Embryonic stem cells (ES cells or ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre-implantation embryo.[1][2] Human embryos reach the blastocyst stage 45 days post fertilization, at which time they consist of 50150 cells. Isolating the embryoblast, or inner cell mass (ICM) results in destruction of the blastocyst, a process which raises ethical issues, including whether or not embryos at the pre-implantation stage should have the same moral considerations as embryos in the post-implantation stage of development.[3][4] Researchers are currently focusing heavily on the therapeutic potential of embryonic stem cells, with clinical use being the goal for many labs. These cells are being studied to be used as clinical therapies, models of genetic disorders, and cellular/DNA repair. However, adverse effects in the research and clinical processes have also been reported.

Embryonic stem cells (ESCs), derived from the blastocyst stage of early mammalian embryos, are distinguished by their ability to differentiate into any cell type and by their ability to propagate. It is these traits that makes them valuable in the scientific/medical fields. ESC are also described as having a normal karyotype, maintaining high telomerase activity, and exhibiting remarkable long-term proliferative potential.[5]

Embryonic stem cells of the inner cell mass are pluripotent, meaning they are able to differentiate to generate primitive ectoderm, which ultimately differentiates during gastrulation into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm. These include each of the more than 220 cell types in the adult human body. Pluripotency distinguishes embryonic stem cells from adult stem cells, which are multipotent and can only produce a limited number of cell types.

Under defined conditions, embryonic stem cells are capable of propagating indefinitely in an undifferentiated state. Conditions must either prevent the cells from clumping, or maintain an environment that supports an unspecialized state.[2] While being able to remain undifferentiated, ESCs also have the capacity, when provided with the appropriate signals, to differentiate (presumably via the initial formation of precursor cells) into nearly all mature cell phenotypes.[6]

Due to their plasticity and potentially unlimited capacity for self-renewal, embryonic stem cell therapies have been proposed for regenerative medicine and tissue replacement after injury or disease. Pluripotent stem cells have shown potential in treating a number of varying conditions, including but not limited to: spinal cord injuries, age related macular degeneration, diabetes, neurodegenerative disorders (such as Parkinson's disease), AIDS, etc.[7] In addition to their potential in regenerative medicine, embryonic stem cells provide an alternative source of tissue/organs which serves as a possible solution to the donor shortage dilemma. Not only that, but tissue/organs derived from ESCs can be made immunocompatible with the recipient. Aside from these uses, embryonic stem cells can also serve as tools for the investigation of early human development, study of genetic disease and as in vitro systems for toxicology testing.[5]

According to a 2002 article in PNAS, "Human embryonic stem cells have the potential to differentiate into various cell types, and, thus, may be useful as a source of cells for transplantation or tissue engineering."[8]

However, embryonic stem cells are not limited to cell/tissue engineering.

Current research focuses on differentiating ESCs into a variety of cell types for eventual use as cell replacement therapies (CRTs). Some of the cell types that have or are currently being developed include cardiomyocytes (CM), neurons, hepatocytes, bone marrow cells, islet cells and endothelial cells.[9] However, the derivation of such cell types from ESCs is not without obstacles, therefore current research is focused on overcoming these barriers. For example, studies are underway to differentiate ESCs in to tissue specific CMs and to eradicate their immature properties that distinguish them from adult CMs.[10]

Besides becoming an important alternative to organ transplants, ESCs are also being used in field of toxicology and as cellular screens to uncover new chemical entities (NCEs) that can be developed as small molecule drugs. Studies have shown that cardiomyocytes derived from ESCs are validated in vitro models to test drug responses and predict toxicity profiles.[9] ES derived cardiomyocytes have been shown to respond to pharmacological stimuli and hence can be used to assess cardiotoxicity like Torsades de Pointes.[17]

ESC-derived hepatocytes are also useful models that could be used in the preclinical stages of drug discovery. However, the development of hepatocytes from ESCs has proven to be challenging and this hinders the ability to test drug metabolism. Therefore, current research is focusing on establishing fully functional ESC-derived hepatocytes with stable phase I and II enzyme activity.[18]

Several new studies have started to address the concept of modeling genetic disorders with embryonic stem cells. Either by genetically manipulating the cells, or more recently, by deriving diseased cell lines identified by prenatal genetic diagnosis (PGD), modeling genetic disorders is something that has been accomplished with stem cells. This approach may very well prove invaluable at studying disorders such as Fragile-X syndrome, Cystic fibrosis, and other genetic maladies that have no reliable model system.

Yury Verlinsky, a Russian-American medical researcher who specialized in embryo and cellular genetics (genetic cytology), developed prenatal diagnosis testing methods to determine genetic and chromosomal disorders a month and a half earlier than standard amniocentesis. The techniques are now used by many pregnant women and prospective parents, especially couples who have a history of genetic abnormalities or where the woman is over the age of 35 (when the risk of genetically related disorders is higher). In addition, by allowing parents to select an embryo without genetic disorders, they have the potential of saving the lives of siblings that already had similar disorders and diseases using cells from the disease free offspring.[19]

Differentiated somatic cells and ES cells use different strategies for dealing with DNA damage. For instance, human foreskin fibroblasts, one type of somatic cell, use non-homologous end joining (NHEJ), an error prone DNA repair process, as the primary pathway for repairing double-strand breaks (DSBs) during all cell cycle stages.[20] Because of its error-prone nature, NHEJ tends to produce mutations in a cells clonal descendants.

ES cells use a different strategy to deal with DSBs.[21] Because ES cells give rise to all of the cell types of an organism including the cells of the germ line, mutations arising in ES cells due to faulty DNA repair are a more serious problem than in differentiated somatic cells. Consequently, robust mechanisms are needed in ES cells to repair DNA damages accurately, and if repair fails, to remove those cells with un-repaired DNA damages. Thus, mouse ES cells predominantly use high fidelity homologous recombinational repair (HRR) to repair DSBs.[21] This type of repair depends on the interaction of the two sister chromosomes formed during S phase and present together during the G2 phase of the cell cycle. HRR can accurately repair DSBs in one sister chromosome by using intact information from the other sister chromosome. Cells in the G1 phase of the cell cycle (i.e. after metaphase/cell division but prior the next round of replication) have only one copy of each chromosome (i.e. sister chromosomes arent present). Mouse ES cells lack a G1 checkpoint and do not undergo cell cycle arrest upon acquiring DNA damage.[22] Rather they undergo programmed cell death (apoptosis) in response to DNA damage.[23] Apoptosis can be used as a fail-safe strategy to remove cells with un-repaired DNA damages in order to avoid mutation and progression to cancer.[24] Consistent with this strategy, mouse ES stem cells have a mutation frequency about 100-fold lower than that of isogenic mouse somatic cells.[25]

On January 23, 2009, Phase I clinical trials for transplantation of oligodendrocytes (a cell type of the brain and spinal cord) derived from human ES cells into spinal cord-injured individuals received approval from the U.S. Food and Drug Administration (FDA), marking it the world's first human ES cell human trial.[26] The study leading to this scientific advancement was conducted by Hans Keirstead and colleagues at the University of California, Irvine and supported by Geron Corporation of Menlo Park, CA, founded by Michael D. West, PhD. A previous experiment had shown an improvement in locomotor recovery in spinal cord-injured rats after a 7-day delayed transplantation of human ES cells that had been pushed into an oligodendrocytic lineage.[27] The phase I clinical study was designed to enroll about eight to ten paraplegics who have had their injuries no longer than two weeks before the trial begins, since the cells must be injected before scar tissue is able to form. The researchers emphasized that the injections were not expected to fully cure the patients and restore all mobility. Based on the results of the rodent trials, researchers speculated that restoration of myelin sheathes and an increase in mobility might occur. This first trial was primarily designed to test the safety of these procedures and if everything went well, it was hoped that it would lead to future studies that involve people with more severe disabilities.[28] The trial was put on hold in August 2009 due to FDA concerns regarding a small number of microscopic cysts found in several treated rat models but the hold was lifted on July 30, 2010.[29]

In October 2010 researchers enrolled and administered ESTs to the first patient at Shepherd Center in Atlanta.[30] The makers of the stem cell therapy, Geron Corporation, estimated that it would take several months for the stem cells to replicate and for the GRNOPC1 therapy to be evaluated for success or failure.

In November 2011 Geron announced it was halting the trial and dropping out of stem cell research for financial reasons, but would continue to monitor existing patients, and was attempting to find a partner that could continue their research.[31] In 2013 BioTime (AMEX:BTX), led by CEO Dr. Michael D. West, acquired all of Geron's stem cell assets, with the stated intention of restarting Geron's embryonic stem cell-based clinical trial for spinal cord injury research.[32]

BioTime company Asterias Biotherapeutics (NYSE MKT: AST) was granted a $14.3 million Strategic Partnership Award by the California Institute for Regenerative Medicine (CIRM) to re-initiate the worlds first embryonic stem cell-based human clinical trial, for spinal cord injury. Supported by California public funds, CIRM is the largest funder of stem cell-related research and development in the world.[33]

The award provides funding for Asterias to reinitiate clinical development of AST-OPC1 in subjects with spinal cord injury and to expand clinical testing of escalating doses in the target population intended for future pivotal trials.[33]

AST-OPC1 is a population of cells derived from human embryonic stem cells (hESCs) that contains oligodendrocyte progenitor cells (OPCs). OPCs and their mature derivatives called oligodendrocytes provide critical functional support for nerve cells in the spinal cord and brain. Asterias recently presented the results from phase 1 clinical trial testing of a low dose of AST-OPC1 in patients with neurologically-complete thoracic spinal cord injury. The results showed that AST-OPC1 was successfully delivered to the injured spinal cord site. Patients followed 23 years after AST-OPC1 administration showed no evidence of serious adverse events associated with the cells in detailed follow-up assessments including frequent neurological exams and MRIs. Immune monitoring of subjects through one year post-transplantation showed no evidence of antibody-based or cellular immune responses to AST-OPC1. In four of the five subjects, serial MRI scans performed throughout the 23 year follow-up period indicate that reduced spinal cord cavitation may have occurred and that AST-OPC1 may have had some positive effects in reducing spinal cord tissue deterioration. There was no unexpected neurological degeneration or improvement in the five subjects in the trial as evaluated by the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) exam.[33]

The Strategic Partnership III grant from CIRM will provide funding to Asterias to support the next clinical trial of AST-OPC1 in subjects with spinal cord injury, and for Asterias product development efforts to refine and scale manufacturing methods to support later-stage trials and eventually commercialization. CIRM funding will be conditional on FDA approval for the trial, completion of a definitive agreement between Asterias and CIRM, and Asterias continued progress toward the achievement of certain pre-defined project milestones.[33]

The major concern with the possible transplantation of ESC into patients as therapies is their ability to form tumors including teratoma.[34] Safety issues prompted the FDA to place a hold on the first ESC clinical trial, however no tumors were observed.

The main strategy to enhance the safety of ESC for potential clinical use is to differentiate the ESC into specific cell types (e.g. neurons, muscle, liver cells) that have reduced or eliminated ability to cause tumors. Following differentiation, the cells are subjected to sorting by flow cytometry for further purification. ESC are predicted to be inherently safer than IPS cells created with genetically-integrating viral vectors because they are not genetically modified with genes such as c-Myc that are linked to cancer. Nonetheless, ESC express very high levels of the iPS inducing genes and these genes including Myc are essential for ESC self-renewal and pluripotency,[35] and potential strategies to improve safety by eliminating c-Myc expression are unlikely to preserve the cells' "stemness". However, N-myc and L-myc have been identified to induce iPS cells instead of c-myc with similar efficiency.[36]More recent protocols to induce pluripotency bypass these problems completely by using non-integrating RNA viral vectors such as sendai virus or mRNA transfection.

Due to the nature of embryonic stem cell research, there is a lot of controversial opinions on the topic. Since harvesting embryonic stem cells necessitates destroying the embryo from which those cells are obtained, the moral status of the embryo comes into question. Scientists argue that the 5-day old mass of cells is too young to achieve personhood or that the embryo, if donated from an IVF clinic (which is where labs typically acquire embryos from), would otherwise go to medical waste anyway. Opponents of ESC research counter that any embryo has the potential to become a human, therefore destroying it is murder and the embryo must be protected under the same ethical view as a developed human being.[37]

In vitro fertilization generates multiple embryos. The surplus of embryos is not clinically used or is unsuitable for implantation into the patient, and therefore may be donated by the donor with consent. Human embryonic stem cells can be derived from these donated embryos or additionally they can also be extracted from cloned embryos using a cell from a patient and a donated egg.[49] The inner cell mass (cells of interest), from the blastocyst stage of the embryo, is separated from the trophectoderm, the cells that would differentiate into extra-embryonic tissue. Immunosurgery, the process in which antibodies are bound to the trophectoderm and removed by another solution, and mechanical dissection are performed to achieve separation. The resulting inner cell mass cells are plated onto cells that will supply support. The inner cell mass cells attach and expand further to form a human embryonic cell line, which are undifferentiated. These cells are fed daily and are enzymatically or mechanically separated every four to seven days. For differentiation to occur, the human embryonic stem cell line is removed from the supporting cells to form embryoid bodies, is co-cultured with a serum containing necessary signals, or is grafted in a three-dimensional scaffold to result.[50]

Embryonic stem cells are derived from the inner cell mass of the early embryo, which are harvested from the donor mother animal. Martin Evans and Matthew Kaufman reported a technique that delays embryo implantation, allowing the inner cell mass to increase. This process includes removing the donor mother's ovaries and dosing her with progesterone, changing the hormone environment, which causes the embryos to remain free in the uterus. After 46 days of this intrauterine culture, the embryos are harvested and grown in in vitro culture until the inner cell mass forms egg cylinder-like structures, which are dissociated into single cells, and plated on fibroblasts treated with mitomycin-c (to prevent fibroblast mitosis). Clonal cell lines are created by growing up a single cell. Evans and Kaufman showed that the cells grown out from these cultures could form teratomas and embryoid bodies, and differentiate in vitro, all of which indicating that the cells are pluripotent.[41]

Gail Martin derived and cultured her ES cells differently. She removed the embryos from the donor mother at approximately 76 hours after copulation and cultured them overnight in a medium containing serum. The following day, she removed the inner cell mass from the late blastocyst using microsurgery. The extracted inner cell mass was cultured on fibroblasts treated with mitomycin-c in a medium containing serum and conditioned by ES cells. After approximately one week, colonies of cells grew out. These cells grew in culture and demonstrated pluripotent characteristics, as demonstrated by the ability to form teratomas, differentiate in vitro, and form embryoid bodies. Martin referred to these cells as ES cells.[42]

It is now known that the feeder cells provide leukemia inhibitory factor (LIF) and serum provides bone morphogenetic proteins (BMPs) that are necessary to prevent ES cells from differentiating.[51][52] These factors are extremely important for the efficiency of deriving ES cells. Furthermore, it has been demonstrated that different mouse strains have different efficiencies for isolating ES cells.[53] Current uses for mouse ES cells include the generation of transgenic mice, including knockout mice. For human treatment, there is a need for patient specific pluripotent cells. Generation of human ES cells is more difficult and faces ethical issues. So, in addition to human ES cell research, many groups are focused on the generation of induced pluripotent stem cells (iPS cells).[54]

On August 23, 2006, the online edition of Nature scientific journal published a letter by Dr. Robert Lanza (medical director of Advanced Cell Technology in Worcester, MA) stating that his team had found a way to extract embryonic stem cells without destroying the actual embryo.[55] This technical achievement would potentially enable scientists to work with new lines of embryonic stem cells derived using public funding in the USA, where federal funding was at the time limited to research using embryonic stem cell lines derived prior to August 2001. In March, 2009, the limitation was lifted.[56]

The iPSC technology was pioneered by Shinya Yamanakas lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells.[57] He was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent." [58]

In 2007 it was shown that pluripotent stem cells highly similar to embryonic stem cells can be generated by the delivery of three genes (Oct4, Sox2, and Klf4) to differentiated cells.[59] The delivery of these genes "reprograms" differentiated cells into pluripotent stem cells, allowing for the generation of pluripotent stem cells without the embryo. Because ethical concerns regarding embryonic stem cells typically are about their derivation from terminated embryos, it is believed that reprogramming to these "induced pluripotent stem cells" (iPS cells) may be less controversial. Both human and mouse cells can be reprogrammed by this methodology, generating both human pluripotent stem cells and mouse pluripotent stem cells without an embryo.[60]

This may enable the generation of patient specific ES cell lines that could potentially be used for cell replacement therapies. In addition, this will allow the generation of ES cell lines from patients with a variety of genetic diseases and will provide invaluable models to study those diseases.

