one copy each of 23 chromosomes.

A chromosome is made up of genetic material (one long piece of DNA) wrapped around structural support proteins (histones). Histones organize the DNA and keep it from getting tangled, much like thread wrapped around a spool. But they also add a lot of bulk. In a sperm cell, a specialized set of tiny support proteins (protamines) pack the DNA down to about one-sixth the volume of a mitotic chromosome.

The size of the carbon atom is based on its van der Waals radius.

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Cell Size and Scale - Learn Genetics

Skin Stem Cells Comments Off on Cell Size and Scale – Learn Genetics | October 7th, 2016

Open Access

Article

The Arabidopsis CERK1associated kinase PBL27 connects chitin perception to MAPK activation

These authors contributed equally to this work as first authors

These authors contributed equally to this work as third authors

Chitin receptor CERK1 transmits immune signals to the intracellular MAPK cascade in plants. This occurs via phosphorylation of MAPKKK5 by the CERK1associated kinase PBL27, providing a missing link between pathogen perception and signaling output.

Chitin receptor CERK1 transmits immune signals to the intracellular MAPK cascade in plants. This occurs via phosphorylation of MAPKKK5 by the CERK1associated kinase PBL27, providing a missing link between pathogen perception and signaling output.

CERK1associated kinase PBL27 interacts with MAPKKK5 at the plasma membrane.

Chitin perception induces disassociation of PBL27 and MAPKKK5.

PBL27 functions as a MAPKKK kinase.

Phosphorylation of MAPKKK5 by PBL27 is enhanced upon phosphorylation of PBL27 by CERK1.

Phosphorylation of MAPKKK5 by PBL27 is required for chitininduced MAPK activation in planta.

Kenta Yamada, Koji Yamaguchi, Tomomi Shirakawa, Hirofumi Nakagami, Akira Mine, Kazuya Ishikawa, Masayuki Fujiwara, Mari Narusaka, Yoshihiro Narusaka, Kazuya Ichimura, Yuka Kobayashi, Hidenori Matsui, Yuko Nomura, Mika Nomoto, Yasuomi Tada, Yoichiro Fukao, Tamo Fukamizo, Kenichi Tsuda, Ken Shirasu, Naoto Shibuya, Tsutomu Kawasaki

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Skin Stem Cells Comments Off on Home | The EMBO Journal | October 6th, 2016

Do you ever wonder what makes up blood? Unless you need to have blood drawn, donate it or have to stop its flow after an injury, you probably don't think much about it. But blood is the most commonly tested part of the body, and it is truly the river of life. Every cell in the body gets its nutrients from blood. Understanding blood will help you as your doctor explains the results of your blood tests. In addition, you will learn amazing things about this incredible fluid and the cells in it.

Blood is a mixture of two components: cells and plasma. The heart pumps blood through the arteries, capillaries and veins to provide oxygen and nutrients to every cell of the body. The blood also carries away waste products.

The adult human body contains approximately 5 liters (5.3 quarts) of blood; it makes up 7 to 8 percent of a person's body weight. Approximately 2.75 to 3 liters of blood is plasma and the rest is the cellular portion.

Plasma is the liquid portion of the blood. Blood cells like red blood cells float in the plasma. Also dissolved in plasma are electrolytes, nutrients and vitamins (absorbed from the intestines or produced by the body), hormones, clotting factors, and proteins such as albumin and immunoglobulins (antibodies to fight infection). Plasma distributes the substances it contains as it circulates throughout the body.

The cellular portion of blood contains red blood cells (RBCs), white blood cells (WBCs) and platelets. The RBCs carry oxygen from the lungs; the WBCs help to fight infection; and platelets are parts of cells that the body uses for clotting. All blood cells are produced in the bone marrow. As children, most of our bones produce blood. As we age this gradually diminishes to just the bones of the spine (vertebrae), breastbone (sternum), ribs, pelvis and small parts of the upper arm and leg. Bone marrow that actively produces blood cells is called red marrow, and bone marrow that no longer produces blood cells is called yellow marrow. The process by which the body produces blood is called hematopoiesis. All blood cells (RBCs, WBCs and platelets) come from the same type of cell, called the pluripotential hematopoietic stem cell. This group of cells has the potential to form any of the different types of blood cells and also to reproduce itself. This cell then forms committed stem cells that will form specific types of blood cells.

We'll learn more about red blood cells in detail next.

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How Blood Works | HowStuffWorks

Skin Stem Cells Comments Off on How Blood Works | HowStuffWorks | October 5th, 2016

An adult stem cell is thought to be an undifferentiated cell, found among differentiated cells in a tissue or organ. The adult stem cell can renew itself and can differentiate to yield some or all of the major specialized cell types of the tissue or organ. The primary roles of adult stem cells in a living organism are to maintain and repair the tissue in which they are found. Scientists also use the term somatic stem cell instead of adult stem cell, where somatic refers to cells of the body (not the germ cells, sperm or eggs). Unlike embryonic stem cells, which are defined by their origin (cells from the preimplantation-stage embryo), the origin of adult stem cells in some mature tissues is still under investigation.

Research on adult stem cells has generated a great deal of excitement. Scientists have found adult stem cells in many more tissues than they once thought possible. This finding has led researchers and clinicians to ask whether adult stem cells could be used for transplants. In fact, adult hematopoietic, or blood-forming, stem cells from bone marrow have been used in transplants for more than 40 years. Scientists now have evidence that stem cells exist in the brain and the heart, two locations where adult stem cells were not at firstexpected to reside. If the differentiation of adult stem cells can be controlled in the laboratory, these cells may become the basis of transplantation-based therapies.

The history of research on adult stem cells began more than 60 years ago. In the 1950s, researchers discovered that the bone marrow contains at least two kinds of stem cells. One population, called hematopoietic stem cells, forms all the types of blood cells in the body. A second population, called bone marrow stromal stem cells (also called mesenchymal stem cells, or skeletal stem cells by some), were discovered a few years later. These non-hematopoietic stem cells make up a small proportion of the stromal cell population in the bone marrow and can generate bone, cartilage, and fat cells that support the formation of blood and fibrous connective tissue.

In the 1960s, scientists who were studying rats discovered two regions of the brain that contained dividing cells that ultimately become nerve cells. Despite these reports, most scientists believed that the adult brain could not generate new nerve cells. It was not until the 1990s that scientists agreed that the adult brain does contain stem cells that are able to generate the brain's three major cell typesastrocytes and oligodendrocytes, which are non-neuronal cells, and neurons, or nerve cells.

Adult stem cells have been identified in many organs and tissues, including brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis. They are thought to reside in a specific area of each tissue (called a "stem cell niche"). In many tissues, current evidence suggests that some types of stem cells are pericytes, cells that compose the outermost layer of small blood vessels. Stem cells may remain quiescent (non-dividing) for long periods of time until they are activated by a normal need for more cells to maintain tissues, or by disease or tissue injury.

Typically, there is a very small number of stem cells in each tissue and, once removed from the body, their capacity to divide is limited, making generation of large quantities of stem cells difficult. Scientists in many laboratories are trying to find better ways to grow large quantities of adult stem cells in cell culture and to manipulate them to generate specific cell types so they can be used to treat injury or disease. Some examples of potential treatments include regenerating bone using cells derived from bone marrow stroma, developing insulin-producing cells for type1 diabetes, and repairing damaged heart muscle following a heart attack with cardiac muscle cells.