However, as a first indication that the induced pluripotent stem cell (iPS) cell technology can in rapid succession lead to new cures, it was used by a research team headed by Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, to cure mice of sickle cell anemia, as reported by Science journal's online edition on December 6, 2007.[61][62]

On January 16, 2008, a California-based company, Stemagen, announced that they had created the first mature cloned human embryos from single skin cells taken from adults. These embryos can be harvested for patient matching embryonic stem cells.[63]

The online edition of Nature Medicine published a study on January 24, 2005, which stated that the human embryonic stem cells available for federally funded research are contaminated with non-human molecules from the culture medium used to grow the cells.[64] It is a common technique to use mouse cells and other animal cells to maintain the pluripotency of actively dividing stem cells. The problem was discovered when non-human sialic acid in the growth medium was found to compromise the potential uses of the embryonic stem cells in humans, according to scientists at the University of California, San Diego.[65]

However, a study published in the online edition of Lancet Medical Journal on March 8, 2005 detailed information about a new stem cell line that was derived from human embryos under completely cell- and serum-free conditions. After more than 6 months of undifferentiated proliferation, these cells demonstrated the potential to form derivatives of all three embryonic germ layers both in vitro and in teratomas. These properties were also successfully maintained (for more than 30 passages) with the established stem cell lines.[66]

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iCON Cell Therapy Platform Launched with Shipment of the 1st BERcellFLEX PODs

COLLEGE STATION, Texas, Sept. 5, 2018 /PRNewswire-PRWeb/ --Following up on the launch of the iCON Turnkey Facility Platform for a mAb manufacturing facility late last year, IPS-Integrated Project Services, LLC and G-CON Manufacturing have successfully designed and delivered the first BERcellFLEX PODs for the manufacturing of autologous cell therapies. The iCON solution provides a pre-fabricated modular cleanroom infrastructure for the drug manufacturers' requirements for both clinical and commercial manufacture of critical therapies. Following the iCON model, IPS provided the engineering design while G-CON built, tested and delivered the BERcellFLEX CAR-T processing suites in both twelve (12) foot and twenty-four (24) foot wide POD configurations.

"This is an exciting time for our companies as the iCON platform is being adopted by clients who recognize that new innovative approaches are needed to meet the growing demand for cell and gene therapy manufacturing" said Dennis Powers, Vice President of Business Development and Sales Engineering at G-CON Manufacturing Inc. "We believe that the iCON platform approach with its faster and more predictable project schedules for new facility construction are essential for supplying life changing therapies to the patients that need them."

"The gene therapy industry needs standardized solutions to meet its speed to market requirements," said Tom J. Piombino, Vice President & Process Architect at IPS. "In addition to our larger 2K mAb facility platform that we rolled out earlier this year, the BERcellFLEX12 and 24 represent a line of gene/cell therapy products that operating companies can buy today, ready-to-order, in either an open or closed-processing format with little to no engineering time we start fabricating almost immediately after URS alignment. Multiple cellFLEX units can be installed to scale up/out from Phase 1 Clinical production to Commercial Manufacturing and serve the needs of thousands of CAR-T patients per year. Being able to meet this critical need is consistent with our vision; we're thrilled to be able to offer this modular solution to help our clients get therapies to their patients."

About iCON The iCON platform, the collaborative efforts of IPS and G-CON Manufacturing, Inc., is redefining facility project execution for the biopharma industry where there is a growing need for more rapidly deployable and flexible manufacturing capability. iCON has launched turnkey designs for monoclonal antibody facilities and autologous cell therapies, and is developing platforms for cell and gene therapies, vaccines, OSD, and aseptic filling. An iCON solution can be deployed for:

About G-CON G-CON Manufacturing designs, produces and installs prefabricated cleanroom PODs. G-CON's cleanroom POD portfolio encompasses a variety of different dimensions and purposes, from laboratory environments to personalized medicine and production process platforms. The POD cleanroom units are unique from traditional cleanroom structures due to the ease of scalability, mobility and the ability to repurpose the PODs once the production process reaches the end of its lifecycle. For more information, please visit the Company's website at http://www.gconbio.com.

About IPS IPS is a global leader in developing innovative facility and bioprocess solutions for the biotechnology and pharmaceutical industries. Through operational expertise and industry-leading knowledge, skill and passion, IPS provides consulting, architecture, engineering, construction management, and compliance services that allow clients to create and manufacture life-impacting products around the world. Headquartered in Blue Bell, PA-USA, IPS is one of the largest multi-national companies servicing the life sciences industry with over 1,100 professionals in the US, Canada, Brazil, UK, Ireland, Switzerland, Singapore, China, and India. Visit our website at http://www.ipsdb.com.

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"Muscle fiber" and "Myofiber" redirect here. For protein structures inside cells, see Myofibril.

A myocyte (also known as a muscle cell)[1] is the type of cell found in muscle tissue. Myocytes are long, tubular cells that develop from myoblasts to form muscles in a process known as myogenesis.[2] There are various specialized forms of myocytes: cardiac, skeletal, and smooth muscle cells, with various properties. The striated cells of cardiac and skeletal muscles are referred to as muscle fibers.[3] Cardiomyocytes are the muscle fibres that form the chambers of the heart, and have a single central nucleus.[4] Skeletal muscle fibers help support and move the body and tend to have peripheral nuclei.[5][6] Smooth muscle cells control involuntary movements such as the peristalsis contractions in the oesophagus and stomach.

The unusual microstructure of muscle cells has led cell biologists to create specialized terminology. However, each term specific to muscle cells has a counterpart that is used in the terminology applied to other types of cells:

The sarcoplasm is the cytoplasm of a muscle fiber. Most of the sarcoplasm is filled with myofibrils, which are long protein cords composed of myofilaments. The sarcoplasm is also composed of glycogen, a polysaccharide of glucose monomers, which provides energy to the cell with heightened exercise, and myoglobin, the red pigment that stores oxygen until needed for muscular activity.[7]

There are three types of myofilaments:[7]

Together, these myofilaments work to produce a muscle contraction.

The sarcoplasmic reticulum, a specialized type of smooth endoplasmic reticulum, forms a network around each myofibril of the muscle fiber. This network is composed of groupings of two dilated end-sacs called terminal cisternae, and a single transverse tubule, or T tubule, which bores through the cell and emerge on the other side; together these three components form the triads that exist within the network of the sarcoplasmic reticulum, in which each T tubule has two terminal cisternae on each side of it. The sarcoplasmic reticulum serves as reservoir for calcium ions, so when an action potential spreads over the T tubule, it signals the sarcoplasmic reticulum to release calcium ions from the gated membrane channels to stimulate a muscle contraction.[7][8]

The sarcolemma is the cell membrane of a striated muscle fiber and receives and conducts stimuli. At the end of each muscle fiber, the outer layer of the sarcolemma combines with tendon fibers.[9] Within the muscle fiber pressed against the sarcolemma are multiple flattened nuclei; this multinuclear condition results from multiple myoblasts fusing to produce each muscle fiber, where each myoblast contributes one nucleus.[7]

The cell membrane of a myocyte has several specialized regions, which may include the intercalated disk and the transverse tubular system. The cell membrane is covered by a lamina coat which is approximately 50nm wide. The laminar coat is separable into two layers; the lamina densa and lamina lucida. In between these two layers can be several different types of ions, including calcium.[10]

The cell membrane is anchored to the cell's cytoskeleton by anchor fibers that are approximately 10nm wide. These are generally located at the Z lines so that they form grooves and transverse tubules emanate. In cardiac myocytes this forms a scalloped surface.[10]

The cytoskeleton is what the rest of the cell builds off of and has two primary purposes; the first is to stabilize the topography of the intracellular components and the second is to help control the size and shape of the cell. While the first function is important for biochemical processes, the latter is crucial in defining the surface to volume ratio of the cell. This heavily influences the potential electrical properties of excitable cells. Additionally deviation from the standard shape and size of the cell can have negative prognostic impact.[10]

Each muscle fiber contains myofibrils, which are very long chains of sarcomeres, the contractile units of the cell. A cell from the biceps brachii muscle may contain 100,000 sarcomeres.[11][verification needed] The myofibrils of smooth muscle cells are not arranged into sarcomeres. The sarcomeres are composed of thin and thick filaments. Thin filaments are made of actin and attach at Z lines which help them line up correctly with each other.[12] Troponins are found at intervals along the thin filaments. Thick filaments are made of the elongated protein myosin.[13] The sarcomere does not contain organelles or a nucleus. Sarcomeres are marked by Z lines which show the beginning and the end of a sarcomere. Individual myocytes are surrounded by endomysium.

Myocytes are bound together by perimysium into bundles called fascicles; the bundles are then grouped together to form muscle tissue, which is enclosed in a sheath of epimysium. The perimysium contains blood vessels and nerves which provide for the muscle fibers. Muscle spindles are distributed throughout the muscles and provide sensory feedback information to the central nervous system. Myosin is shaped like a long shaft with a rounded end pointed out towards the surface. This structure forms the cross bridge that connects with the thin filaments.[13]

A myoblast is a type of embryonic progenitor cell that differentiates to give rise to muscle cells.[14] Differentiation is regulated by myogenic regulatory factors, including MyoD, Myf5, myogenin, and MRF4.[15] GATA4 and GATA6 also play a role in myocyte differentiation.[16]

Skeletal muscle fibers are made when myoblasts fuse together; muscle fibers therefore are cells with multiple nuclei, known as myonuclei, with each cell nucleus originating from a single myoblast. The fusion of myoblasts is specific to skeletal muscle (e.g., biceps brachii) and not cardiac muscle or smooth muscle.

Myoblasts in skeletal muscle that do not form muscle fibers dedifferentiate back into myosatellite cells. These satellite cells remain adjacent to a skeletal muscle fiber, situated between the sarcolemma and the basement membrane[17] of the endomysium (the connective tissue investment that divides the muscle fascicles into individual fibers). To re-activate myogenesis, the satellite cells must be stimulated to differentiate into new fibers.

Myoblasts and their derivatives, including satellite cells, can now be generated in vitro through directed differentiation of pluripotent stem cells.[18]

Kindlin-2 plays a role in developmental elongation during myogenesis.[19]

Muscle fibers grow when exercised and shrink when not in use. This is due to the fact that exercise stimulates the increase in myofibrils which increase the overall size of muscle cells. Well exercised muscles can not only add more size but can also develop more mitochondria, myoglobin, glycogen and a higher density of capillaries. However muscle cells cannot divide to produce new cells, and as a result we have fewer muscle cells as an adult than a newborn.[20]

When contracting, thin and thick filaments slide with respect to each other by using adenosine triphosphate. This pulls the Z discs closer together in a process called sliding filament mechanism. The contraction of all the sarcomeres results in the contraction of the whole muscle fiber. This contraction of the myocyte is triggered by the action potential over the cell membrane of the myocyte. The action potential uses transverse tubules to get from the surface to the interior of the myocyte, which is continuous within the cell membrane. Sarcoplasmic reticula are membranous bags that transverse tubules touch but remain separate from. These wrap themselves around each sarcomere and are filled with Ca2+.[13]

Excitation of a myocyte causes depolarization at its synapses, the neuromuscular junctions, which triggers action potential. With a singular neuromuscular junction, each muscle fiber receives input from just one somatic efferent neuron. Action potential in a somatic efferent neuron causes the release of the neurotransmitter acetylcholine.[21]

When the acetylcholine is released it diffuses across the synapse and binds to a receptor on the sarcolemma, a term unique to muscle cells that refers to the cell membrane. This initiates an impulse that travels across the sarcolemma.[20]

When the action potential reaches the sarcoplasmic reticulum it triggers the release of Ca2+ from the Ca2+ channels. The Ca2+ flows from the sarcoplasmic reticulum into the sarcomere with both of its filaments. This causes the filaments to start sliding and the sarcomeres to become shorter. This requires a large amount of ATP, as it is used in both the attachment and release of every myosin head. Very quickly Ca2+ is actively transported back into the sarcoplasmic reticulum, which blocks the interaction between the thin and thick filament. This in turn causes the muscle cell to relax.[20]

There are four main different types of muscle contraction: twitch, treppe, tetanus and isometric/isotonic. Twitch contraction is the process previously described, in which a single stimulus signals for a single contraction. In twitch contraction the length of the contraction may vary depending on the size of the muscle cell. During treppe (or summation) contraction muscles do not start at maximum efficiency; instead they achieve increased strength of contraction due to repeated stimuli. Tetanus involves a sustained contraction of muscles due to a series of rapid stimuli, which can continue until the muscles fatigue. Isometric contractions are skeletal muscle contractions that do not cause movement of the muscle. However, isotonic contractions are skeletal muscle contractions that do cause movement.[20]

Specialized cardiomyocytes located in the sinoatrial node are responsible for generating the electrical impulses that control the heart rate. These electrical impulses coordinate contraction throughout the remaining heart muscle via the electrical conduction system of the heart. Sinoatrial node activity is modulated, in turn, by nerve fibres of both the sympathetic and parasympathetic nervous systems. These systems act to increase and decrease, respectively, the rate of production of electrical impulses by the sinoatrial node.

There are numerous methods employed for fiber-typing, and confusion between the methods is common among non-experts. Two commonly confused methods are histochemical staining for myosin ATPase activity and immunohistochemical staining for Myosin heavy chain (MHC) type. Myosin ATPase activity is commonlyand correctlyreferred to as simply "fiber type", and results from the direct assaying of ATPase activity under various conditions (e.g. pH).[22] Myosin heavy chain staining is most accurately referred to as "MHC fiber type", e.g. "MHC IIa fibers", and results from determination of different MHC isoforms.[22] These methods are closely related physiologically, as the MHC type is the primary determinant of ATPase activity. Note, however, that neither of these typing methods is directly metabolic in nature; they do not directly address oxidative or glycolytic capacity of the fiber. When "type I" or "type II" fibers are referred to generically, this most accurately refers to the sum of numerical fiber types (I vs. II) as assessed by myosin ATPase activity staining (e.g. "type II" fibers refers to type IIA + type IIAX + type IIXA... etc.).

Below is a table showing the relationship between these two methods, limited to fiber types found in humans. Note the sub-type capitalization used in fiber typing vs. MHC typing, and that some ATPase types actually contain multiple MHC types. Also, a subtype B or b is not expressed in humans by either method.[23] Early researchers believed humans to express a MHC IIb, which led to the ATPase classification of IIB. However, later research showed that the human MHC IIb was in fact IIx,[23] indicating that the IIB is better named IIX. IIb is expressed in other mammals, so is still accurately seen (along with IIB) in the literature. Non human fiber types include true IIb fibers, IIc, IId, etc.

Further fiber typing methods are less formally delineated, and exist on more of a spectrum. They tend to be focused more on metabolic and functional capacities (i.e., oxidative vs. glycolytic, fast vs. slow contraction time). As noted above, fiber typing by ATPase or MHC does not directly measure or dictate these parameters. However, many of the various methods are mechanistically linked, while others are correlated in vivo.[26][27] For instance, ATPase fiber type is related to contraction speed, because high ATPase activity allows faster crossbridge cycling.[22] While ATPase activity is only one component of contraction speed, type I fibers are "slow", in part, because they have low speeds of ATPase activity in comparison to type II fibers. However, measuring contraction speed is not the same as ATPase fiber typing.

Because of these types of relationships, Type I and Type II fibers have relatively distinct metabolic, contractile, and motor-unit properties. The table below differentiates these types of properties. These types of propertieswhile they are partly dependent on the properties of individual fiberstend to be relevant and measured at the level of the motor unit, rather than individual fiber.[22]

Traditionally, fibers were categorized depending on their varying color, which is a reflection of myoglobin content. Type I fibers appear red due to the high levels of myoglobin. Red muscle fibers tend to have more mitochondria and greater local capillary density. These fibers are more suited for endurance and are slow to fatigue because they use oxidative metabolism to generate ATP (adenosine triphosphate). Less oxidative type II fibers are white due to relatively low myoglobin and a reliance on glycolytic enzymes.

Fibers can also be classified on their twitch capabilities, into fast and slow twitch. These traits largely, but not completely, overlap the classifications based on color, ATPase, or MHC.

Some authors define a fast twitch fiber as one in which the myosin can split ATP very quickly. These mainly include the ATPase type II and MHC type II fibers. However, fast twitch fibers also demonstrate a higher capability for electrochemical transmission of action potentials and a rapid level of calcium release and uptake by the sarcoplasmic reticulum. The fast twitch fibers rely on a well-developed, short term, glycolytic system for energy transfer and can contract and develop tension at 23 times the rate of slow twitch fibers. Fast twitch muscles are much better at generating short bursts of strength or speed than slow muscles, and so fatigue more quickly.[28]

The slow twitch fibers generate energy for ATP re-synthesis by means of a long term system of aerobic energy transfer. These mainly include the ATPase type I and MHC type I fibers. They tend to have a low activity level of ATPase, a slower speed of contraction with a less well developed glycolytic capacity. They contain high mitochondrial volumes, and the high levels of myoglobin that give them a red pigmentation. They have been demonstrated to have high concentrations of mitochondrial enzymes, thus they are fatigue resistant. Slow twitch muscles fire more slowly than fast twitch fibers, but are able to contract for a longer time before fatiguing.[28]

Individual muscles tend to be a mixture of various fiber types, but their proportions vary depending on the actions of that muscle and the species. For instance, in humans, the quadriceps muscles contain ~52% type I fibers, while the soleus is ~80% type I.[29] The orbicularis oculi muscle of the eye is only ~15% type I.[29] Motor units within the muscle, however, have minimal variation between the fibers of that unit. It is this fact that makes the size principal of motor unit recruitment viable.

The total number of skeletal muscle fibers has traditionally been thought not to change.It is believed there are no sex or age differences in fiber distribution; however, proportions of fiber types vary considerably from muscle to muscle and person to person.Sedentary men and women (as well as young children) have 45% type II and 55% type I fibers.[citation needed]People at the higher end of any sport tend to demonstrate patterns of fiber distribution e.g. endurance athletes show a higher level of type I fibers.Sprint athletes, on the other hand, require large numbers of type IIX fibers.Middle distance event athletes show approximately equal distribution of the two types. This is also often the case for power athletes such as throwers and jumpers.It has been suggested that various types of exercise can induce changes in the fibers of a skeletal muscle.[30]It is thought that if you perform endurance type events for a sustained period of time, some of the type IIX fibers transform into type IIA fibers. However, there is no consensus on the subject.It may well be that the type IIX fibers show enhancements of the oxidative capacity after high intensity endurance training which brings them to a level at which they are able to perform oxidative metabolism as effectively as slow twitch fibers of untrained subjects. This would be brought about by an increase in mitochondrial size and number and the associated related changes, not a change in fiber type.

Continued here:
Myocyte - Wikipedia

1. Cellular Dynamics International, Owned by FujiFilm Holdings

Founded in 2004 and listed on NASDAQ in July 2013, Cellular Dynamics International (CDI) is headquartered in Madison, Wisconsin. The company is known for its extremely robust patent portfolio containing more than 900 patents.

According to the company, CDI is the worlds largest producer of fully functional human cells derived from induced pluripotent stem (iPS) cells.[1] Their trademarked, iCell Cardiomyocytes, derived from iPSCs, are human cardiac cells used to aid drug discovery, improve the predictability of a drugs worth, and screen for toxicity. In addition, CDI provides: iCell Endothelial Cells for use in vascular-targeted drug discovery and tissue regeneration, iCell Hepatocytes, and iCell Neurons for pre-clinical drug discovery, toxicity testing, disease prediction, and cellular research.[2]

Induced pluripotent stem cells were first produced in 2006 from mouse cells and in 2007 from human cells, by Shinya Yamanaka at Kyoto University,[3] who also won the Nobel Prize in Medicine or Physiology for his work on iPSCs.[4] Yamanaka has ties to Cellular Dynamics International as a member of the scientific advisory board of iPS Academia Japan. IPS Academia Japan was originally established to manage the patents and technology of Yamanakas work, and is now the distributor of several of Cellular Dynamics products, including iCell Neurons, iCell Cardiomyocytes, and iCell Endothelial Cells.[5]

Importantly, in 2010 Cellular Dynamics became the first foreign company to be granted rights to use Yamanakas iPSC patent portfolio. Not only has CDI licensed rights to Yamanakas patents, but it also has a license to use Otsu, Japan-based Takara Bios RetroNectin product, which it uses as a tool to produce its iCell and MyCell products.[6]

Furthermore, in February 2015, Cellular Dynamics International announced it would be manufacturing cGMP HLA Superdonor stem cell lines that will support cellular therapy applications through genetic matching.[8] Currently, CDI has two HLA super donor cell lines that provide a partial HLA match to approximately 19% of the population within the U.S., and it aims to expand its master stem cell bank by collecting more donor cell lines that will cover 95% of the U.S. population.[9] The HLA super donor cell lines were manufactured using blood samples and used to produce pluripotent iPSC lines, giving the cells the capacity to differentiate into nearly any cell within the human body.

On March 30, 2015, Fujifilm Holdings Corporation announced that it was acquiring CDI for $307 million, allowing CDI to continue to run its operations in Madison, Wisconsin, and Novato, California as a consolidated subsidiary of Fujifilm.[14] A key benefit of the merger is that CDIs technology platform enables the production of high-quality fully functioning iPSCs (and other human cells) on an industrial scale, while Fujifilm has developed highly-biocompatible recombinant peptides that can be shaped into a variety of forms for use as a cellular scaffold in regenerative medicine when used in conjunction with CDIs products.[15]

Additionally, Fujifilm has been strengthening its presence in the regenerative medicine field over the past several years, including a recent A$4M equity stake in Cynata Therapeutics and an acquisition of Japan Tissue Engineering Co. Ltd. in December 2014. Most commonly called J-TEC, Japan Tissue Engineering Co. Ltd. successfully launched the first two regenerative medicine products in the country of Japan. According to Kaz Hirao, CEO of CDI, It is very important for CDI to get into the area of therapeutic products, and we can accelerate this by aligning it with strategic and technical resources present within J-TEC.

Kaz Hirao also states, For our Therapeutic businesses, we will aim to file investigational new drugs (INDs) with the U.S. FDA for the off-the-shelf iPSC-derived allogeneic therapeutic products. Currently, we are focusing on retinal diseases, heart disorders, Parkinsons disease, and cancers. For those four indicated areas, we would like to file several INDs within the next five years.

Finally, in September 2015, CDI again strengthened its iPS cell therapy capacity by setting up a new venture, Opsis Therapeutics. Opsis is focused on discovering and developing novel medicines to treat retinal diseases and is a partnership with Dr. David Gamm, the pioneer of iPS cell-derived retinal differentiation and transplantation.

In summary, several key events indicate CDIs commitment to developing iPS cell therapeutics, including:

Australian stem cell company Cynata Therapeutics (ASX:CYP) is taking a unique approach by creating allogeneic iPSC derived mesenchyal stem cell (MSCs) on a commercial scale. Cynatas Cymerus technology utilizes iPSCs provided by Cellular Dynamics International, a Fujifilm company, as the starting material for generating mesenchymoangioblasts (MCAs), and subsequently, for manufacturing clinical-grade MSCs. According to Cynatas Executive Chairman Stewart Washer who was interviewed by The Life Sciences Report, The Cymerus technology gets around the loss of potency with the unlimited iPS cellor induced pluripotent stem cellwhich is basically immortal.

On January 19, 2017, Fujifilm took an A$3.97 million (10%) strategic equity stake in Cynata, positioning the parties to collaborate on the further development and commercialization of Cynatas lead Cymerus therapeutic MSC product CYP-001 for graft-versus-host disease (GvHD). (CYP-001 is the product designation unique to the GVHD indication). The Fujifilm partnership also includes potential future upfront and milestone payments in excess of A$60 million and double-digit royalties on CYP-001 product net sales for Cynata Therapeutics, as well as a strategic relationship for the potential future manufacture of CYP-001 and certain rights to other Cynata technology.

One of the key inventors of Cynatas technology is Igor Slukvin, MD, Ph.D., Scientific Founder of Cellular Dynamics International (CDI) and Cynata Therapeutics. Dr. Slukvin has released more than 70 publications about stem cell topics, including the landmark article in Cell describing the now patented Cymerus technique. Dr. Slukvins co-inventor is Dr. James Thomson, the first person to isolate an embryonic stem cell (ESC) and one of the first people to create a human induced pluripotent stem cell (hiPSC). Dr. James Thompson was the Founder of CDI in 2004.

There are three strategic connections between Cellular Dynamics International (CDI) and Cynata Therapeutics, which include:

Recently, Cynata received advice from the UK Medicines and Healthcare products Regulatory Agency (MHRA) that its Phase I clinical trial application has been approved, titled An Open-Label Phase 1 Study to Investigate the Safety and Efficacy of CYP-001 for the Treatment of Adults With Steroid-Resistant Acute Graft Versus Host Disease. It will be the worlds first clinical trial involving a therapeutic product derived from allogeneic (unrelated to the patient) induced pluripotent stem cells (iPSCs).

Participants for Cynatas upcoming Phase I clinical trial will be adults who have undergone an allogeneic haematopoietic stem cell transplant (HSCT) to treat a hematological disorder and subsequently been diagnosed with steroid-resistant Grade II-IV GvHD. The primary objective of the trial is to assess safety and tolerability, while the secondary objective is to evaluate the efficacy of two infusions of CYP-001 in adults with steroid-resistant GvHD.

Using Professor Yamanakas Nobel Prize-winning achievement of ethically uncontentious iPSCs and CDIs high-quality iPSCs as source material, Cynata has achieved two world firsts:

Cynata has also released promising pre-clinical data in Asthma, Myocardial Infarction (Heart Attack), and Critical Limb Ischemia.

There are four key advantages of Cynatas proprietary Cymerus MSC manufacturing platform. Because the proprietary Cymerus technology allows nearly unlimited production of MSCs from a single iPSC donor, there is batch-to-batch uniformity. Utilizing a consistent starting material allows for a standardized cell manufacturing process and a consistent cell therapy product. Unlike other companies involved with MSC manufacturing, Cynata does not require a constant stream of new donors in order to source fresh stem cells for its cell manufacturing process, nor does it require the massive expansion of MSCs necessitated by reliance on freshly isolated donations.

Finally, Cynata has achieved a cost-savings advantage through its unique approach to MSC manufacturing. Its proprietary Cymerus technology addresses a critical shortcoming in existing methods of production of MSCs for therapeutic use, which is the ability to achieve economic manufacture at commercial scale.

On June 22, 2016, RIKEN announced that it is resuming its retinal induced pluripotent stem cell (iPSC) study in partnership with Kyoto University.

2013 was the first time in which clinical research involving transplant of iPSCs into humans was initiated, led by Masayo Takahashi of the RIKEN Center for Developmental Biology (CDB) in Kobe, Japan. Dr. Takahashi and her team were investigating the safety of iPSC-derived cell sheets in patients with wet-type age-related macular degeneration. Although the trial was initiated in 2013 and production of iPSCs from patients began at that time, it was not until August of 2014 that the first patient, a Japanese woman, was implanted with retinal tissue generated using iPSCs derived from her own skin cells.

A team of three eye specialists, led by Yasuo Kurimoto of the Kobe City Medical Center General Hospital, implanted a 1.3 by 3.0mm sheet of iPSC-derived retinal pigment epithelium cells into the patients retina.[196] Unfortunately, the study was suspended in 2015 due to safety concerns. As the lab prepared to treat the second trial participant, Yamanakas team identified two small genetic changes in the patients iPSCs and the retinal pigment epithelium (RPE) cells derived from them. Therefore, it is major news that the RIKEN Institute will now be resuming the worlds first clinical study involving the use of iPSC-derived cells in humans.

According to the Japan Times, this attempt at the clinical study will involve allogeneic rather than autologous iPSC-derived cells for purposes of cost and time efficiency. Specifically, the researchers will be developing retinal tissues from iPS cells supplied by Kyoto Universitys Center for iPS Cell Research and Application, an institution headed by Nobel prize winner Shinya Yamanaka. To learn about this announcement, view this article from Asahi Shimbun, a Tokyo- based newspaper.

In November 2015 Astellas Pharma announced it was acquiring Ocata Therapeutics for $379M. Ocata Therapeutics is a biotechnology company that specializes in the development of cellular therapies, using both adult and human embryonic stem cells to develop patient-specific therapies. The companys main laboratory and GMP facility are in Marlborough, Massachusetts, and its corporate offices are in Santa Monica, California.

When a number of private companies began to explore the possibility of using artificially re-manufactured iPSCs for therapeutic purposes, one such company that was ready to capitalize on the breakthrough technology was Ocata Therapeutics, at the time called Advanced Cell Technology. In 2010, the company announced that it had discovered several problematic issues while conducting experiments for the purpose of applying for U.S. Food and Drug Administration approval to use iPSCs in therapeutic applications. Concerns such as premature cell death, mutation into cancer cells, and low proliferation rates were some of the problems that surfaced. [17]

As a result, the company shifted its induced pluripotent stem cell approach to producing iPS cell-derived human platelets, as one of the benefits of a platelet-based product is that platelets do not contain nuclei, and therefore, cannot divide or carry genetic information. While the companys Induced Pluripotent Stem Cell-Derived Human Platelet Program received a great deal of media coverage in late 2012, including being awarded the December 2012 honor of being named one of the 10 Ideas that Will Shape the Year by New Scientist Magazine,[178]. Unfortunately, the company did not succeed in moving the concept through to clinical testing in 2013.