Scientists often use one or more of the following methods to identify adult stem cells: (1) label the cells in a living tissue with molecular markers and then determine the specialized cell types they generate; (2) remove the cells from a living animal, label them in cell culture, and transplant them back into another animal to determine whether the cells replace (or "repopulate") their tissue of origin.

Importantly, scientists must demonstrate that a single adult stem cell can generate a line of genetically identical cells that then gives rise to all the appropriate differentiated cell types of the tissue. To confirm experimentally that a putative adult stem cell is indeed a stem cell, scientists tend to show either that the cell can give rise to these genetically identical cells in culture, and/or that a purified population of these candidate stem cells can repopulate or reform the tissue after transplant into an animal.

As indicated above, scientists have reported that adult stem cells occur in many tissues and that they enter normal differentiation pathways to form the specialized cell types of the tissue in which they reside.

Normal differentiation pathways of adult stem cells. In a living animal, adult stem cells are available to divide for a long period, when needed, and can give rise to mature cell types that have characteristic shapes and specialized structures and functions of a particular tissue. The following are examples of differentiation pathways of adult stem cells (Figure 2) that have been demonstrated in vitro or in vivo.

Figure 2. Hematopoietic and stromal stem cell differentiation. Click here for larger image. ( 2008 Terese Winslow)

Transdifferentiation. A number of experiments have reported that certain adult stem cell types can differentiate into cell types seen in organs or tissues other than those expected from the cells' predicted lineage (i.e., brain stem cells that differentiate into blood cells or blood-forming cells that differentiate into cardiac muscle cells, and so forth). This reported phenomenon is called transdifferentiation.

Although isolated instances of transdifferentiation have been observed in some vertebrate species, whether this phenomenon actually occurs in humans is under debate by the scientific community. Instead of transdifferentiation, the observed instances may involve fusion of a donor cell with a recipient cell. Another possibility is that transplanted stem cells are secreting factors that encourage the recipient's own stem cells to begin the repair process. Even when transdifferentiation has been detected, only a very small percentage of cells undergo the process.

In a variation of transdifferentiation experiments, scientists have recently demonstrated that certain adult cell types can be "reprogrammed" into other cell types in vivo using a well-controlled process of genetic modification (see Section VI for a discussion of the principles of reprogramming). This strategy may offer a way to reprogram available cells into other cell types that have been lost or damaged due to disease. For example, one recent experiment shows how pancreatic beta cells, the insulin-producing cells that are lost or damaged in diabetes, could possibly be created by reprogramming other pancreatic cells. By "re-starting" expression of three critical beta cell genes in differentiated adult pancreatic exocrine cells, researchers were able to create beta cell-like cells that can secrete insulin. The reprogrammed cells were similar to beta cells in appearance, size, and shape; expressed genes characteristic of beta cells; and were able to partially restore blood sugar regulation in mice whose own beta cells had been chemically destroyed. While not transdifferentiation by definition, this method for reprogramming adult cells may be used as a model for directly reprogramming other adult cell types.

In addition to reprogramming cells to become a specific cell type, it is now possible to reprogram adult somatic cells to become like embryonic stem cells (induced pluripotent stem cells, iPSCs) through the introduction of embryonic genes. Thus, a source of cells can be generated that are specific to the donor, thereby increasing the chance of compatibility if such cells were to be used for tissue regeneration. However, like embryonic stem cells, determination of the methods by which iPSCs can be completely and reproducibly committed to appropriate cell lineages is still under investigation.

Many important questions about adult stem cells remain to be answered. They include:

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On behalf of the organizing committee, it is my distinct pleasure to invite you to attend the Stem Cell Congress-2017. After the success of the Cell Science-2011, 2012, 2013, 2014, 2015, Conference series.LLC is proud to announce the 6th World Congress and expo on Cell & Stem Cell Research (Stem Cell Congress-2017) which is going to be held during March 20-22, 2017, Orlando, Florida, USA. The theme of Stem Cell Congress-2017 is Explore and Exploit the Novel Techniques in Cell and Stem Cell Research.

This annual Cell Science conference brings together domain experts, researchers, clinicians, industry representatives, postdoctoral fellows and students from around the world, providing them with the opportunity to report, share, and discuss scientific questions, achievements, and challenges in the field.

Examples of the diverse cell science and stem cell topics that will be covered in this comprehensive conference include Cell differentiation and development, Cell metabolism, Tissue engineering and regenerative medicine, Stem cell therapy, Cell and gene therapy, Novel stem cell technologies, Stem cell and cancer biology, Stem cell treatment, Tendency in cell biology of aging and Apoptosis and cancer disease, Drugs and clinical developments. The meeting will focus on basic cell mechanism studies, clinical research advances, and recent breakthroughs in cell and stem cell research. With the support of many emerging technologies, dramatic progress has been made in these areas. In Stem Cell Congress-2017, you will be able to share experiences and research results, discuss challenges encountered and solutions adopted and have opportunities to establish productive new academic and industry research collaborations.

In association with the Stem Cell Congress-2017 conference, we will invite those selected to present at the meeting to publish a manuscript from their talk in the journal Cell Science with a significantly discounted publication charge. Please join us in Philadelphia for an exciting all-encompassing annual Stem Cell get together with the theme of better understanding from basic cell mechanisms to latest Stem Cell breakthroughs!

Haval Shirwan, Ph.D. Executive Editor, Journal of Clinical & Cellular Immunology Dr. Michael and Joan Hamilton Endowed Chair in Autoimmune Disease Professor, Department of Microbiology and Immunology Director, Molecular Immunomodulation Program, Institute for Cellular Therapeutics, University of Louisville, Louisville, KY

Track01:Stem Cells

The most well-established and widely used stem cell treatment is thetransplantationof blood stem cells to treat diseases and conditions of the blood and immune system, or to restore the blood system after treatments for specific cancers. Since the 1970s,skin stem cellshave been used to grow skin grafts for patients with severe burns on very large areas of the body. Only a few clinical centers are able to carry out this treatment and it is usually reserved for patients with life-threatening burns. It is also not a perfect solution: the new skin has no hair follicles or sweat glands. Research aimed at improving the technique is ongoing.

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7thAnnual Conference on Stem Cell and Regenerative MedicineAug 4-5, 2016, Manchester, UK;2nd InternationalConference on AntibodiesJuly 14-15, 2016 Philadelphia, USA; 2nd InternationalConference on Innate ImmunityJuly 21-22, 2016 Berlin, Germany; 2ndInternational Congress on Neuroimmunology March 31-April 02, 2016 Atlanta, USA; InternationalConference on Cancer Immunology July 28-30, 2016 Melbourne, Australia; 5th InternationalConference on ImmunologyOctober 24-26, 2016 Chicago, USA;Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Mar 610 2016, Whistler, Canada;Systems Immunology: From Molecular Networks to Human Biology, Jan 1014 2016, Big Sky, USA;Novel Immunotherapeutics Summit, Jan 2526 2016, San Diego, USA;Stromal Cells in Immunity, Feb 711 2016, Keystone, USA; 26th European Congress ofClinical Microbiology, April 912 2016, Istanbul, Turkey

Track 02: Stem Cell Banking:

Stem Cell Banking is a facility that preserves stem cells derived from amniotic fluid for future use. Stem cell samples in private or family banks are preserved precisely for use by the individual person from whom such cells have been collected and the banking costs are paid by such person. The sample can later be retrieved only by that individual and for the use by such individual or, in many cases, by his or her first-degree blood relatives.