Nonetheless, Astellas is clearly continuing to develop Ocatas pluripotent stem cell technologies involving embryonic stem cells (ESCs) and induced pluripotent stem cells (iPS cells). In a November 2015 presentation by Astellas President and CEO, Yoshihiko Hatanaka, he indicated that the company will aim to develop an Ophthalmic Disease Cell Therapy Franchise based around its embryonic stem cell (ESC) and induced pluripotent stem cell (iPS cell) technology. [19]

What other companies are developing iPSC derived therapeutics and products? Share your thoughts in the comments below.

BioInformant is the first and only market research firm to specialize in the stem cell industry. BioInformant research has been cited by major news outlets that include the Wall Street Journal, Nature Biotechnology, Xconomy, and Vogue Magazine. Serving Fortune 500 leaders that include GE Healthcare, Pfizer, and Goldman Sachs. BioInformant is your global leader in stem cell industry data.

Footnotes[1] CellularDynamics.com (2014). About CDI. Available at: http://www.cellulardynamics.com/about/index.html. Web. 1 Apr. 2015.[2] Ibid.[3] Takahashi K, Yamanaka S (August 2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126 (4): 66376.[4] 2012 Nobel Prize in Physiology or Medicine Press Release. Nobelprize.org. Nobel Media AB 2013. Web. 7 Feb 2014. Available at: http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/press.html. Web. 1 Apr. 2015.[5] Striklin, D (Jan 13, 2014). Three Companies Banking on Regenerative Medicine. Wall Street Cheat Sheet. Retrieved Feb 1, 2014 from, http://wallstcheatsheet.com/stocks/3-companies-banking-on-regenerative-medicine.html/?a=viewall.%5B6%5D Striklin, D (2014). Three Companies Banking on Regenerative Medicine. Wall Street Cheat Sheet [Online]. Available at: http://wallstcheatsheet.com/stocks/3-companies-banking-on-regenerative-medicine.html/?a=viewall. Web. 1 Apr. 2015.[7] Cellular Dynamics International (July 30, 2013). Cellular Dynamics International Announces Closing of Initial Public Offering [Press Release]. Retrieved from http://www.cellulardynamics.com/news/pr/2013_07_30.html.%5B8%5D Investors.cellulardynamics.com,. Cellular Dynamics Manufactures Cgmp HLA Superdonor Stem Cell Lines To Enable Cell Therapy With Genetic Matching (NASDAQ:ICEL). N.p., 2015. Web. 7 Mar. 2015.[9] Ibid.[10] Cellulardynamics.com,. Cellular Dynamics | Mycell Products. N.p., 2015. Web. 7 Mar. 2015.[11]Sirenko, O. et al. Multiparameter In Vitro Assessment Of Compound Effects On Cardiomyocyte Physiology Using Ipsc Cells.Journal of Biomolecular Screening 18.1 (2012): 39-53. Web. 7 Mar. 2015.[12] Sciencedirect.com,. Prevention Of -Amyloid Induced Toxicity In Human Ips Cell-Derived Neurons By Inhibition Of Cyclin-Dependent Kinases And Associated Cell Cycle Events. N.p., 2015. Web. 7 Mar. 2015.[13] Sciencedirect.com,. HER2-Targeted Liposomal Doxorubicin Displays Enhanced Anti-Tumorigenic Effects Without Associated Cardiotoxicity. N.p., 2015. Web. 7 Mar. 2015.[14] Cellular Dynamics International, Inc. Fujifilm Holdings To Acquire Cellular Dynamics International, Inc.. GlobeNewswire News Room. N.p., 2015. Web. 7 Apr. 2015.[15] Ibid.[16] Cyranoski, David. Japanese Woman Is First Recipient Of Next-Generation Stem Cells. Nature (2014): n. pag. Web. 6 Mar. 2015.[17] Advanced Cell Technologies (Feb 11, 2011). Advanced Cell and Colleagues Report Therapeutic Cells Derived From iPS Cells Display Early Aging [Press Release]. Available at: http://www.advancedcell.com/news-and-media/press-releases/advanced-cell-and-colleagues-report-therapeutic-cells-derived-from-ips-cells-display-early-aging/.%5B18%5D Advanced Cell Technology (Dec 20, 2012). New Scientist Magazine Selects ACTs Induced Pluripotent Stem (iPS) Cell-Derived Human Platelet Program As One of 10 Ideas That Will Shape The Year [Press Release]. Available at: http://articles.latimes.com/2009/mar/06/science/sci-stemcell6. Web. 9 Apr. 2015.[19] Astellas Pharma (2015). Acquisition of Ocata Therapeutics New Step Forward in Ophthalmology with Cell Therapy Approach. Available at: https://www.astellas.com/en/corporate/news/pdf/151110_2_Eg.pdf. Web. 29 Jan. 2017.

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Market Players Developing iPS Cell Therapies - BioInformant

The old rats appeared newly invigorated after receiving their injections. As hoped, the cardiac stem cells improved heart function yet also provided additional benefits. The rats' fur fur, shaved for surgery, grew back more quickly than expected, and their chromosomal telomeres, which commonly shrink with age, lengthened.

The old rats receiving the cardiac stem cells also had increased stamina overall, exercising more than before the infusion.

"It's extremely exciting," said Dr. Eduardo Marbn, primary investigator on the research and director of the Cedars-Sinai Heart Institute. Witnessing "the systemic rejuvenating effects," he said, "it's kind of like an unexpected fountain of youth."

"We've been studying new forms of cell therapy for the heart for some 12 years now," Marbn said.

Some of this research has focused on cardiosphere-derived cells.

"They're progenitor cells from the heart itself," Marbn said. Progenitor cells are generated from stem cells and share some, but not all, of the same properties. For instance, they can differentiate into more than one kind of cell like stem cells, but unlike stem cells, progenitor cells cannot divide and reproduce indefinitely.

Since heart failure with preserved ejection fraction is similar to aging, Marbn decided to experiment on old rats, ones that suffered from a type of heart problem "that's very typical of what we find in older human beings: The heart's stiff, and it doesn't relax right, and it causes fluid to back up some," Marbn explained.

He and his team injected cardiosphere-derived cells from newborn rats into the hearts of 22-month-old rats -- that's elderly for a rat. Similar old rats received a placebo injection of saline solution. Then, Marbn and his team compared both groups to young rats that were 4 months old. After a month, they compared the rats again.

Even though the cells were injected into the heart, their effects were noticeable throughout the body, Marbn said

"The animals could exercise further than they could before by about 20%, and one of the most striking things, especially for me (because I'm kind of losing my hair) the animals ... regrew their fur a lot better after they'd gotten cells" compared with the placebo rats, Marbn said.

The rats that received cardiosphere-derived cells also experienced improved heart function and showed longer heart cell telomeres.

Why did it work?

The working hypothesis is that the cells secrete exosomes, tiny vesicles that "contain a lot of nucleic acids, things like RNA, that can change patterns of the way the tissue responds to injury and the way genes are expressed in the tissue," Marbn said.

It is the exosomes that act on the heart and make it better as well as mediating long-distance effects on exercise capacity and hair regrowth, he explained.

Looking to the future, Marbn said he's begun to explore delivering the cardiac stem cells intravenously in a simple infusion -- instead of injecting them directly into the heart, which would be a complex procedure for a human patient -- and seeing whether the same beneficial effects occur.

Dr. Gary Gerstenblith, a professor of medicine in the cardiology division of Johns Hopkins Medicine, said the new study is "very comprehensive."

"Striking benefits are demonstrated not only from a cardiac perspective but across multiple organ systems," said Gerstenblith, who did not contribute to the new research. "The results suggest that stem cell therapies should be studied as an additional therapeutic option in the treatment of cardiac and other diseases common in the elderly."

Todd Herron, director of the University of Michigan Frankel Cardiovascular Center's Cardiovascular Regeneration Core Laboratory, said Marbn, with his previous work with cardiac stem cells, has "led the field in this area."

"The novelty of this bit of work is, they started to look at more precise molecular mechanisms to explain the phenomenon they've seen in the past," said Herron, who played no role in the new research.

One strength of the approach here is that the researchers have taken cells "from the organ that they want to rejuvenate, so that makes it likely that the cells stay there in that tissue," Herron said.

He believes that more extensive study, beginning with larger animals and including long-term followup, is needed before this technique could be used in humans.

"We need to make sure there's no harm being done," Herron said, adding that extending the lifetime and improving quality of life amounts to "a tradeoff between the potential risk and the potential good that can be done."

Capicor hasn't announced any plans to do studies in aging, but the possibility exists.

After all, the cells have been proven "completely safe" in "over 100 human patients," so it would be possible to fast-track them into the clinic, Marbn explained: "I can't tell you that there are any plans to do that, but it could easily be done from a safety viewpoint."

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Cardiac stem cells rejuvenate rats' aging hearts ... - CNN

Charles A. Goldthwaite, Jr., Ph.D.

Cardiovascular disease (CVD), which includes hypertension, coronary heart disease (CHD), stroke, and congestive heart failure (CHF), has ranked as the number one cause of death in the United States every year since 1900 except 1918, when the nation struggled with an influenza epidemic.1 In 2002, CVD claimed roughly as many lives as cancer, chronic lower respiratory diseases, accidents, diabetes mellitus, influenza, and pneumonia combined. According to data from the 19992002 National Health and Nutrition Examination Survey (NHANES), CVD caused approximately 1.4 million deaths (38.0 percent of all deaths) in the U.S. in 2002. Nearly 2600 Americans die of CVD each day, roughly one death every 34 seconds. Moreover, within a year of diagnosis, one in five patients with CHF will die. CVD also creates a growing economic burden; the total health care cost of CVD in 2005 was estimated at $393.5 billion dollars.

Given the aging of the U.S. population and the relatively dramatic recent increases in the prevalence of cardiovascular risk factors such as obesity and type 2 diabetes,2,3 CVD will continue to be a significant health concern well into the 21st century. However, improvements in the acute treatment of heart attacks and an increasing arsenal of drugs have facilitated survival. In the U.S. alone, an estimated 7.1 million people have survived a heart attack, while 4.9 million live with CHF.1 These trends suggest an unmet need for therapies to regenerate or repair damaged cardiac tissue.

Ischemic heart failure occurs when cardiac tissue is deprived of oxygen. When the ischemic insult is severe enough to cause the loss of critical amounts of cardiac muscle cells (cardiomyocytes), this loss initiates a cascade of detrimental events, including formation of a non-contractile scar, ventricular wall thinning (see Figure 6.1), an overload of blood flow and pressure, ventricular remodeling (the overstretching of viable cardiac cells to sustain cardiac output), heart failure, and eventual death.4 Restoring damaged heart muscle tissue, through repair or regeneration, therefore represents a fundamental mechanistic strategy to treat heart failure. However, endogenous repair mechanisms, including the proliferation of cardiomyocytes under conditions of severe blood vessel stress or vessel formation and tissue generation via the migration of bone-marrow-derived stem cells to the site of damage, are in themselves insufficient to restore lost heart muscle tissue (myocardium) or cardiac function.5 Current pharmacologic interventions for heart disease, including beta-blockers, diuretics, and angiotensin-converting enzyme (ACE) inhibitors, and surgical treatment options, such as changing the shape of the left ventricle and implanting assistive devices such as pacemakers or defibrillators, do not restore function to damaged tissue. Moreover, while implantation of mechanical ventricular assist devices can provide long-term improvement in heart function, complications such as infection and blood clots remain problematic.6 Although heart transplantation offers a viable option to replace damaged myocardium in selected individuals, organ availability and transplant rejection complications limit the widespread practical use of this approach.

Figure 6.1. Normal vs. Infarcted Heart. The left ventricle has a thick muscular wall, shown in cross-section in A. After a myocardial infarction (heart attack), heart muscle cells in the left ventricle are deprived of oxygen and die (B), eventually causing the ventricular wall to become thinner (C).

2007 Terese Winslow

The difficulty in regenerating damaged myocardial tissue has led researchers to explore the application of embryonic and adult-derived stem cells for cardiac repair. A number of stem cell types, including embryonic stem (ES) cells, cardiac stem cells that naturally reside within the heart, myoblasts (muscle stem cells), adult bone marrow-derived cells, mesenchymal cells (bone marrow-derived cells that give rise to tissues such as muscle, bone, tendons, ligaments, and adipose tissue), endothelial progenitor cells (cells that give rise to the endothelium, the interior lining of blood vessels), and umbilical cord blood cells, have been investigated to varying extents as possible sources for regenerating damaged myocardium. All have been tested in mouse or rat models, and some have been tested in large animal models such as pigs. Preliminary clinical data for many of these cell types have also been gathered in selected patient populations.

However, clinical trials to date using stem cells to repair damaged cardiac tissue vary in terms of the condition being treated, the method of cell delivery, and the primary outcome measured by the study, thus hampering direct comparisons between trials.7 Some patients who have received stem cells for myocardial repair have reduced cardiac blood flow (myocardial ischemia), while others have more pronounced congestive heart failure and still others are recovering from heart attacks. In some cases, the patient's underlying condition influences the way that the stem cells are delivered to his/her heart (see the section, quot;Methods of Cell Deliveryquot; for details). Even among patients undergoing comparable procedures, the clinical study design can affect the reporting of results. Some studies have focused on safety issues and adverse effects of the transplantation procedures; others have assessed improvements in ventricular function or the delivery of arterial blood. Furthermore, no published trial has directly compared two or more stem cell types, and the transplanted cells may be autologous (i.e., derived from the person on whom they are used) or allogeneic (i.e., originating from another person) in origin. Finally, most of these trials use unlabeled cells, making it difficult for investigators to follow the cells' course through the body after transplantation (see the section quot;Considerations for Using These Stem Cells in the Clinical Settingquot; at the end of this article for more details).

Despite the relative infancy of this field, initial results from the application of stem cells to restore cardiac function have been promising. This article will review the research supporting each of the aforementioned cell types as potential source materials for myocardial regeneration and will conclude with a discussion of general issues that relate to their clinical application.

In 2001, Menasche, et.al. described the successful implantation of autologous skeletal myoblasts (cells that divide to repair and/or increase the size of voluntary muscles) into the post-infarction scar of a patient with severe ischemic heart failure who was undergoing coronary artery bypass surgery.8 Following the procedure, the researchers used imaging techniques to observe the heart's muscular wall and to assess its ability to beat. When they examined patients 5 months after treatment, they concluded that treated hearts pumped blood more efficiently and seemed to demonstrate improved tissue health. This case study suggested that stem cells may represent a viable resource for treating ischemic heart failure, spawning several dozen clinical studies of stem cell therapy for cardiac repair (see Boyle, et.al.7 for a complete list) and inspiring the development of Phase I and Phase II clinical trials. These trials have revealed the complexity of using stem cells for cardiac repair, and considerations for using stem cells in the clinical setting are discussed in a subsequent section of this report.

The mechanism by which stem cells promote cardiac repair remains controversial, and it is likely that the cells regenerate myocardium through several pathways. Initially, scientists believed that transplanted cells differentiated into cardiac cells, blood vessels, or other cells damaged by CVD.911 However, this model has been recently supplanted by the idea that transplanted stem cells release growth factors and other molecules that promote blood vessel formation (angiogenesis) or stimulate quot;residentquot; cardiac stem cells to repair damage.1214 Additional mechanisms for stem-cell mediated heart repair, including strengthening of the post-infarct scar15 and the fusion of donor cells with host cardiomyocytes,16 have also been proposed.

Regardless of which mechanism(s) will ultimately prove to be the most significant in stem-cell mediated cardiac repair, cells must be successfully delivered to the site of injury to maximize the restored function. In preliminary clinical studies, researchers have used several approaches to deliver stem cells. Common approaches include intravenous injection and direct infusion into the coronary arteries. These methods can be used in patients whose blood flow has been restored to their hearts after a heart attack, provided that they do not have additional cardiac dysfunction that results in total occlusion or poor arterial flow.12, 17 Of these two methods, intracoronary infusion offers the advantage of directed local delivery, thereby increasing the number of cells that reach the target tissue relative to the number that will home to the heart once they have been placed in the circulation. However, these strategies may be of limited benefit to those who have poor circulation, and stem cells are often injected directly into the ventricular wall of these patients. This endomyocardial injection may be carried out either via a catheter or during open-heart surgery.18

To determine the ideal site to inject stem cells, doctors use mapping or direct visualization to identify the locations of scars and viable cardiac tissue. Despite improvements in delivery efficiency, however, the success of these methods remains limited by the death of the transplanted cells; as many as 90% of transplanted cells die shortly after implantation as a result of physical stress, myocardial inflammation, and myocardial hypoxia.4 Timing of delivery may slow the rate of deterioration of tissue function, although this issue remains a hurdle for therapeutic approaches.

Embryonic and adult stem cells have been investigated to regenerate damaged myocardial tissue in animal models and in a limited number of clinical studies. A brief review of work to date and specific considerations for the application of various cell types will be discussed in the following sections.

Because ES cells are pluripotent, they can potentially give rise to the variety of cell types that are instrumental in regenerating damaged myocardium, including cardiomyocytes, endothelial cells, and smooth muscle cells. To this end, mouse and human ES cells have been shown to differentiate spontaneously to form endothelial and smooth muscle cells in vitro19 and in vivo,20,21 and human ES cells differentiate into myocytes with the structural and functional properties of cardiomyocytes.2224 Moreover, ES cells that were transplanted into ischemically-injured myocardium in rats differentiated into normal myocardial cells that remained viable for up to four months,25 suggesting that these cells may be candidates for regenerative therapy in humans.

However, several key hurdles must be overcome before human ES cells can be used for clinical applications. Foremost, ethical issues related to embryo access currently limit the avenues of investigation. In addition, human ES cells must go through rigorous testing and purification procedures before the cells can be used as sources to regenerate tissue. First, researchers must verify that their putative ES cells are pluripotent. To prove that they have established a human ES cell line, researchers inject the cells into immunocompromised mice; i.e., mice that have a dysfunctional immune system. Because the injected cells cannot be destroyed by the mouse's immune system, they survive and proliferate. Under these conditions, pluripotent cells will form a teratoma, a multi-layered, benign tumor that contains cells derived from all three embryonic germ layers. Teratoma formation indicates that the stem cells have the capacity to give rise to all cell types in the body.

The pluripotency of ES cells can complicate their clinical application. While undifferentiated ES cells may possibly serve as sources of specific cell populations used in myocardial repair, it is essential that tight quality control be maintained with respect to the differentiated cells. Any differentiated cells that would be used to regenerate heart tissue must be purified before transplantation can be considered. If injected regenerative cells are accidentally contaminated with undifferentiated ES cells, a tumor could possibly form as a result of the cell transplant.4 However, purification methodologies continue to improve; one recent report describes a method to identify and select cardiomyocytes during human ES cell differentiation that may make these cells a viable option in the future.26

This concern illustrates the scientific challenges that accompany the use of all human stem cells, whether derived from embryonic or adult tissues. Predictable control of cell proliferation and differentiation requires additional basic research on the molecular and genetic signals that regulate cell division and specialization. Furthermore, long-term cell stability must be well understood before human ES-derived cells can be used in regenerative medicine. The propensity for genetic mutation in the human ES cells must be determined, and the survival of differentiated, ES-derived cells following transplantation must be assessed. Furthermore, once cells have been transplanted, undesirable interactions between the host tissue and the injected cells must be minimized. Cells or tissues derived from ES cells that are currently available for use in humans are not tissue-matched to patients and thus would require immunosuppression to limit immune rejection.18

While skeletal myoblasts (SMs) are committed progenitors of skeletal muscle cells, their autologous origin, high proliferative potential, commitment to a myogenic lineage, and resistance to ischemia promoted their use as the first stem cell type to be explored extensively for cardiac application. Studies in rats and humans have demonstrated that these cells can repopulate scar tissue and improve left ventricular function following transplantation.27 However, SM-derived cardiomyocytes do not function in complete concert with native myocardium. The expression of two key proteins involved in electromechanical cell integration, N-cadherin and connexin 43, are downregulated in vivo,28 and the engrafted cells develop a contractile activity phenotype that appears to be unaffected by neighboring cardiomyocytes.29

To date, the safety and feasibility of transplanting SM cells have been explored in a series of small studies enrolling a collective total of nearly 100 patients. Most of these procedures were carried out during open-heart surgery, although a couple of studies have investigated direct myocardial injection and transcoronary administration. Sustained ventricular tachycardia, a life-threatening arrhythmia and unexpected side-effect, occurred in early implantation studies, possibly resulting from the lack of electrical coupling between SM-derived cardiomyocytes and native tissue.30,31 Changes in preimplantation protocols have minimized the occurrence of arrhythmias in conjunction with the use of SM cells, and Phase II studies of skeletal myoblast therapy are presently underway.

In 2001, Jackson, et.al. demonstrated that cardiomyocytes and endothelial cells could be regenerated in a mouse heart attack model through the introduction of adult mouse bone marrow-derived stem cells.9 That same year, Orlic and colleagues showed that direct injection of mouse bone marrow-derived cells into the damaged ventricular wall following an induced heart attack led to the formation of new cardiomyocytes, vascular endothelium, and smooth muscle cells.11 Nine days after transplanting the stem cells, the newly-formed myocardium occupied nearly 70 percent of the damaged portion of the ventricle, and survival rates were greater in mice that received these cells than in those that did not. While several subsequent studies have questioned whether these cells actually differentiate into cardiomyocytes,32,33 the evidence to support their ability to prevent remodeling has been demonstrated in many laboratories.7

Based on these findings, researchers have investigated the potential of human adult bone marrow as a source of stem cells for cardiac repair. Adult bone marrow contains several stem cell populations, including hematopoietic stem cells (which differentiate into all of the cellular components of blood), endothelial progenitor cells, and mesenchymal stem cells; successful application of these cells usually necessitates isolating a particular cell type on the basis of its' unique cell-surface receptors. In the past three years, the transplantation of bone marrow mononuclear cells (BMMNCs), a mixed population of blood and cells that includes stem and progenitor cells, has been explored in more patients and clinical studies of cardiac repair than any other type of stem cell.7

The results from clinical studies of BMMNC transplantation have been promising but mixed. However, it should be noted that these studies have been conducted under a variety of conditions, thereby hampering direct comparison. The cells have been delivered via open-heart surgery and endomyocardial and intracoronary catheterization. Several studies, including the Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) and the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trials, have shown that intracoronary infusion of BMMNCs following a heart attack significantly improves the left ventricular (LV) ejection fraction, or the volume of blood pumped out of the left ventricle with each heartbeat.3436 However, other studies have indicated either no improvement in LV ejection fraction upon treatment37 or an increased LV ejection fraction in the control group.38 An early study that used endomyocardial injection to enhance targeted delivery indicated a significant improvement in overall LV function.39 Discrepancies such as these may reflect differences in cell preparation protocols or baseline patient statistics. As larger trials are developed, these issues can be explored more systematically.

Mesenchymal stem cells (MSCs) are precursors of non-hematopoietic tissues (e.g., muscle, bone, tendons, ligaments, adipose tissue, and fibroblasts) that are obtained relatively easily from autologous bone marrow. They remain multipotent following expansion in vitro, exhibit relatively low immunogenicity, and can be frozen easily. While these properties make the cells amenable to preparation and delivery protocols, scientists can also culture them under special conditions to differentiate them into cells that resemble cardiac myocytes. This property enables their application to cardiac regeneration. MSCs differentiate into endothelial cells when cultured with vascular endothelial growth factor40 and cardiomyogenic (CMG) cells when treated with the dna-demethylating agent, 5-azacytidine.41 More important, however, is the observation that MSCs can differentiate into cardiomyocytes and endothelial cells in vivo when transplanted to the heart following myocardial infarct (MI) or non-injury in pig, mouse, or rat models.4245 Additionally, the ability of MSCs to restore functionality may be enhanced by the simultaneous transplantation of other stem cell types.43

Several animal model studies have shown that treatment with MSCs significantly increases myocardial function and capillary formation.5,41 One advantage of using these cells in human studies is their low immunogenicity; allogeneic MSCs injected into infarcted myocardium in a pig model regenerated myocardium and reduced infarct size without evidence of rejection.46 A randomized clinical trial implanting MSCs after MI has demonstrated significant improvement in global and regional LV function,47 and clinical trials are currently underway to investigate the application of allogeneic and autologous MSCs for acute MI and myocardial ischemia, respectively.

Recent evidence suggests that the heart contains a small population of endogenous stem cells that most likely facilitate minor repair and turnover-mediated cell replacement.7 These cells have been isolated and characterized in mouse, rat, and human tissues.48,49 The cells can be harvested in limited quantity from human endomyocardial biopsy specimens50 and can be injected into the site of infarction to promote cardiomyocyte formation and improvements in systolic function.49 Separation and expansion ex vivo over a period of weeks are necessary to obtain sufficient quantities of these cells for experimental purposes. However, their potential as a convenient resource for autologous stem cell therapy has led the National Heart, Lung, and Blood Institute to fund forthcoming clinical trials that will explore the use of cardiac stem cells for myocardial regeneration.

The endothelium is a layer of specialized cells that lines the interior surface of all blood vessels (including the heart). This layer provides an interface between circulating blood and the vessel wall. Endothelial progenitor cells (EPCs) are bone marrow-derived stem cells that are recruited into the peripheral blood in response to tissue ischemia.4 EPCs are precursor cells that express some cell-surface markers characteristic of mature endothelium and some of hematopoietic cells.19,5153 EPCs home in on ischemic areas, where they differentiate into new blood vessels; following a heart attack, intravenously injected EPCs home to the damaged region within 48 hours.12 The new vascularization induced by these cells prevents cardiomyocyte apoptosis (programmed cell death) and LV remodeling, thereby preserving ventricular function.13 However, no change has been observed in non-infarcted regions upon EPC administration. Clinical trials are currently underway to assess EPC therapy for growing new blood vessels and regenerating myocardium.

Several other cell populations, including umbilical cord blood (UCB) stem cells, fibroblasts (cells that synthesize the extracellular matrix of connective tissues), and peripheral blood CD34+ cells, have potential therapeutic uses for regenerating cardiac tissue. Although these cell types have not been investigated in clinical trials of heart disease, preliminary studies in animal models indicate several potential applications in humans.

Umbilical cord blood contains enriched populations of hematopoietic stem cells and mesencyhmal precursor cells relative to the quantities present in adult blood or bone marrow.54,55 When injected intravenously into the tail vein in a mouse model of MI, human mononuclear UCB cells formed new blood vessels in the infarcted heart.56 A human DNA assay was used to determine the migration pattern of the cells after injection; although they homed only to injured areas within the heart, they were also detected in the marrow, spleen, and liver. When injected directly into the infarcted area in a rat model of MI, human mononuclear UCB cells improved ventricular function.57 Staining for CD34 and other markers found on the cell surface of hematopoietic stem cells indicated that some of the cells survived in the myocardium. Results similar to these have been observed following the injection of human unrestricted somatic stem cells from UCB into a pig MI model.58

Adult peripheral blood CD34+ cells offer the advantage of being obtained relatively easily from autologous sources.59 Although some studies using a mouse model of MI claim that these cells can transdifferentiate into cardiomyocytes, endothelial cells, and smooth muscle cells at the site of tissue injury,60 this conclusion is highly contested. Recent studies that involve the direct injection of blood-borne or bone marrow-derived hematopoietic stem cells into the infarcted region of a mouse model of MI found no evidence of myocardial regeneration following injection of either cell type.33 Instead, these hematopoietic stem cells followed traditional differentiation patterns into blood cells within the microenvironment of the injured heart. Whether these cells will ultimately find application in myocardial regeneration remains to be determined.

Autologous fibroblasts offer a different strategy to combat myocardial damage by replacing scar tissue with a more elastic, muscle-like tissue and inhibiting host matrix degradation.4 The cells may be manipulated to express muscle-specific transcription factors that promote their differentiation into myotubes such as those derived from skeletal myoblasts.61 One month after these cells were implanted into the post-infarction scar in a rat model of MI, they occupied a large portion of the scar but were not functionally integrated.61 Although the effects on ventricular function were not evaluated in this study, authors noted that modified autologous fibroblasts may ultimately prove useful in elderly patients who have a limited population of autologous skeletal myoblasts or bone marrow stem cells.

As these examples indicate, many types of stem cells have been applied to regenerate damaged myocardium. In select applications, stem cells have demonstrated sufficient promise to warrant further exploration in large-scale, controlled clinical trials. However, the current breadth of application of these cells has made it difficult to compare and contextualize the results generated by the various trials. Most studies published to date have enrolled fewer than 25 patients, and the studies vary in terms of cell types and preparations used, methods of delivery, patient populations, and trial outcomes. However, the mixed results that have been observed in these studies do not necessarily argue against using stem cells for cardiac repair. Rather, preliminary results illuminate the many gaps in understanding of the mechanisms by which these cells regenerate myocardial tissue and argue for improved characterization of cell preparations and delivery methods to support clinical applications.

Future clinical trials that use stem cells for myocardial repair must address two concerns that accompany the delivery of these cells: 1) safety and 2) tracking the cells to their ultimate destination(s). Although stem cells appear to be relatively safe in the majority of recipients to date, an increased frequency of non-sustained ventricular tachycardia, an arrhythmia, has been reported in conjunction with the use of skeletal myoblasts.30,6264 While this proarrhythmic effect occurs relatively early after cell delivery and does not appear to be permanent, its presence highlights the need for careful safety monitoring when these cells are used. Additionally, animal models have demonstrated that stem cells rapidly diffuse from the heart to other organs (e.g., lungs, kidneys, liver, spleen) within a few hours of transplantation,65,66 an effect observed regardless of whether the cells are injected locally into the myocardium. This migration may or may not cause side-effects in patients; however, it remains a concern related to the delivery of stem cells in humans. (Note: Techniques to label stem cells for tracking purposes and to assess their safety are discussed in more detail in other articles in this publication).

In addition to safety and tracking, several logistical issues must also be addressed before stem cells can be used routinely in the clinic. While cell tracking methodologies allow researchers to determine migration patterns, the stem cells must target their desired destination(s) and be retained there for a sufficient amount of time to achieve benefit. To facilitate targeting and enable clinical use, stem cells must be delivered easily and efficiently to their sites of application. Finally, the ease by which the cells can be obtained and the cost of cell preparation will also influence their transition to the clinic.

The evidence to date suggests that stem cells hold promise as a therapy to regenerate damaged myocardium. Given the worldwide prevalence of cardiac dysfunction and the limited availability of tissue for cardiac transplantation, stem cells could ultimately fulfill a large-scale unmet clinical need and improve the quality of life for millions of people with CVD. However, the use of these cells in this setting is currently in its infancymuch remains to be learned about the mechanisms by which stem cells repair and regenerate myocardium, the optimal cell types and modes of their delivery, and the safety issues that will accompany their use. As the results of large-scale clinical trials become available, researchers will begin to identify ways to standardize and optimize the use of these cells, thereby providing clinicians with powerful tools to mend a broken heart.

Chapter 5|Table of Contents|Chapter 7

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Mending a Broken Heart: Stem Cells and Cardiac Repair ...