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8thWorld Congress on Stem Cell ResearchMarch 20-22, 2017 Orlando, USAInternationalConference on Cancer ImmunologyJuly 28-30, 2016 Melbourne, Australia; 5th InternationalConference on ImmunologyOctober 24-26, 2016 Chicago, USA;Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Mar 610 2016, Whistler, Canada;Systems Immunology: From Molecular Networks to Human Biology, Jan 1014 2016, Big Sky, USA;Novel Immunotherapeutics Summit, Jan 2526 2016, San Diego, USA;Stromal Cells in Immunity, Feb 711 2016, Keystone, USA; 26th European Congress ofClinical Microbiology, April 912 2016, Istanbul, Turkey

Track 03: Stem Cell Therapy:

Autologous cells are obtained from one's own body, just as one may bank his or her own blood for elective surgical procedures. Adult stem cells are frequently used in medical therapies, for example in bone marrow transplantation. Human embryonic stem cells may be grown in vivo and stimulated to produce pancreatic -cells and later transplanted to the patient. Its success depends on response of the patients immune system and ability of the transplanted cells to proliferate, differentiate and integrate with the target tissue.

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4th InternationalConference on Plant GenomicsJuly 14-15, 2016 Brisbane, Australia; 8thWorld Congress on Stem Cell ResearchMarch 20-22, 2017 Orlando, USA; 7thAnnual Conference on Stem Cell and Regenerative MedicineAug 4-5, 2016, Manchester, UK; 2nd InternationalConference on Tissue preservation and BiobankingSeptember 12-13, 2016 Philadelphia, USA, USA;World Congress on Human GeneticsOctober 31- November 02, 2016 Valencia, Spain; 12thEuro Biotechnology CongressNovember 7-9, 2016 Alicante, Spain; 2nd InternationalConference on Germplasm of Ornamentals, Aug 8-12, 2016, Atlanta, USA; 7th Internationalconference on Crop Science, Aug 1419 2016, Beijing, China;Plant Epigenetics: From Genotype to Phenotype, Feb 1519 2016, Taos, USA;Germline Stem Cells Conference, June 1921 2016, San Francisco, USA;Conference on Water Stressin Plants, 29 May 3 June 2016, Ormont-Dessus, Switzerland

Track 04: Novel Stem Cell Technologies:

Stem cell technology is a rapidly developing field that combines the efforts of cell biologists, geneticists, and clinicians and offers hope of effective treatment for a variety of malignant and non-malignant diseases. Stem cells are defined as totipotent progenitor cells capable of self-renewal and multilineage differentiation. Stem cells survive well and show stable division in culture, making them ideal targets for in vitro manipulation. Although early research has focused on haematopoietic stem cells, stem cells have also been recognised in other sites. Research into solid tissue stem cells has not made the same progress as that on haematopoietic stem cells.

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InternationalConference on Next Generation SequencingJuly 21-22, 2016 Berlin, Germany; 5th InternationalConference on Computational Systems BiologyAugust 22-23, 2016 Philadelphia, USA; 7th InternationalConference on BioinformaticsOctober 27-28, 2016 Chicago, USA; InternationalConference on Synthetic BiologySeptember 28-30, 2015 Houston, USA; 4th InternationalConference on Integrative BiologyJuly 18-20, 2016 Berlin, Germany; 1st InternationalConference on Pharmaceutical BioinformaticsJan 2426 2016, Pattaya, Thailand; EMBL Conference: TheEpitranscriptome, Apr 2022 2016, Heidelberg, Germany; 2016Whole-Cell ModelingSummer School, Apr 38 2016, Barcelona, Spain; 3rd InternationalMolecular Pathological Epidemiology, May 1213 2016, Boston, USA; 5thDrug FormulationSummit, Jan 2527 2016, Philadelphia, USA

Track 05: Stem Cell Treatment:

Bone marrow transplant is the most extensively used stem-cell treatment, but some treatment derived from umbilical cord blood are also in use. Research is underway to develop various sources for stem cells, and to apply stem-cell treatments for neurodegenerative diseases and conditions, diabetes, heart disease, and other conditions.

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7th InternationalConference on BioinformaticsOctober 27-28, 2016 Chicago, USA; InternationalConference on Synthetic BiologySeptember 28-30, 2015 Houston, USA; 7thAnnual Conference on Stem Cell and Regenerative MedicineAug 4-5, 2016, Manchester, UK; 4th InternationalConference on Integrative BiologyJuly 18-20, 2016 Berlin, Germany; 1st InternationalConference on Pharmaceutical BioinformaticsJan 2426 2016, Pattaya, Thailand; EMBL Conference: TheEpitranscriptome, Apr 2022 2016, Heidelberg, Germany; 2016Whole-Cell ModelingSummer School, Apr 38 2016, Barcelona, Spain; 3rd InternationalMolecular Pathological Epidemiology, May 1213 2016, Boston, USA; 5thDrug FormulationSummit, Jan 2527 2016, Philadelphia, USA

Track 06: Stem cell apoptosis and signal transduction:

Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global mRNA decay. Most cytotoxic anticancer agents induce apoptosis, raising the intriguing possibility that defects in apoptotic programs contribute to treatment failure. Because the same mutations that suppress apoptosis during tumor development also reduce treatment sensitivity, apoptosis provides a conceptual framework to link cancer genetics with cancer therapy.

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InternationalConference on Restorative MedicineOctober 24-26, 2016 Chicago, USA;; 3rdWorld Congress onHepatitis and Liver Diseases October 17-19, 2016 Dubai, UAE; InternationalConference on Molecular BiologyOctober 13-15, 2016 Dubai, UAE; 2nd InternationalConference on Tissue preservation and Biobanking September12-13, 2016 Philadelphia USA; 26thEuropean Congress ofClinical Microbiology, April 912 2016, Istanbul, Turkey;Conference onCell Growth and Regeneration, Jan 1014 2016, Breckenridge, USA ;

Track 07: Stem Cell Biomarkers:

Molecular biomarkers serve as valuable tools to classify and isolate embryonic stem cells (ESCs) and to monitor their differentiation state by antibody-based techniques. ESCs can give rise to any adult cell type and thus offer enormous potential for regenerative medicine and drug discovery. A number of biomarkers, such as certain cell surface antigens, are used to assign pluripotent ESCs; however, accumulating evidence suggests that ESCs are heterogeneous in morphology, phenotype and function, thereby classified into subpopulations characterized by multiple sets of molecular biomarkers.

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8thWorld Congress on Stem Cell ResearchMarch 20-22, 2017 Orlando, USA; 5th International Conference onCell and Gene TherapyMay 19-21, 2016 San Antonio, USA; 7thAnnual Conference on Stem Cell and Regenerative MedicineAug 4-5, 2016, Manchester, UK; InternationalConference on Restorative MedicineOctober 24-26, 2016 Chicago, USA; InternationalConference on Molecular BiologyOctober 13-15, 2016 Dubai, UAE; 2nd InternationalConference on Tissue preservation and Biobanking September12-13, 2016 Philadelphia USA;Conference on Cardiac Development, Regeneration and RepairApril 3 7, 2016 Snowbird, Utah, USA; Stem Cell DevelopmentMay 22-26, 2016 Hillerd, Denmark; Conference onHematopoietic Stem Cells, June 3-5, 2016 Heidelberg, Germany; ISSCR Pluripotency - March 22-24, 2016 Kyoto, Japan

Track 08: Cellular therapies:

Cellular therapy also called Cell therapy is therapy in which cellular material is injected into a patient, this generally means intact, living cells. For example, T cells capable of fighting cancer cells via cell-mediated immunity may be injected in the course of immunotherapy.

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InternationalConference on Genetic Counseling and Genomic MedicineAugust 11-12, 2016 Birmingham, UK;World Congress on Human GeneticsOctober 31- November 02, 2016 Valencia, Spain; InternationalConference on Molecular BiologyOctober 13-15, 2016 Dubai, UAE; 3rd InternationalConference on Genomics & PharmacogenomicsSeptember 21-23, 2015 San Antonio, USA; EuropeanConference on Genomics and Personalized MedicineApril 25-27, 2016 Valencia, Spain;Genomics and Personalized Medicine, Feb 711 2016, Banff, Canada; Drug Discovery for Parasitic Diseases, Jan 2428 2016, Tahoe City, USA; Heart Failure: Genetics,Genomics and Epigenetics, April 37 2016, Snowbird, USA; Understanding the Function ofHuman Genome Variation, May 31 June 4 2016, Uppsala, Sweden; 5thDrug Formulation SummitJan2527,2016,Philadelphia, USA

Track 09: Stem cells and cancer:

Cancer can be defined as a disease in which a group of abnormal cells grow uncontrollably by disregarding the normal rules of cell division. Normal cells are constantly subject to signals that dictate whether the cells should divide, differentiate into another cell or die. Cancer cells develop a degree of anatomy from these signals, resulting in uncontrolled growth and proliferation. If this proliferation is allowed to continue and spread, it can be fatal.

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2ndWorld Congress on Applied MicrobiologyOctober 31-November 02, 2016 Istanbul, Turkey; InternationalConference on Infectious Diseases & Diagnostic MicrobiologyOct 3-5, 2016 Vancouver, Canada;18th International conference on Neuroscience, April 26 2016, Sweden, Austria; 6th Annual Traumatic Brain Injury Conference, May 1112 2016, Washington, D.C., USA; Common Mechanisms of Neurodegeneration, June 1216 2016, Keystone, USA; Neurology Caribbean Cruise, Aug 2128 2016, Fort Lauderdale, USA; Annual Meeting of the German Society ofNeurosurgery(DGNC), June 1215 2016, Frankfurt am Main, Germany

Track 10: Embryonic stem cells:

Embryonic stem cells have a major potential for studying early steps of development and for use in cell therapy. In many situations, however, it will be necessary to genetically engineer these cells. A novel generation of lentivectors which permit easy genetic engineering of mouse and human embryonic stem cells.

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4thCongress on Bacteriology and Infectious DiseasesMay 16-18, 2016 San Antonio, USA; 2ndWorld Congress on Applied MicrobiologyOctober 31-November 02, 2016 Istanbul, Turkey; InternationalConference on Infectious Diseases & Diagnostic MicrobiologyOct 3-5, 2016 Vancouver, Canada; InternationalConference on Water MicrobiologyJuly 18-20, 2016 Chicago, USA; 5th InternationalConference on Clinical MicrobiologyOctober 24-26, 2016 Rome, Italy; Axons: FromCell Biologyto Pathology Conference, 2427 January 2016, Santa Fe, USA; 26th EuropeanCongress of Clinical MicrobiologyApril 912 2016, Istanbul, Turkey;Conference on Gut Microbiota, Metabolic Disorders and Beyond, April 1721 2016, Newport, USA; 7th EuropeanSpores Conference, April 1820 2016, Egham, UK; New Approaches to Vaccines forHuman and Veterinary Tropical Diseases, May 2226 2016, Cape Town, South Africa

Track 11: Cell differentiation and disease modeling:

Cellular differentiation is the progression, whereas a cell changes from one cell type to another. Variation occurs numerous times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics. With a few exceptions, cellular differentiationalmost never involves a change in the DNA sequence itself. Thus, different cells can have very different physical characteristics despite having the same genome.

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Track 12: Tissue engineering:

Tissue Engineering is the study of the growth of new connective tissues, or organs, from cells and a collagenous scaffold to produce a fully functional organ for implantation back into the donor host. Powerful developments in the multidisciplinary field of tissue engineering have produced a novel set of tissue replacement parts and implementation approaches. Scientific advances in biomaterials, stem cells, growth and differentiation factors, and biomimetic environments have created unique opportunities to fabricate tissues in the laboratory from combinations of engineered extracellular matrices cells, and biologically active molecules.

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Track 13: Stem cell plasticity and reprogramming:

Stem cell plasticity denotes to the potential of stem cells to give rise to cell types, previously considered outside their normal repertoire of differentiation for the location where they are found. Included under this umbrella title is often the process of transdifferentiation the conversion of one differentiated cell type into another, and metaplasia the conversion of one tissue type into another. From the point of view of this entry, some metaplasias have a clinical significance because they predispose individuals to the development of cancer.

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Track 14: Gene therapy and stem cells

Gene therapy is the therapeutic delivery of nucleic acid polymers into a patient's cells as a drug to treat disease. Gene therapy could be a way to fix a genetic problem at its source. The polymers are either expressed as proteins, interfere with protein expression, or possibly correct genetic mutations. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient's cells instead of using drugs or surgery.

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Track 15: Tumour cell science:

An abnormal mass of tissue. Tumors are a classic sign of inflammation, and can be benign or malignant. Tomour usually reflect the kind of tissue they arise in. Treatment is also specific to the location and type of the tumor. Benign tumors can sometimes simply be ignored, cancerous tumors; options include chemotherapy, radiation, and surgery.

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Track 16: Reprogramming stem cells: computational biology

Computational Biology, sometimes referred to as bioinformatics, is the science of using biological data to develop algorithms and relations among various biological systems. Bioinformatics groups use computational methods to explore the molecular mechanisms underpinning stem cells. To accomplish this bioinformaticsdevelop and apply advanced analysis techniques that make it possible to dissect complex collections of data from a wide range of technologies and sources.

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The fields of stem cell biology and regenerative medicine research are fundamentally about understanding dynamic cellular processes such as development, reprogramming, repair, differentiation and the loss, acquisition or maintenance of pluripotency. In order to precisely decipher these processes at a molecular level, it is critical to identify and study key regulatory genes and transcriptional circuits. Modern high-throughput molecular profiling technologies provide a powerful approach to addressing these questions as they allow the profiling of tens of thousands of gene products in a single experiment. Whereas bioinformatics is used to interpret the information produced by such technologies.

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8th World Congress on Cell & Stem Cell Research

The success of the 7 Cell Science conferences series has given us the prospect to bring the gathering one more time for our 8thWorld Congress 2017 meet in Orlando, USA. Since its commencement in 2011 cell science series has perceived around 750 researchers of great potentials and outstanding research presentations around the globe. The awareness of stem cells and its application is increasing among the general population that also in parallel offers hope and add woes to the researchers of cell science due to the potential limitations experienced in the real-time.

Stem Cell Research-2017has the goal to fill the prevailing gaps in the transformation of this science of hope to promptly serve solutions to all in the need.World Congress 2017 will have an anticipated participation of 100-120 delegates from around the world to discuss the conference goal.