12.15.17CIRM Grants ViaCyte $1.4M to Create Immune-Evasive Pluripotent Stem Cell Lines

SAN DIEGO, December 15, 2017 ViaCyte, Inc., a privately-held regenerative medicine company, today announced that the California Institute for Regenerative Medicine (CIRM) approved a grant of $1.4 million to support the initial development of []

ViaCyte is developing PEC-Direct to address the urgent medical need of high-risk type 1 diabetes and provide a potentially life-saving therapy SAN DIEGO,December 6, 2017 ViaCyte today announced that CONNECT, a premier innovation company []

SAN DIEGO, October 4, 2017 ViaCyte, Inc., a privately-held regenerative medicine company, today announced upcoming company presentations at the Cell and Gene Meeting on the Mesa and the BIO Investor Forum. In addition, ViaCyte []

SAN DIEGO, September 28, 2017 ViaCyte, Inc., a privately-held regenerative medicine company, today announced that the California Institute for Regenerative Medicine (CIRM) approved a grant of $20 million to support the clinical development of []

Developing PEC-Direct to address urgent medical need in patients with high-risk type 1 diabetes SAN DIEGO, September 21, 2017 Today, ViaCyte announced that its PEC-Direct product candidate has been selected as one of three []

SAN DIEGO, September 7, 2017 ViaCyte, Inc., a privately-held, leading regenerative medicine company, today announced upcoming scientific presentations. ViaCyte is developing novel stem cell-derived islet replacement therapies for insulin-requiring diabetes. ViaCytes product candidates have []

San Diego, August 1, 2017 ViaCyte, Inc., a privately-held, leading regenerative medicine company, announced today that the first patients have been implanted with the PEC-Direct product candidate, a novel islet cell replacement therapy in []

SAN DIEGO, June 15, 2017 ViaCyte, Inc., a privately-held regenerative medicine company, today announced a presentation at the International Society for Stem Cell Research (ISSCR) 2017 Annual Meeting in Boston. ViaCyte is developing novel []

San Diego, May 22, 2017 ViaCyte, Inc., a privately-held leading regenerative medicine company, announced today that the U.S. Food and Drug Administration (FDA) has allowed the companys Investigational New Drug Application (IND) for the []

San Diego, May 22, 2017 ViaCyte, Inc., a privately-held leading regenerative medicine company, announced today $10 million in financing to support operations. Participants in the financing included Asset Management Partners, W.L. Gore & Associates, []

New York and San Diego, May 22, 2017 ViaCyte, Inc., a privately-held leading regenerative medicine company, and JDRF, the leading global organization funding type 1 diabetes research, jointly announced today JDRF grant funding to []

ViaCyte to also present at World Advanced Therapies and Regenerative Medicine Congress in London SAN DIEGO, April 24, 2017 ViaCyte, Inc., a privately-held regenerative medicine company, today announced two presentations on April 27 at []

SAN DIEGO, California and NEWARK, Delaware, March 29, 2017 ViaCyte, Inc., a privately-held regenerative medicine company, and W. L. Gore & Associates, Inc. (Gore), a global materials science company, today announced a collaborative research []

SAN DIEGO and SAN FRANCISCO, February 23, 2017 ViaCyte, Inc., a privately-held regenerative medicine company, and Beyond Type 1, a not-for-profit advocacy and education group for those living with type 1 diabetes, today []

SAN DIEGO, February 21, 2017 ViaCyte, Inc., a privately-held regenerative medicine company, today announced four presentations at upcoming healthcare events. ViaCyte is advancing two novel cell replacement therapies as long-term diabetes treatments. ViaCytes product []

President and CEO, Paul Laikind, PhD to present at 2017 Biotech Showcase SAN DIEGO, January 4, 2017 ViaCyte, Inc., a privately-held regenerative medicine company, today announced the addition of twenty-two new patents in 2016. []

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Story highlights

On a June day in 2009, a 39-year-old man named Ken Milles lay on an exam table at Cedars-Sinai Medical Center in Los Angeles. A month earlier, he'd suffered a massive heart attack that destroyed nearly a third of his heart.

"The most difficult part was the uncertainty," he recalls. "Your heart is 30% damaged, and they tell you this could affect you the rest of your life." He was about to receive an infusion of stem cells, grown from cells taken from his own heart a few weeks earlier. No one had ever tried this before.

About three weeks later, in Kentucky, a patient named Mike Jones underwent a similar procedure at the University of Louisville's Jewish Hospital. Jones suffered from advanced heart failure, the result of a heart attack years earlier. Like Milles, he received an infusion of stem cells, grown from his own heart tissue.

"Once you reach this stage of heart disease, you don't get better," says Dr. Robert Bolli, who oversaw Jones' procedure, explaining what doctors have always believed and taught. "You can go down slowly, or go down quickly, but you're going to go down."

Conventional wisdom took a hit Monday, as Bolli's group and a team from Cedars-Sinai each reported that stem cell therapies were able to reverse heart damage, without dangerous side effects, at least in a small group of patients.

In Bolli's study, published in The Lancet, 16 patients with severe heart failure received a purified batch of cardiac stem cells. Within a year, their heart function markedly improved. The heart's pumping ability can be quantified through the "Left Ventricle Ejection Fraction," a measure of how much blood the heart pumps with each contraction. A patient with an LVEF of less than 40% is considered to suffer severe heart failure. When the study began, Bolli's patients had an average LVEF of 30.3%. Four months after receiving stem cells, it was 38.5%. Among seven patients who were followed for a full year, it improved to an astounding 42.5%. A control group of seven patients, given nothing but standard maintenance medications, showed no improvement at all.

"We were surprised by the magnitude of improvement," says Bolli, who says traditional therapies, such as placing a stent to physically widen the patient's artery, typically make a smaller difference. Prior to treatment, Mike Jones couldn't walk to the restroom without stopping for breath, says Bolli. "Now he can drive a tractor on his farm, even play basketball with his grandchildren. His life was transformed."

At Cedars-Sinai, 17 patients, including Milles, were given stem cells approximately six weeks after suffering a moderate to major heart attack. All had lost enough tissue to put them "at big risk" of future heart failure, according to Dr. Eduardo Marban, the director of the Cedars-Sinai Heart Institute, who developed the stem cell procedure used there.

The results were striking. Not only did scar tissue retreat -- shrinking 40% in Ken Milles, and between 30% and 47% in other test subjects -- but the patients actually generated new heart tissue. On average, the stem cell recipients grew the equivalent of 600 million new heart cells, according to Marban, who used MRI imaging to measure changes. By way of perspective, a major heart attack might kill off a billion cells.

"This is unprecedented, the first time anyone has grown living heart muscle," says Marban. "No one else has demonstrated that. It's very gratifying, especially when the conventional teaching has been that the damage is irreversible."

Perhaps even more important, no treated patient in either study suffered a significant health setback.

The twin findings are a boost to the notion that the heart contains the seeds of its own rebirth. For years, doctors believed that heart cells, once destroyed, were gone forever. But in a series of experiments, researchers including Bolli's collaborator, Dr. Piero Anversa, found that the heart contains a type of stem cell that can develop into either heart muscle or blood vessel components -- in essence, whatever the heart requires at a particular point in time. The problem for patients like Mike Jones or Ken Milles is that there simply aren't enough of these repair cells waiting around. The experimental treatments involve removing stem cells through a biopsy, and making millions of copies in a laboratory.

The Bolli/Anversa group and Marban's team both used cardiac stem cells, but Bolli and Anversa "purified" the CSCs, so that more than 90% of the infusion was actual stem cells. Marban, on the other hand, used a mixture of stem cells and other types of cells extracted from the patient's heart. "We've found that the mixture is more potent than any subtype we've been able to isolate," he says. He says the additional cells may help by providing a supportive environment for the stem cells to multiply.

Other scientists, including Dr. Douglas Losordo, have produced improvements in cardiac patients using stem cells derived from bone marrow. "The body contains cells that seem to be pre-programmed for repair," explains Losordo. "The consistent thing about all these approaches is that they're leveraging what seems to be the body's own repair mechanism."

Losordo praised the Lancet paper, and recalls the skepticism that met Anversa's initial claims, a decade ago, that there were stem cells in the adult heart. "Some scientists are always resistant to that type of novelty. You know the saying: First they ignore you, then they attack you and finally they imitate you."

Denis Buxton, who oversees stem cell research at the National Heart, Lung and Blood Institute at the National Institutes of Health, calls the new studies "a paradigm shift, harnessing the heart's own regenerative processes." But he says he would like to see more head-to-head comparisons to determine which type of cells are most beneficial.

Questions also remain about timing. Patients who suffer large heart attacks are prone to future damage, in part because the weakened heart tries to compensate by dilating -- swelling -- and by changing shape. In a vicious circle, the changes make the heart a less efficient pump, which leads to more overcompensation, and so on, until the end result is heart failure. Marban's study aimed to treat patients before they could develop heart failure in the first place.

In a third study released Monday, researchers treated patients with severe heart failure with stem cells derived from bone marrow. In a group of 60 patients, those receiving the treatment had fewer heart problems over the course of a year, as well as improved heart function.

A fourth study also used cells derived from bone marrow, but injected them into patients two to three weeks after a heart attack. Previous studies, with the cells given just days afterward, found a modest improvement in heart function. But Monday, the lead researcher, Dr. Dan Simon of UH Case Medical Center, reported that with the three-week delay, patients did not see the same benefit.

With other methods, there may be a larger window of opportunity. At least in initial studies, Losordo's bone marrow treatments helped some patients with long-standing heart problems. Bolli's Lancet paper suggests that CSCs, too, might help patients with advanced disease. "These patients had had heart failure for several years. They were a wreck!" says Bolli. "But we found their stem cells were still very competent." By that, he means the cells were still capable of multiplying and of turning into useful muscle and blood vessel walls.

Marban has an open mind on the timing issue. In fact, one patient from his control group e-mailed after the study was complete, saying he felt terrible and pleading for an infusion of stem cells. At Marban's request, the FDA granted special approval to treat him. "He had a very nice response. That was 14 months after his heart attack. Of course that's just one person, and we need bigger studies," says Marban.

For Ken Milles, the procedure itself wasn't painful, but it was unsettling. The biopsy to harvest the stem cells felt "weird," he recalls, as he felt the doctor poking around inside his heart. The infusion, a few weeks later, was harder. The procedure -- basically the same as an angioplasty -- involved stopping blood flow through the damaged artery for three minutes, while the stem cells were infused. "It felt exacfly like I was having a heart attack again," Milles remembers.

Milles had spent the first weeks after his heart attack just lying in bed re-watching his "Sopranos" DVDs, but within a week of the stem cell infusion, he says, "I was reinvigorated." Today he's back at work full time, as an accounting manager at a construction company. He's cut out fast food and shed 50 pounds. His wife and two teenage sons are thrilled.

Denis Buxton says the new papers could prove a milestone. "We don't have anything else to actually regenerate the heart. These stem cell therapies have the possibility of actually reversing damage."

Bolli says he'll have to temper his enthusiasm until he can duplicate the results in larger studies, definitive enough to get stem cell therapy approved as a standard treatment. "If a phase 3 study confirmed this, it would be the biggest advance in cardiology in my lifetime. We would possibly be curing heart failure. It would be a revolution."

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Studies: Stem cells reverse heart damage - CNN

When people talk about something that saved their skin, they usually mean that it helped them out of a difficult situation. But a young boy in Germany has literally had his skinand his lifesaved through the use of genetically-engineered adult stem cells.

The boy suffered from a condition called junctional epidermolysis bullosa, a severe and often lethal disease in which a mutation leaves the skin cells unable to interconnect and maintain epidermal integrity. The skin blisters and falls off, and the slightest touch or abrasion can leave a patch of skin gone and a painful, difficult-to-heal wound behind. There is no cure for the disease and little other than palliative care available for sufferers of the most severe forms.

Now researchers have combined use of adult stem cells with genetic engineering to successfully treat the young boys life-threatening condition. The boys doctors in Germany called on Dr. Michele De Luca at the University of Modena and Reggio Emilia in Italy to use a technique he has developed to correct the genetic problem and grow new skin.

Over many years, Dr. De Luca has developed a method to grow skin from a patients own epidermal adult stem cells, correct the genetic mutation in the laboratory, and use the genetically-engineered adult stem cells to grow healthy new skin. Dr. De Luca and his team took a tiny patch of skin from the boy, isolated the epidermal stem cells and corrected the genetic problem in stem cell culture. Then they grew sheets of genetically-corrected skin and transplanted them onto the boy.

Reports called the boys recovery stunning, with successful replacement of 80 percent of his skin. Before the procedure, the boys doctors tried several treatments to no avail. One doctor even said, We had a lot of problems in the first days keeping this kid alive. Yet within six months of starting the process, the boy was back in school.

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His skin has remained healthy and completely blister-free. According to the published reports now 21 months after the boys transplant, he loves to show off his new skin and is enjoying school, playing soccer, and being a normal kid. The research has also taught scientists much about the possibilities of using adult stem cells in combination with gene therapy for treatment of diseases.

LifeNews Note: File photo.

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Adult Stem Cells and Gene Therapy Save a Young Boy With ...

The Problem with Chronic Pulmonary Diseases

Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung disorder that often occurs as a result of prolonged cigarette smoking, second-hand smoke, and polluted air or working conditions. COPD is the most prevalent form of chronic lung disease. The physiological symptoms of COPD include shortness of breath (dyspnea), cough, and sputum production, exercise intolerance and reduced Quality of Life (QOL). These signs and symptoms are brought about by chronic inflammation of the airways, which restricts breathing. When fibrotic tissues contract, the lumen is narrowed, compromising lung function. As histological studies confirm, airway fibrosis and luminal narrowing are major features that lead to airflow limitation in COPD1-3.

Today, COPD is a serious global health issue, with a prevalence of 9-10% of adults aged 40 and older4. And the prevalence of the disease is only expected to rise. Currently COPD accounts for 27% of tobacco related deaths and is anticipated to become the fourth leading cause of death worldwide by 2030 5. Today, COPD affects approximately 600 million individualsroughly 5% of the worlds population 6. Despite modern medicine and technological advancements, there is no known cure for COPD.

The difficulty in treating COPD and other lung diseases rests in the trouble of stimulating alveolar wall formation15. Until recently, treatment has been limited by two things: a lack of understanding of the pathophysiology of these disease processes on a molecular level and a lack of pharmaceutical development that would affect these molecular mechanisms. This results in treatment focused primarily in addressing the symptoms of the disease rather than healing or slowing the progression of the disease itself.

The result is that there are few options available outside of bronchodilators and corticosteroids7. Although lung transplants are performed as an alternative option, there is currently a severe shortage of donor lungs, leaving many patients to die on waiting lists prior to transplantation. Lung transplantation is also a very invasive form of treatment, commonly offering poor results, a poor quality of life with a 5-year mortality rate of approximately 50%, and a litany of health problems associated with lifelong immunosuppression13.

However, it has been shown that undifferentiated multipotent endogenous tissue stem cells (cells that have been identified in nearly all tissues) may contribute to tissue maintenance and repair due to their inherent anti-inflammatory properties. Human mesenchymal stromal cells have been shown to produce large quantities of bioactive factors including cytokines and various growth factors which provide molecular cueing for regenerative pathways. This affects the status of responding cells intrinsic in the tissue 18. These bioactive factors have the ability to influence multiple immune effector functions including cell development, maturation, and allo-reactive T-cell responses 19. Although research on the use of autologous stem cells (both hematopoietic and mesenchymal) in regenerative stem cell therapy is still in the early stages of implementation, it has shown substantive progress in treating patients with few if any adverse effects.