History of Stem cells Research

Stem cells have an interesting history, in the mid-1800s it was revealed that cells were basically the building blocks of life and that some cells had the ability to produce other cells. Efforts were made to fertilize mammalian eggs outside of the human body and in the early 1900s, it was discovered that some cells had the capacity to generate blood cells. In 1968, the first bone marrow transplant was achieved successfully to treat two siblings with severe combined immunodeficiency. Other significant events in stem cell research include:

1978: Stem cells were discovered in human cord blood 1981: First in vitro stem cell line developed from mice 1988: Embryonic stem cell lines created from a hamster 1995: First embryonic stem cell line derived from a primate 1997: Cloned lamb from stem cells 1997: Leukaemia origin found as haematopoietic stem cell, indicating possible proof of cancer stem cells

Funding in USA:

No federal law forever did embargo stem cell research in the United States, but only placed restrictions on funding and use, under Congress's power to spend. By executive order on March 9, 2009, President Barack Obama removed certain restrictions on federal funding for research involving new lines of humanembryonic stem cells. Prior to President Obama's executive order, federal funding was limited to non-embryonic stem cell research and embryonic stem cell research based uponembryonic stem celllines in existence prior to August 9, 2001. In 2011, a United States District Court "threw out a lawsuit that challenged the use of federal funds for embryonic stem cell research.

Members Associated with Stem Cell Research:

Discussion on Development, Regeneration, and Stem Cell Biology takes an interdisciplinary approach to understanding the fundamental question of how a single cell, the fertilized egg, ultimately produces a complex fully patterned adult organism, as well as the intimately related question of how adult structures regenerate. Stem cells play critical roles both during embryonic development and in later renewal and repair. More than 65 faculties in Philadelphia from both basic science and clinical departments in the Division of Biological Sciences belong to Development, Regeneration, and Stem Cell Biology. Their research uses traditional model species including nematode worms, fruit-flies, Arabidopsis, zebrafish, amphibians, chick and mouse as well as non-traditional model systems such as lampreys and cephalopods. Areas of research focus include stem cell biology, regeneration, developmental genetics, and cellular basis of development, developmental neurobiology, and evo-devo (Evolutionary developmental biology).

Stem Cell Market Value:

Worldwide many companies are developing and marketing specialized cell culture media, cell separation products, instruments and other reagents for life sciences research. We are providing a unique platform for the discussions between academia and business.

Global Tissue Engineering & Cell Therapy Market, By Region, 2009 2018

$Million

Why to attend???

Stem Cell Research-2017 could be an outstanding event that brings along a novel and International mixture of researchers, doctors, leading universities and stem cell analysis establishments creating the conference an ideal platform to share knowledge, adoptive collaborations across trade and world, and assess rising technologies across the world. World-renowned speakers, the most recent techniques, tactics, and the newest updates in cell science fields are assurances of this conference.

A Unique Opportunity for Advertisers and Sponsors at this International event:

http://stemcell.omicsgroup.com/sponsors.php

UAS Major Universities which deals with Stem Cell Research

University of Washington/Hutchinson Cancer Center

Oregon Stem Cell Center

University of California Davis

University of California San Francisco

University of California Berkeley

Stanford University

Mayo Clinic

Major Stem Cell Organization Worldwide:

Norwegian Center for Stem Cell Research

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Skin Stem Cells Comments Off on Stem Cell Conferences | Cell and Stem Cell Congress | Stem … | August 29th, 2016

Presented at the 8th World Congress for Hair Research (2014) Jeju Island, South Korea.

Understanding molecular mechanisms for regeneration of hair follicles during wound healing provides new opportunities for developing treatments for hair loss and other skin disorders. We show that fibroblast growth factor 9 (fgf9) modulates hair follicle regeneration following wounding of adult mice. Inhibition of fgf9 during wound healing severely impedes this wound-induced hair follicle neogenesis (WIHN). Conversely, overexpression of fgf9 results in a 2-3 fold increase in the number of neogenic hair follicles. Remarkably, gamma-delta T cells in the wound dermis are the initial source of fgf9. Deletion of fgf9 gene in T cells in Lck-Cre;floxed fgf9 results in a marked reduction in WIHN. Similarly, mice lacking gamma-delta T cells demonstrate impaired follicular neogenesis.

We found that fgf9, secreted by gamma-delta T cells, initiates a regenerative response by triggering Wnt expression and subsequent Wnt activation in wound fibroblasts. Employing a unique feedback mechanism, activated fibroblasts then express fgf9, thus amplifying Wnt activity throughout the wound dermis during a critical phase of skin regeneration. Strikingly, humans lack a robust population of resident dermal gamma-delta T cells, potentially explaining their inability to regenerate hair.

These findings which highlight the essential relationship between the immune system and tissue regeneration, establish the importance of fgf9 in hair follicle regeneration and suggests its applicability for therapeutic use in humans.

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Dr George Cotsarelis: Hair Follicle Stem Cells & Skin ...

Skin Stem Cells Comments Off on Dr George Cotsarelis: Hair Follicle Stem Cells & Skin … | November 2nd, 2015

We observed similar stem cell plasticity when we purified and tested the myoepithelial stem cells from sweat glands (Lu et al., 2012; Blanpain and Fuchs, 2014). Similar to myoepithelial stem cells of mammary glands, these stem cells normally act unipotently and only replenish dying myoepithelial cells of the gland. However, when purified by fluorescence activated cell sorting (FACS) and transplanted directly into a mammary fat pad, the stem cells can regenerate the complete bi-layered gland, and the new luminal cells secrete sweat. Moreover, when engrafted to the skin, these stem cells can make epidermis. An area of interest in my lab is to understand the environmental cues that dictate the fascinating plasticity of epithelial stem cells, and to elucidate the chromatin remodeling that leads to the changes in gene expression necessary to generate different tissues from a common progenitor.

To understand how a stem cell chooses its differentiation pathway, we have taken several approaches. An ongoing approach of the lab is to express different fluorescent proteins under the control of various skin promoters, active at different stages in stem cells and their lineages. Through FACS, we've purified cells at different time points along the lineages and generated a battery of lineage-specific profiles, enabling us to define at an mRNA (RNA-seq) and chromatin (ChIP-seq) level how stem cells change as they transition from quiescence to activation to lineage determination. Our global objective is to exploit this information to understand how stem cells receive signals, change their program of gene expression and select a lineage. We also want to understand the functional significance of these changes. The beauty of the hair follicle as a model is that it is currently the only system where sufficient quantities of stem cells can be isolated directly from their native niche in order to carry out whole-genome wide analyses in vivo. This eliminates the caveats arising from culturing cells, namely induction of a stress response and large-scale epigenetic changes in gene expression.

For the hair follicle, >150 mRNAs are selectively upregulated in the bulge stem cells relative to their short-lived progeny (Tumbar et al., 2004; Blanpain et al., 2004; Keyes et al., 2013). A number of these changes are in transcription factors and epigenetic regulators. Weve conducted in vivo chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) on chromatin from hair follicle stem cells (HFSCs) and their short-lived progeny. Bioinformatics reveals which genes bind these transcription factors, and how this changes as the stem cells progress to form transiently dividing cells that then terminally differentiate along one of the 7 distinct concentric cell layers that constitute the hair and its channel. By conducting high throughput RNA sequencing (RNA-seq) on HFSCs lacking each of these genes, weve learned which target genes depend upon binding these transcription factors. Finally, by engineering inducible-conditional knockouts to selectively remove these transcription factors in the stem cells, weve learned the physiological relevance of these factors.

Based upon these analyses, TCF3/TCF4, LHX2 and SOX9 are all essential for maintaining the hair follicle stem cells in their native niche (Nguyen et al., 2006; 2009; Rhee et al., 2006; Folgueras et al., 2013; Lien et al., 2011; 2014; Nowak et al., 2008; Kadaja et al., 2014). In addition, LHX2 represses sebaceous gland differentiation: following its loss, the stem cell niche soon becomes a sebaceous gland (Folgueras et al., 2013). SOX9 represses epidermal differentiation: following its loss, the niche becomes an epidermal cyst (Kadaja et al., 2014). TCF3 and TCF4 repress HF differentiation: following their loss, quiescent HFSCs precociously activate a new hair cycle (Lien et al., 2014). TCF3 and TCF4 can partner with -catenin, which is stabilized and becomes nuclear upon Wnt signaling: if -catenin is silenced in the quiescent HFSCs, they never reenter a new hair cycle. In their native niche, quiescent HFSCs express a transcriptional repressor TLE4 which binds to TCF3 and TCF4: our findings are consistent with the view that Wnt signaling functions by relieving TCF3/4/TLE4-mediated repression (Lien et al., 2014).

NFATc1 is required for maintaining HFSC quiescence, and in its absence, HFs cycle precociously (Horsley et al., 2008). Additionally, NFATc1 is downstream of BMP signaling, offering a potential explanation as to why BMP signaling must be lowered to activate hair cycling. A major feature of the aging HFSC signature is elevated NFATc1 target genes, and we can stimulate old follicles by inhibiting NFATc1 (Keyes et al., 2013). A major question still to be answered is whether HFSCs have an endless capacity for hair cycling and whether this same phenomenon operates in aging scalp hairs in humans. If so, these findings may open new doors for future therapeutics.

NFiB is a transcription factor which is specific to the HFSCs, but functions by repressing the expression of genes that are essential for the differentiation of the melanocyte stem cells, which reside within the same stem cell niche (Chang et al., 2013). These two stem cell populations must be activated at the same time so that differentiating melanocytes can transfer pigment to the differentiating hair cells to provide the natural coloring to our hair. Loss of NFiB uncouples this crosstalk and leads to the precocious activation of a key NFiB target gene that encodes a secreted melanocyte differentiation factor (Chang et al., 2013).

There are a number of additional transcription factors and epigenetic regulators which are enhanced in the complex milieu of HF stem cell chromatin, and there is still much to be learned. Of the epigenetic regulators, weve thus far examined only the role of polycomb chromatin repressor complexes, which weve shown function critically in controlling the fate switch from a stem cell to a committed, transit-amplifying state (Ezhkova et al., 2009; 2011; Lien et al., 2011). In coming years, we will continue to systematically work our way through the functional significance and mechanism of action of epigenetic and transcriptional controls on stem cells as they transit from a quiescent to activated to committed state. When coupled with our recent ability to efficiently knockdown genes in a few days using lentiviral-mediated shRNA delivery (Beronja et al., 2010), this now becomes a powerful tool for exploiting bioinformatics analyses to gain biological insights.

Our ultimate goal is to understand how external signals from the surrounding niche microenvironment impact chromatin dynamics to achieve tissue production. Equally important will be the expression of specific genes that enables them to remodel their cytoskeleton and adhesive contacts and either form a stratified epidermis or an epithelial bud that can then develop into a hair follicle (Perez-Moreno et al., 2003; Blanpain and Fuchs, 2009; Hsu et al., 2014). While our model is the skin, the problem is a general one of how a single epithelial stem cell gives rise to a spatially organized, functional tissue. It is also integrally linked to understanding the basis of cancer progression.

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The Rockefeller University Stem Cells of the Skin and ...

Skin Stem Cells Comments Off on The Rockefeller University Stem Cells of the Skin and … | October 26th, 2015

OK, so now we know the problem. There are certain genes needed to make a cell turn into an ES cell. Since these genes are presumably off in a skin cell, we need to turn them on again. And have all of the skin cell genes shut off too.

The way the scientists decided to do this was to add back whatever genes are needed to erase the pattern in the skin cell. (These genes are off in a skin cell.) This is a lot easier than specifically turning on this small set of genes.

The way they decided to add back the genes was with a virus. A lot of gene therapy gets done this way.

Many viruses work by sticking themselves into a cell's DNA. What the scientists planned to do was to take out some of the nonessential virus DNA and put in the necessary genes.

We're all set except we don't yet have the genes. Scientists had figured out through various means that if they added 24 different genes to a skin cell, it would turn into an ES cell. Yikes!

That is way too many to do gene therapy. So they started taking one away at a time to find the really key ones. They finally settled on 4 genes. This is still an awful lot but it is at least doable.

Last year they added back these genes and got some promising results. The skin cells took on many of the properties of ES cells but not all of them. This is encouraging but not good enough.

To fix this, they changed the skin cells to make selecting the most ES-like ones easier to do. When they did this, they were able to grow cells that essentially looked like an ES cell.

As a final test, they added some of these cells to an early mouse embryo. The embryo grew into a pup that contained different cell types derived from the original embryo and the skin cells (a chimera). This test proved these cells had been turned into something that could be used as ES cells.

Cool. But it is not a slam dunk to get this to work in people. We don't know if these same 4 genes are the ones that work in people too. And around 20% of the mice died from cancers caused by one of the added genes.

But these are problems we can deal with. Of course we'll have to continue to use "real" ES cells to figure out the genes needed to turn skin cells into ES cells. In other words, we need to destroy embryos now to stop destroying them in the future.

This research will progress very quickly. Because the experiments are easier to do than cloning, little labs all over the world can tackle these kinds of questions with no government interference. Personalized medicine may be here sooner than we think.

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Embryonic stem cells from skin cells | Understanding Genetics

Skin Stem Cells Comments Off on Embryonic stem cells from skin cells | Understanding Genetics | October 16th, 2015

Scientists have discovered a new type of stem cell in the skin that acts surprisingly like certain stem cells found in embryos: both can generate fat, bone, cartilage, and even nerve cells. These newly-described dermal stem cells may one day prove useful for treating neurological disorders and persistent wounds, such as diabetic ulcers, says Freda Miller, an HHMI international research scholar.

Miller and her colleagues first saw the cells several years ago in both rodents and people, but only now confirmed that the cells are stem cells. Like other stem cells, these cell scan self-renew and, under the right conditions, they can grow into the cell types that constitute the skins dermal layer, which lies under the surface epidermal layer. We showed that these cells are, in fact, the real thing, says Miller, a professor at the University of Toronto and a senior scientist in the department of developmental biology at the Hospital for Sick Children in Toronto. The dermal stem cells also appear tohelp form the basis for hair growth.The new work was published December 4, 2009, in the journal Cell Stem Cells.

Stem cell researchers like to talk about building organs in a dish. You can imagine, if you have all the right playersdermal stem cells and epidermal stem cellsworking together, you could do that with skin in a very real way.

Freda D. Miller

Though this research focuses on the skin, Miller has spent her career searching for cures for neurological diseases such as Parkinsons. About a decade ago, she decided to find an easily accessible cell that could be coaxed into making nerves. Brain stem cells, some of which can grow into nerves, lie deep in the middle of the organ and are too difficult to reach if the scientists eventually wanted to cultivate the cells from individual patients. I thought, This is blue sky stuff, but you never know. She searched the literature and found that amphibians can regenerate nerves in their skin. She also found published hints that mammalian nerve cells could do the same.