The Lung Institute (LI) provided treatment by harvesting autologous stem cells (hematopoietic stem cells and mesenchymal stromal cells) by withdrawing adipose tissue (fat), bone marrow or peripheral blood. These harvested cells are isolated and concentrated, and along with platelet-rich plasma, are then reintroduced into the body and enter the pulmonary vasculature (vessels of the lungs) where cells are trapped in the microcirculation (the pulmonary trap). Alternatively, nebulized stem cells are reintroduced through the airways in patients who have undergone an adipose (fat tissue) treatment.

Individuals diagnosed with COPD were tracked by the Lung Institute to measure the effects of treatment via either the venous protocol or adipose protocol on both their pulmonary function as well as their Quality of Life.

All PFTs were performed according to national practice guideline standards for repeatability and acceptability8-10. On PFTs, pre-treatment data was collected through on-site testing or through previous medical examinations by the patients primary physician (if done within two weeks). The test was then repeated by their primary physician 6 months after treatment.*

* Due to the examination information required from primary physicians, only 25 out of 100 patients are reflected in the PFT data.

Patients with progressive COPD will typically experience a steady decrease in their Quality of Life. Given this development, a patients Quality of Life score is frequently used to define additional therapeutic effects, with regulatory authorities frequently encouraging their use as primary or secondary outcomes17.

On quality of life testing, data was collected through the implementation of the Clinical COPD Questionnaire (CCQ) based survey17. The survey measured the patients self-assessed quality of life on a 0-6 scale, with adverse Quality of Life correlated in ascending numerical order. It was implemented in three stages: pre-treatment, 3-months post-treatment, and 6-months post-treatment. The survey measured two distinct outcomes: the QLS score, which measured the patients self-assessed quality of life score, and the QIS, a percentage-based measurement determining the proportion of patients within the sample that experienced QLS score improvements.

Over the duration of six months, the results of 100 patients treated for COPD through venous and adipose based therapies were tracked by the Lung Institute in order to measure changes in pulmonary function and any improvement in Quality of Life.

Of the 100 patients treated by the Lung Institute, 64 were male (64%) and 36 were female (36%). Ages of those treated range from 55-88 years old with an average age of 71. Throughout the study, 82 (82%) were treated with venous derived stem cells, while 18 (18%) were treated from stem cells derived from adipose tissue.

* The survey measured the patients self-assessed quality of life on a 0-6 scale, with adverse Quality of Life correlated in ascending numerical order.

Over the course of the study, the patient group averaged an increase of 35.5% to their Quality of Life (QLS) score within three months of treatment. While in the QIS, 84% of all patients found that their Quality of Life score had improved within three months of treatment (figure 1.3).

Within the PFT results, 48% of patients tested saw an increase of over 10% to their original pulmonary function with an average increase of 16%. During the three to six month period after treatment, patients saw a small decline in their progress, with QLS scores dropping from 35.5% to 32%, and the QIS from 84% to 77%.Fletcher and Petos work shows that patient survival rate can be improved through appropriate or positive intervention14 (figure 1.4). It remains to be seen if better quality of life will translate to longevity, but if one examines what factors allow for improved quality of life such as improvement in oxygen use, exercise tolerance, medication use, visits to the hospital and reduction in disease flare ups then one can see that quality of life improves in association with clinical improvement.

Currently the most utilized options for treating COPD are bronchodilator inhalers with or without corticosteroids and lung transplant each has downsides. Inhalers are often used incorrectly11, are expensive over time, and can only provide temporary relief of symptoms. Corticosteroids, though useful, have risk of serious adverse side effects such as infections, blood sugar imbalance, and weight gain to name a few 16. Lung transplants are expensive, have an adverse impact on quality of life and have a high probability of rejection by the body the treatment of which creates a new set of problems for patients. In contrast, initial studies of stem cells treatments show efficacy, lack of adverse side effects and may be used safely in conjunction with other treatments.

Through the data collected by the Lung Institute, developing methodologies for this form of treatment are quickly taking place as other entities of the medical community follow suit. In a recent study of regenerative stem cell therapy done by the University of Utah, patients exhibited improvement in PFTs and oxygen requirement compared to the control group with no acute adverse events12. Through the infusion of stem cells derived from the patients own body, stem cell therapy minimizes the chance of rejection to the highest degree, promotes healing and can improve the patients pulmonary function and quality of life with no adverse side effects.

Although more studies using a greater number of patients is needed to further examine objective parameters such as PFTs, exercise tests, oxygen, medication use and hospital visits, larger sample sizes will also help determine if one protocol is more beneficial than others. With deeper research, utilizing economic analysis along with longer-term follow up will answer questions on patient selection, the benefits of repeated treatments, and a possible reduction in healthcare costs for COPD treatment.

The field of Cellular Therapy and Regenerative Medicine is rapidly advancing and providing effective treatments for diseases in many areas of medicine.The Lung Institutes strives to provide the latest in safe, effective therapy for chronic lung disease and maintain a leadership role in the clinical application of these technologies.

In a landscape of scarce options and rising costs, the Lung Institute believes that stem cell therapy is the future of treatment for those suffering from COPD and other lung diseases. Although data is limited at this stage, we are proud to champion this form of treatment while sharing our findings.

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Lung Institute | Stem Cell Research Study for Lung Disease

Engineered human stem cells have been used to enable paraplegic rats to walk independently and regain sensory perception. The implanted rats had some healing in their spinal cords.

Led by Dr. Shulamit Levenberg, of the Technion-Israel Institute of Technology, the researchers implanted human stem cells into rats with a complete spinal cord transection. The stem cells, which were derived from the membrane lining of the mouth, were induced to differentiate into support cells that secrete factors for neural growth and survival.

The work involved more than simply inserting stem cells at various intervals along the spinal cord. The research team also built a three-dimensional scaffold that provided an environment in which the stem cells could attach, grow and differentiate into support cells. This engineered tissue was also seeded with human thrombin and fibrinogen, which served to stabilize and support neurons in the rats spinal cord.

5 of 12 rats (42%) treated with the induced constructs demonstrated BBB scores exceeding 17, a compiled reflection of improved coordinated gait, plantar placement, weight support, recovery of toe clearance, trunk stability, and predominant parallel paw and tail position, suggesting regained cortical motor control.

The induced constructs promoted remarkable recovery in 42% of the rats, and show no efficacy in the remainder of the rats within the same group. This binary effect compels further investigation, since understanding of the underlying mechanisms causing substantial improvement in some animals and no practical improvement in others can render this method into an effective treatment.

Spinal cord injury (SCI), involving damaged axons and glial scar tissue, often culminates in irreversible impairments. Achieving substantial recovery following complete spinal cord transection remains an unmet challenge. Here, we report of implantation of an engineered 3D construct embedded with human oral mucosa stem cells (hOMSC) induced to secrete neuroprotective, immunomodulatory, and axonal elongation-associated factors, in a complete spinal cord transection rat model. Rats implanted with induced tissue engineering constructs regained fine motor control, coordination and walking pattern in sharp contrast to the untreated group that remained paralyzed (42 vs. 0%). Immunofluorescence, CLARITY, MRI, and electrophysiological assessments demonstrated a reconnection bridging the injured area, as well as presence of increased number of myelinated axons, neural precursors, and reduced glial scar tissue in recovered animals treated with the induced cell-embedded constructs. Finally, this construct is made of bio-compatible, clinically approved materials and utilizes a safe and easily extractable cell population. The results warrant further research with regards to the effectiveness of this treatment in addressing spinal cord injury.

Frontiers in Neuroscience Implantation of 3D Constructs Embedded with Oral Mucosa-Derived Cells Induces Functional Recovery in Rats with Complete Spinal Cord Transection.

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Engineered Stem Cells repaired spinal cords in 5 out of 12 ...

Overview

A spinal cord injury damage to any part of the spinal cord or nerves at the end of the spinal canal (cauda equina) often causes permanent changes in strength, sensation and other body functions below the site of the injury.

If you've recently experienced a spinal cord injury, it might seem like every aspect of your life has been affected. You might feel the effects of your injury mentally, emotionally and socially.

Many scientists are optimistic that advances in research will someday make the repair of spinal cord injuries possible. Research studies are ongoing around the world. In the meantime, treatments and rehabilitation allow many people with spinal cord injuries to lead productive, independent lives.

Your ability to control your limbs after a spinal cord injury depends on two factors: the place of the injury along your spinal cord and the severity of injury to the spinal cord.

The lowest normal part of your spinal cord is referred to as the neurological level of your injury. The severity of the injury is often called "the completeness" and is classified as either of the following:

Additionally, paralysis from a spinal cord injury may be referred to as:

Your health care team will perform a series of tests to determine the neurological level and completeness of your injury.

Spinal cord injuries of any kind may result in one or more of the following signs and symptoms:

Emergency signs and symptoms of a spinal cord injury after an accident may include:

Anyone who experiences significant trauma to his or her head or neck needs immediate medical evaluation for the possibility of a spinal injury. In fact, it's safest to assume that trauma victims have a spinal injury until proved otherwise because:

Spinal cord injuries may result from damage to the vertebrae, ligaments or disks of the spinal column or to the spinal cord itself.

A traumatic spinal cord injury may stem from a sudden, traumatic blow to your spine that fractures, dislocates, crushes or compresses one or more of your vertebrae. It also may result from a gunshot or knife wound that penetrates and cuts your spinal cord.

Additional damage usually occurs over days or weeks because of bleeding, swelling, inflammation and fluid accumulation in and around your spinal cord.

A nontraumatic spinal cord injury may be caused by arthritis, cancer, inflammation, infections or disk degeneration of the spine.

The central nervous system comprises the brain and spinal cord. The spinal cord, made of soft tissue and surrounded by bones (vertebrae), extends downward from the base of your brain and is made up of nerve cells and groups of nerves called tracts, which go to different parts of your body.

The lower end of your spinal cord stops a little above your waist in the region called the conus medullaris. Below this region is a group of nerve roots called the cauda equina.

Tracts in your spinal cord carry messages between the brain and the rest of the body. Motor tracts carry signals from the brain to control muscle movement. Sensory tracts carry signals from body parts to the brain relating to heat, cold, pressure, pain and the position of your limbs.

Whether the cause is traumatic or nontraumatic, the damage affects the nerve fibers passing through the injured area and may impair part or all of your corresponding muscles and nerves below the injury site.

A chest (thoracic) or lower back (lumbar) injury can affect your torso, legs, bowel and bladder control, and sexual function. A neck (cervical) injury affects the same areas in addition to affecting movements of your arms and, possibly, your ability to breathe.

The most common causes of spinal cord injuries in the United States are:

Although a spinal cord injury is usually the result of an accident and can happen to anyone, certain factors may predispose you to a higher risk of sustaining a spinal cord injury, including:

At first, changes in the way your body functions may be overwhelming. However, your rehabilitation team will help you develop the tools you need to address the changes caused by the spinal cord injury, in addition to recommending equipment and resources to promote quality of life and independence. Areas often affected include:

Bladder control. Your bladder will continue to store urine from your kidneys. However, your brain may not be able to control your bladder as well because the message carrier (the spinal cord) has been injured.

The changes in bladder control increase your risk of urinary tract infections. The changes also may cause kidney infections and kidney or bladder stones. During rehabilitation, you'll learn new techniques to help empty your bladder.

Skin sensation. Below the neurological level of your injury, you may have lost part of or all skin sensations. Therefore, your skin can't send a message to your brain when it's injured by certain things such as prolonged pressure, heat or cold.

This can make you more susceptible to pressure sores, but changing positions frequently with help, if needed can help prevent these sores. You'll learn proper skin care during rehabilitation, which can help you avoid these problems.

Circulatory control. A spinal cord injury may cause circulatory problems ranging from low blood pressure when you rise (orthostatic hypotension) to swelling of your extremities. These circulation changes may also increase your risk of developing blood clots, such as deep vein thrombosis or a pulmonary embolus.

Another problem with circulatory control is a potentially life-threatening rise in blood pressure (autonomic hyperreflexia). Your rehabilitation team will teach you how to address these problems if they affect you.

Respiratory system. Your injury may make it more difficult to breathe and cough if your abdominal and chest muscles are affected. These include the diaphragm and the muscles in your chest wall and abdomen.

Your neurological level of injury will determine what kind of breathing problems you may have. If you have a cervical and thoracic spinal cord injury, you may have an increased risk of pneumonia or other lung problems. Medications and therapy can help prevent and treat these problems.

Fitness and wellness. Weight loss and muscle atrophy are common soon after a spinal cord injury. Limited mobility may lead to a more sedentary lifestyle, placing you at risk of obesity, cardiovascular disease and diabetes.

A dietitian can help you eat a nutritious diet to sustain an adequate weight. Physical and occupational therapists can help you develop a fitness and exercise program.

Following this advice may reduce your risk of a spinal cord injury:

Drive safely. Car crashes are one of the most common causes of spinal cord injuries. Wear a seat belt every time you drive or ride in a car.

Make sure that your children wear a seat belt or use an age- and weight-appropriate child safety seat. To protect them from air bag injuries, children under age 12 should always ride in the back seat.

Dec. 19, 2017

Continued here:
Spinal cord injury - Symptoms and causes - Mayo Clinic

Epidermolysis bullosais is rare, but the charity DEBRA, which campaigns for EB patients, estimates half a million people are affected around the world.

There are different forms of epidermolysis bullosa, including simplex, dystrophic and, as in this case, junctional.

Each is caused by different genetic faults leading to different building blocks of skin being missing.

Prof Michele De Luca, from the University of Modena and Reggio Emilia, told the BBC: The gene is different, the protein is different and the outcome may be different [for each form of EB] so we need formal clinical trials.

But if they can make it work, it could be a therapy that lasts a lifetime.

An analysis of the structure of the skin of the first patient to get 80% of his replaced has discovered a group of long-lived stem cells are that constantly renewing his genetically modified skin.

Genetically modified skin cells were grown to make skin grafts totalling 0.85 sq m (9 sq ft). It took three operations over that winter to cover 80% of the childs body in the new skin. But 21 months later, the skin is functioning normally with no sign of blistering.

Nature Regeneration of the entire human epidermis using transgenic stem cells

Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes. This study provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and gene therapies

SOURCES BBC News, Nature

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Regeneration of the entire human skin using transgenic ...

Stem cell research is often controversial but it has also led to incredible medical progress in recent years.

Stem cell research is at defining moment. Although it can be controversial and does raise a lot of important ethical issues, this area of medical science has been characterised by a number of important advances, ever since the first embryonic stem cells were isolated from mice in the 1980s. In the near future, it could reshape the way we treat some of the worlds most debilitating diseases.

Stem cells have already been used as treatment for a number of years think bone marrow transplant and they have the potential to help with many other medical conditions. They could also prove crucial for scientists wishing to understand more about human biology and development.

Studies using stem cells have benefited from important media coverage in recent years and many of them hailed as breakthroughs. However, the reality is often more complex, and a number of scientific and ethical challenges often stand in the way of successes in animal models being replicated in humans.

IBTimes UK takes a look at what stem cell research is, what it is used for and what the future looks like.

Stem cells could be defined as building block cells that have not yet differentiated into one cell type and could develop into many different cell types. Stem cells can continue to divide almost indenitely.

There are two main types of stem cells: embryonic stem cells and adult stem cells.

Embryonic stem cells were first isolated in mice in the early 1980s at the University of Cambridge. All developing embryos contains a number of stem cells that can go on to develop into different cell types. In humans, these cells can be isolated from around five days after the egg has been fertilised around 50 to 100 stem cells are present at that stage.