Her team looked in the dermal layer of the skin in both mice and people. Hair follicles and sweat glands are rooted in the dermis, a thick layer of cells that also help support and nourish blood vessels and touch-perceiving nerves. In 2001, Millers team hit paydirt when they discovered cells that respond to the same growth factors that make brain stem cells differentiate. She named them skin-derived precursors (SKPs, or skips).

Miller soon discovered that the cells act like neural crest cells from embryosstem cells that generate the entire peripheral nervous system and part of the headin that they could turn into nerves, fat, bone, and cartilage.That gave us the idea that these were some kind of embryonic-like precursor cell that migrated into the skin of the embryo, Miller said. But instead of disappearing as the embryo develops, the cells survive into adulthood.

Even though the SKPs acted like stem cells in Petri dishes, Miller didnt know if they behaved the same way in the body. We were obviously very excited about these cells, she said. The problem was, cells can do all kinds of weird things in culture dishes that look right but really arent. We thought, Maybe were being deceived.So lab member Jeffrey Biernaskie put the cells through their paces, performing a series of experiments to test whether the SKPs indeed acted like stem cells in the body.

Earlier work in the lab had shown that the SKPs produce a transcription factor called SOX2, which is produced in many types of stem cells. The team used genetically engineered mice with SOX2 genes tagged with green fluorescent protein, which allowed them to track where SOX2 was expressed in the animals. They found that about 1% of skin cells from adult mice contained the SOX2-making cells, and they were concentrated in the bulb at the base of hair follicles.When the team cultured these cells, they began behaving like SKPs.

Next, the scientists decided to see if the cells would not just settle at the base of hair follicles but grow new hair. They took the fluorescent cells, mixed them with epidermal cellswhich make up the majority of cells in a hair follicleand transplanted the mixture under the skin of hairless mice. These mice began growing hair, and analysis showed the green cells migrated to their home base in the bulb of the new hair follicles. The team also transplanted rat SKP cells under the skin of mice. The cells behaved exactly like dermal stem cellsthey spread out through the dermis and differentiated into various dermal cell types, including fat cells and dermal fibroblasts, which form the structural framework of the dermal layer. Intriguingly, the mice that carried transplanted rat SKPs also grew longer, thicker,rat-like hair, instead of short, thin mouse hair. These cells are instructive, they tell the epidermal cellswhich form the bulk of the hair follicleto make bigger, rat-like hair follicles, Miller said. There are a lot of jokes in my lab about bald men running around with rat hair on their heads.

Finally, the team gave mice small puncture wounds and then transplanted their fluorescent SKPs next to the wound. Within a month, many transplanted cells appeared in the scar, showing they had contributed to wound healing. The SKPs were also found in new hair follicles in the healed skin.

The cells behavior both in wound healing and hair growth led the team to conclude that the SKPs are, in fact, dermal stem cells. Miller said the finding complements work by HHMI investigator Elaine Fuchs, who found epidermal stem cells, which help renew the top layer of skin. Combining the evidence from the two labs suggests a possible path to baldness treatments, Miller saidthe dermal stem cells at the base of the hair follicle seem to be signaling the epidermal cells that form the shaft of the follicle to grow hair. But much about the signaling mechanism remains unknown.

Miller wants to investigate less cosmetic applications, such as treating nerve and brain diseases. Experiments she published between 2005 and 2007 showed that SKPs can grow into nerves and help repair spinal cord damage in rats. Her lab is continuing to pursue that research. She is also searching for signals that could trigger the dermal stem cells to rev up their innate wound-healing ability. If such a signal can be found and mimicked, Miller can envision one day treating chronic woundssuch as diabetic ulcerswith a topical cream. Such a treatment is years or decades away, she said, but now researchers know which cell types to focus on. Another possibility: improving skin grafts, which today consist of only epidermal, not dermal, cells. While skin grafts can dramatically help burn victims, those grafts dont function like normal skin.

Stem cell researchers like to talk about building organs in a dish, said Miller. You can imagine, if you have all the right playersdermal stem cells and epidermal stem cellsworking together, you could do that with skin in a very real way.

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Research News: New Skin Stem Cells Surprisingly Similar to ...

Skin Stem Cells Comments Off on Research News: New Skin Stem Cells Surprisingly Similar to … | October 5th, 2015

At a Glance

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Our skin is an extremely important and multi-faceted organ. It protects our insides by providing a cover for our body and is responsible for preventing pathogens entering our organism. The skin also fulfills other important roles by regulating body temperature, in the area of metabolism, and for our sensitivity to touch and stimuli.

In addition, our skin also contains a large quantity of autologous stem cells (so-called adult stem cells). Autologous stem cells are on the one hand relevant for the external appearance of the skin, and on the other hand they offer a great deal of positive therapeutic potential in the area of regenerative medicine.

If we bear in mind what kind of functions our skin has, it becomes obvious why we should be paying special attention to its health.

Already in the traditional European medicine there was the tenet As inside, so outside. Even in modern science we know that it is important to distinguish between cause and effect and that many degenerative processes inside the body manifest externally.

For example, various factors can lead to a massive acceleration of the per se normal skin aging: Stress, overload and unhealthy diet can cause hormonal dysfunction, which in turn leads to premature aging and tissue slackening. Certain lifestyle habits such as tanning booths as well as smoking can cause skin damages over time, which can often make people concerned look more than 10 years older than they actually are.

Our therapeutic approach is not only to treat the symptom (= premature aging of the skin), but the cause (= e.g., hormone deficiency) as far as possible. Combinations of both the therapy of the cause and targeted local treatments can be useful, especially when a large distress is present and/or the skin damages are very advanced.

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We use the autologous substances for our skin treatments. We never use artificial fillers (e.g., silicone) or Botox, because their side effects often lead to a worsening of skin quality.

When we are young, the body still has enough stem cells and produces sufficient growth factors and hormones, however, as the years pass, the body produces less of them. This wear process can be accelerated by stress, overwork, poor nutrition and certain lifestyle habits. The external signs of premature aging appear, such as wrinkles, slackening of tissue, sagging cheeks and greying of the skin.

All types of treatment offered by our clinic serve the purpose of giving your skin back a certain amount of quality, elasticity and freshness by targeted application of the autologous substances or substances similar to the bodys own.

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Skin Regeneration with Stem Cells, Growth Factors ...

Skin Stem Cells Comments Off on Skin Regeneration with Stem Cells, Growth Factors … | October 5th, 2015

WHAT ARE STEM CELLS?

Stem cells are super unique in that they have the ability to go through numerous cycles and cell divisions while maintaining the undifferentiated state. Primarily, stem cells are capable of self-renewal and can transform themselves into other cell types of the same tissue. Their crucial role is to replenish dying cells and regenerate damaged tissue. Stem cells have a limited life expectation due to environmental and intrinsic stress factors. Because their life is endangered by internal and external stresses, stem cells have to be protected and supported to delay preliminary aging. In aged bodies, the number and activity of stem cells in reduced.

Until several years ago, the tart, unappealing breed of the Swiss-grown Uttwiler Sptlauber apples, did not seem to offer anything of value. That was until Swiss scientists discovered the unusual longevity of the stem cells that kept these apples alive months after other apples shriveled and fell off their trees. In the rural region of Switzerland, home of these magical apples, it was discovered that when the unpicked apples or tree bark was punctured, Swiss Apple trees have the ability to heal themselves and last longer than other varieties. What was the secret to these apples prolonged lives?

These scientists got to work to find out. What they revealed was that apple stem cells work just like human stem cells, they work to maintain and repair skin tissue. The main difference is that unlike apple stem cells, skin stem cells do not have a long lifespan, and once they begin depleting, the signs of aging start kicking in (in the forms of loose skin, wrinkles, the works). Time to harness these apple stem cells into anti aging skin care! Not so fast. As mentioned, Uttwiler Sptlauber apples are now very rare to the point that the extract can no longer be made in a traditional fashion. The great news is that scientists developed a plant cell culture technology, which involves breeding the apple stem cells in the laboratory.

Human stem cells on the skins epidermis are crucial to replenish the skin cells that are lost due to continual shedding. When epidermal stem cells are depleted, the number of lost or dying skin cells outpaces the production of new cells, threatening the skins health and appearance.

Like humans, plants also have stem cells. Enter the stem cells of the Uttwiler Sptlauber apple tree, whose fruit demonstrates an exceptionally long shelf-life. How can these promising stem cells help our skin?

Studies show that apple stem cells boosts production of human stem cells, protect the cell from stress, and decreases wrinkles. How does it work? The internal fluid of these plant cells contains components that help to protect and maintain human stem cells. Apple stem cells contain metabolites to ensure longevity as the tree is known for the fact that its fruit keep well over long periods of time.

When tested in vitro, the apple stem cell extract was applied to human stem cells from umbilical cords and was found to increase the number of the stem cells in culture. Furthermore, the addition of the ingredient to umbilical cord stem cells appeared to protect the cells from environmental stress such as UV light.

Apple stem cells do not have to be fed through the umbilical cord to benefit our skin! The extract derived from the plant cell culture technology is being harnessed as an active ingredient in anti aging skincare products. When delivered into the skin nanotechnology, the apple stem cells provide more dramatic results in decreasing lines, wrinkles, and environmental damage.

Currently referred to as The Fountain of Youth, intense research has proved that with just a concentration level of 0.1 % of the PhytoCellTec (apple stem cell extract) could proliferate a wealth of human stem cells by an astounding 80%! These wonder cells work super efficiently and are completely safe. Of the numerous benefits of apple stems cells, the most predominant include:

Skin Layers

Skin Cell Activity Before

Skin Cell Activity After 1 Hour

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Apple Stem Cells - Sonya Dakar Skin Clinic

Skin Stem Cells Comments Off on Apple Stem Cells – Sonya Dakar Skin Clinic | September 25th, 2015

explore

Stem cells play many important roles in our bodies from embryonic development through adulthood.

learn more

Stem cells can now be created from differentiated cells.

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Learn about some different types of stem cells and their potential for treating diseases.

interactive explore

Send activating signals to stem cells and watch them get to work!

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Stem cell therapies have been curing diseases for decades.

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Researchers are working on new ways to use stem cells in medicine.

learn more

New developments in research are changing the conversation about stem cells.

Supported by a Science Education Partnership Award (SEPA) Grant No. R25RR023288 from the National Center for Research Resources, a component of the NIH. The contents provided here are solely the responsibility of the authors and do not necessarily represent the official views of NIH.

APA format: Genetic Science Learning Center (2014, June 22) Stem Cells. Learn.Genetics. Retrieved September 26, 2015, from http://learn.genetics.utah.edu/content/stemcells/ MLA format: Genetic Science Learning Center. "Stem Cells." Learn.Genetics 26 September 2015 <http://learn.genetics.utah.edu/content/stemcells/> Chicago format: Genetic Science Learning Center, "Stem Cells," Learn.Genetics, 22 June 2014, <http://learn.genetics.utah.edu/content/stemcells/> (26 September 2015)

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Stem Cells - Learn Genetics

Skin Stem Cells Comments Off on Stem Cells – Learn Genetics | September 25th, 2015

Published August 19, 2015

This image of the lab-grown brain is labeled to show identifiable structures: the cerebral hemisphere, the optic stalk and the cephalic flexure, a bend in the mid-brain region, all characteristic of the human fetal brain.(The Ohio State University)

Researchers at The Ohio State University were able to create a nearly complete human brain that matches the brain maturity of a 5-week-old fetus by using adult human skin cells.

The brain organoid is about the size of a pencil eraser and has an identifiable structure containing 99 percent of the genes present in the human fetal brain, according to a news release. Scientists say its the most complete human brain model yet developed.

It not only looks like the developing brain, its diverse cell types express nearly all genes like a brain, Rene Anand, a professor of biological chemistry and pharmacology at Ohio State, said in a news release. Weve struggled for a long time trying to solve complex brain disease problems that cause tremendous pain and suffering. The power of this brain model bodes very well for human health because it gives us better and more relevant options to test and develop therapeutics other than rodents.

Anand, who began his quest four years ago, studies the association between nicotinic receptors and central nervous system disorders. Hes hopeful that the lab-grown brain will provide ethical and more rapid and accurate testing of experimental drugs before the clinical trial stage.

In central nervous system diseases, this will enable studies of either underlying genetic susceptibility or purely environmental influences, or a combination, Anand said in the news release. Genomic science infers there are up to 600 genes that give rise to autism, but we are stuck there. Mathematical correlations and statistical methods are insufficient to in themselves identify causation. You need an experimental system you need a human brain.

Anand and his team built the model system in 15 weeks, using techniques to convert adult skin cells into pluripotent cells, which are immature cells that can be programmed to become any tissue in the body. They worked to differentiate pluripotent stem cells into cells that are designed to become neural tissue, according to the news release.

While the model lacks a vascular system, it does contain a spinal cord, all major regions of the brain, multiple cell types, signaling circuitry and a retina, according to the news release.

Anand reported on his research at the 2015 Military Health System Research Symposium.

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Researchers create lab-grown brain using human skin cells ...

Skin Stem Cells Comments Off on Researchers create lab-grown brain using human skin cells … | August 20th, 2015

This is an achievement: Scientists have used skin cells to build a rudimentary human brain. (These were induced pluripotent stem cells.) From The Guardian story:

Though not conscious the miniature brain, which resembles that of a five-week-old foetus, could potentially be useful for scientists who want to study the progression of developmental diseases. It could also be used to test drugs for conditions such as Alzheimers and Parkinsons, since the regions they affect are in place during an early stage of brain development.

The brain, which is about the size of a pencil eraser, is engineered from adult human skin cells and is the most complete human brain model yet developed, claimed Rene Anand of Ohio State University, Columbus, who presented the work today at the Military Health System Research Symposium in Fort Lauderdale, Florida.

May it be so.

Lets analyze what this breakthrough could portend:

1. No need for unethical human cloning to derive cells for use in research and drug testing.

2. No need for fetal farming for experimentation and organ transplants.

3. No need for Planned Parenthood dismemberments of fetuses killed in a less crunchy way in abortion.

Remember when embryonic stem cells were OUR ONLY HOPE?

And that those of us who said that particular meme wasnt true were anti science? Pshaw.

#applause

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ETHICAL Stem Cells Grow Human Brain | National Review Online

Skin Stem Cells Comments Off on ETHICAL Stem Cells Grow Human Brain | National Review Online | August 20th, 2015