These cells are isolated from embryos that have been donated by couples who have been through IVF and have extra embryos left which were not used during the treatment.

Stem cells are also found in adults, particularly in the bone marrow, the blood, the eyes, the brain and the muscles. They are also known as somatic stem cells.

They can also differentiate into other cells, but into a much more limited number than embryonic stem cells. They range from cells that are able to form different kinds of tissues to more specialised cells that form just some of the cells of a particular tissue or organ. They also have the ability to divide and reproduce indefinitely.

19th Place: Dr Gist F Croft, Lauren Pietilla, Stephanie Tse, Dr. Szilvia Galgoczi, Maria Fenner, Dr Ali H. Brivanlou, Rockefeller University, Brivanlou Laboratory New York, New York, USA: Human neural rosette primordial brain cells, differentiated from embryonic stem cells Confocal, 10x (Dr Gist F Croft, Lauren Pietilla, Stephanie Tse, Dr. Szilvia Galgoczi, Maria Fenner, Dr Ali H. Brivanlou)

Scientists have also found a way to make induced pluripotent stem cells cells taken from any adult tissue and genetically modified to behave like an embryonic stem cell (and thus able to differentiate into any cell type). The term pluripotant refers to the fact that the stem cells can produce almost all of the cells in the body.

To create these induced pluripotent stem cells, researchershave learnt to reprogramme the genes of human adult cells. A major 2007 US study, found that introducing 14 genes could reprogramme the cells to become stem cells, and the researchers then narrowed this down to four genes. Subsequent studies have built on this knowledge to find new, safer ways to turn adult cells into pluripotant stem cells.

Stem cells are already used to help a number of patients around the world. For nearly 50 years, they have been used in the form of bone marrow transplants.

Indeed, bone marrow contains stem cells that can produce many different blood cells. A bone marrow transplant can be used to treat people with blood cancers or genetic blood disorders, such as sickle cell anaemia. The stem cell turn into healthy blood cells that can help the patient. Some hospitals also use stem cells to grow skin grafts for patients with life-threatening burns. It is also possible to receive a stem cell therapy based on limbal stem cells (in the eye) to repair damaged corneas.

Stem cells are also very useful for scientists conducting basic research on diseases, as they can be used to model a large number of conditions. Recent studies have used stem cells to model the nerve cells that are lost in Alzheimers disease or to model deafness or Autism Spectrum disorder.

Scientists have gained a better understanding of blood stem cells (Alden Chadwick/Flickr)

A number of treatment using stem cells has been tested by researchers around the world. A type of patients that could be helped by stems cells are those suffering from spinal cord injuries. Stem cell therapy for spinal cord repair could be used to promote the growth of nerve cells directly or to transplant cells that protect the nerves and help them function.

One of most important studies in this area was published in October 2010. tested the used embryonic stem cells on patients in the US who had sustained a spinal cord injury in the previous 14 days. Preliminary findings were encouraging.

Studies have also been conducted to assess the safety and efficacy of stem cells in helping patients who suffered a stroke. The idea is that stem cells could help in rehabilitation after a persons brain has been damaged by the stroke. Stem cells have also been investigated to treat diseases such as MS, diabetes and to reverse ageing.

Beyond clinical trials, which still remain limited in number, many of the preliminary research opens up a number of very interesting perspectives. One of the main area of interest is growing organs in the lab from tissues created from stem cells. These organs may one day be used for transplantation in humans.

Recently, stem cells have been shown to present an interest to improve fertility treatments with the creation of a new technique in mice in-vitro gametogenesis. The idea is to create eggs and sperm using pluripotant stem cells.

By La Surugue

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What are stem cells and how will they be used to treat the ...

A new therapy could restore healthy and protective skin to patients with a rare genetic disease.

iStock.com/Andrey Prokhorov

By Kelly ServickNov. 8, 2017 , 1:00 PM

A 7-year-old who lost most of his skin to a rare genetic disease has made a dramatic recovery after receiving an experimental gene therapy, researchers announced today. The treatmenta whole-body graft of genetically modified stem cellsis the most ambitious attempt yet to treat a severe form of epidermolysis bullosa (EB), an often-fatal group of conditions that cause skin to blister and tear off at the slightest touch.

The new approach can address only a subset of the genetic mutations that cause EB. But the boys impressive recoveryhes now back inschool and is even playing soccercould yield insights that help researchers use stem cells to treat other genetic skin conditions.

It is very unusual that we would see a publication with a single case study anymore, but this one is a little different, says Jakub Tolar, a bone marrow transplant physician at the Masonic Cancer Center, University of Minnesotain Minneapolis who is developing therapies for EB. This is one of these [studies] that can determine where the future of the field is going to go.

EB results from mutations to any of several genes that encode proteins crucial for anchoring the outer layer of skin, the epidermis, to the tissue below. The missing or defective protein can cause skin to slough off from minor damage, creating chronic injuries prone to infection. Some forms of EB can be lethal in infancy, and some predispose patients to an aggressive and deadly skin cancer. The only treatment involves painfully dressing and redressing wounds daily. Bandage costs can approach $100,000 a year, says Peter Marinkovich, a dermatologist at Stanford University in Palo Alto, California, who treats EB patients. Theyre like walking burn victims, he says.

In fact, the new approach is similar to an established treatment for severe burns, in which sheets of healthy skin are grown from a patients own cells and grafted over wounds. But stem cell biologist and physician Michele De Luca of the University of Modena and Reggio Emilia in Italy and his colleagues have been developing a way to counteract an EB-causing mutation by inserting a new gene into the cells used for grafts. His group has already treated two EB patients with this approach. They publishedencouraging resultsfrom their first attemptwith small patches of gene-corrected skin on a patients legsin 2006.

In 2015, De Lucas team got a desperate request from doctors in Germany. Their young patient had a severe form of the disease known as junctional EB, caused by a mutation in a gene encoding part of the protein laminin 332, which makes up a thin membrane just below the epidermis. It was the same gene De Lucas team was targeting in an ongoing clinical trial, but this case was especially dire: Lacking most of his skin, the boy had contracted multiple infections and was in a life-threatening septic state. The emergency treatment would be the first test of their gene therapy approach over such a large and severely damaged area.

De Lucas team used a patch of skin a little bigger than a U.S. postage stamp from an unblistered part of the boys groin to culture epidermal cells, which include stem cells that periodically regenerate the skin. They infected those cells with a retrovirus bearing healthy copies of the needed gene,LAMB3, and grew them into sheets ranging from 50 to 150 square centimeters. In two surgeries, a team at Ruhr University in Bochum, Germany, covered the boys arms, legs, back, and some of his chest in the new skin.

After a month,most of the new skin had begun to regenerate, covering 80% of the boys body in strong and elastic epidermis, the researchers report online today inNature. Whats more, hes developed no blisters in the grafted areas in the 2 years since the surgery.

Other researchers have long been concerned that using a retrovirus to insert genes at random points in cells genomes might cause cancer. (In the early 2000s, five children who participated in a retrovirus-based gene therapy trial for severe combined immunodeficiencydeveloped leukemia.) But the current study found no evidence that the insertion affected cancer genes.

De Luca and colleagues were also able to track which grafted cells regenerated the skin over time by using the different locations of the genetic insert as markers for individual cells and their progeny. They found that most cells from the graft disappeared after a few months, but a small population of long-lived cells called holoclones formed colonies that renewed the epidermis.

Epidermal stem cells known as holoclones (shown in pink) were responsible for regenerating the young epidermolysis bullosapatients skin, whileother cell types disappeared over time.

News & Views/Nature; adapted by E. Petersen/Science

Thats an important lesson, Tolar says; it suggests that future attempts to correct genetic skin diseases should focus on culture conditions that nourish these stem cells, and potentially even target them for modification. If you have a gene correction strategy, he says, youd better have these primitive epidermal stem cells in mind.

The current results could benefit several thousand EB patients across the world, Marinkovich says, but it wont work for all of them. More than half have a form of the disease called EB simplex, which is causednot by a missing protein, but by mutations that produce an active but dysfunctional protein. For these errors, correction with a gene-editing tool like CRISPR makes more sense, De Luca says.

The grafts also cant repair damage to internal surfaces such as the esophagus, Tolar notes, which occurs in some EB cases. Fortunately, that wasnt an issue for the boy in this study. The treatment is a good step in the right direction, he says, but its not curative.

Both De Luca and Marinkovichs teams are exploring a similar gene therapy for another major form of the disease, called dystrophic EB, caused by a different genetic error affecting a larger protein. Biotech companies are working with each group to test the approach in larger clinical trials.

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A boy with a rare disease gets new skin, thanks to gene ...

T

he complications of the little boys genetic skin disease grew as he did. Tiny blisters had covered his back as a newborn. Then came the chronic skin wounds that extended from his buttocks down to his legs.

By June 2015, at age 7, the boy had lost nearly two-thirds of his skin due to an infection related to the genetic disorder junctional epidermolysis bullosa, which causes the skin to become extremely fragile. Theres no cure for the disease, and it is often fatal for kids. At the burn unit at Childrens Hospital in Bochum, Germany, doctors offered him constant morphine and bandaged much of his body, but nothing not even his fathers offer to donate his skin worked to heal his wounds.

We were absolutely sure we could do nothing for this kid, Dr. Tobias Rothoeft, a pediatrician with Childrens Hospital in Bochum, which is affiliated with Ruhr University. [We thought] that he would die.

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As a last-ditch effort, the boys father asked if there were any available experimental treatments. The German doctors reached out to Dr. Michele De Luca, an Italian stem cell expert who heads the Center for Regenerative Medicine at the University of Modena and Reggio Emilia, to see if a transplant of genetically modified skin cells might be possible. De Luca knew the odds were against them such a transplant had only been performed twice in the past, and never on such a large portion of the body. But he said yes.

The doctors were ultimately able to reconstruct fully functional skin for 80 percent of the boys body by grafting on genetically modified cells taken from the boys healthy skin. The researchers say the results of this single-person clinical trial, published on Wednesday in Nature, show that transgenic stem cells can regenerate an entire tissue. De Luca told reporters the procedure not only offers hope to the 500,000 epidermolysis bullosa patients worldwide but also could offer a blueprint for using genetically modified stem cells to treat a variety of other diseases.

To cultivate replacement skin, the medical team took a biopsy the size of a matchbook from the boys healthy skin and sent it to De Lucas team in Italy. There, researchers cloned the skin cells and genetically modified them to have a healthy version of the gene LAMB3, responsible for making the protein laminin-332. They grew the corrected cultures into sheets, which they sent back to Germany. Then, over a series of three operations between October 2015 and January 2016, the surgical team attached the sheets on different parts of the boys body.

The gene-repaired skin took, and spread. Within just a month the wounds were islands within intact skin. The boy was sent home from the hospital in February 2016, and over the next 21 months, researchers said his skin healed normally. Unlike burn patients whose skin grafts arent created from genetically modified cells the boy wont need ointment for his skin and can regrow his hair.

And unlike simple grafts of skin from one body part to another, we had the opportunity to reproduce as much as those cells as we want, said plastic surgeon Dr. Tobias Hirsch, one of the studys authors. You can have double the whole body surface or even more. Thats a fantastic option for a surgeon to treat this child.

Dr. John Wagner, the director of the University of Minnesota Masonic Childrens Hospitals blood and marrow transplant program, told STAT the findings have extraordinary potential because, until now, the only stem cell transplants proven to work in humans was of hematopoietic stem cells those in blood and bone marrow.

Theyve proven that a stem cell is engraftable, Wagner said. In humans, what we have to demonstrate is that a parent cell is able to reproduce or self-renew, and differentiate into certain cell populations for that particular organ. This is the first indication that theres another stem cell population [beyond hematopoietic stem cells] thats able to do that.

The researchers said the aggressive treatment outlined in the study necessary in the case of the 7-year-old patient could eventually help other patients in less critical condition. One possibility, they noted in the paper, was to bank skin samples from infants with JEB before they develop symptoms. These could then be used to treat skin lesions as they develop rather than after they become life-threatening.

The treatment might be more effective in children, whose stem cells have higher renewal potential and who have less total skin to replace, than in adults, Mariaceleste Aragona and Cdric Blanpain, stem cell researchers with the Free University of Brussels, wrote in an accompanying commentary for Nature.

But De Luca said more research must be conducted to see if the methods could be applied beyond this specific genetic disease. His group is currently running a pair of clinical trials in Austria using genetically modified skin stem cells to treat another 12 patients with two different kinds of epidermolysis bullosa, including JEB.

For the 7-year-old boy, life has become more normal now that it ever was before, the researchers said. Hes off pain meds. While he has some small blisters in areas that didnt receive a transplant, they havent stopped him from going to school, playing soccer, or behaving like a healthy child.

The kid is doing quite well. If he gets bruises like small kids [do], they just heal as normal skin heals, Rothoeft said. Hes quite healthy.

Southern Correspondent

Max covers hospitals and health care.

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'Extraordinary' tale: Stem cells heal a young boy's lethal ...

Scientists reported Wednesday that they genetically modified stem cells to grow skin that they successfully grafted over nearly all of a child's body - a remarkable achievement that could revolutionize treatment of burn victims and people with skin diseases.

The research, published in the journal Nature, involved a 7-year-old boy who suffers from a genetic disease known as junctional epidermolysis bullosa (JEB) that makes skin so fragile that minor friction such as rubbing causes the skin to blister or come apart.

By the time the boy arrived at Children's Hospital of Ruhr-University in Germany in 2015, he was gravely ill. Doctors noted that he had "complete epidural loss" on about 60 percent of his body surface area, was in so much pain that he was on morphine, and fighting off a systemic staph infection. The doctors tried everything they could think of: Antibiotics, changing dressings, grafting skin donated by his father. But nothing worked, and they told his parents to prepare for the worst.

"We had a lot of problems in the first days keeping this kid alive," Tobias Hirsch, one of the treating physicians, recalled in a conference call with reporters this week.

Hirsch and his colleague Tobias Rothoeft began to scour the medical literature for anything that might help and came across an article describing a highly experimental procedure to genetically engineer skin cells. They contacted the author, Michele De Luca, of the Center for Regenerative Medicine University of Modena and Reggio Emilia in Italy. De Luca flew out right away.

Using a technique he had used only twice before and even then only on small parts of the body, De Luca harvested cells from a four-square-centimeter patch of skin on an unaffected part of the boy's body and brought them into the lab. There, he genetically modified them so that they no longer contained the mutated form of a gene known to cause the disease and grew the cells into patches of genetically modified epidermis. They discovered, the researchers reported, that "the human epidermis is sustained by a limited number of long-lived stem cells which are able to extensively self-renew."

In three surgeries, the child's doctors took that lab-grown skin and used it to cover nearly 80 percent of the boy's body - mostly on the limbs and on his back, which had suffered the most damage. The procedure was permitted under a "compassionate use" exception that allows researchers under certain dire circumstances to make a treatment available even though it is not approved by regulators for general use. Then, over the course of the next eight months while the child was in the intensive care unit, they watched and waited.

The boy's recovery was stunning.

The regenerated epidermis "firmly adhered to the underlying dermis," the researchers reported. Hair follicles grew out of some areas. And even bumps and bruises healed normally. Unlike traditional skin grafts that require ointment once or twice a day to remain functional, the boy's new skin was fine with the normal amount of washing and moisturizing.

"The epidermis looks basically normal. There is no big difference," De Luca said. He said he expects the skin to last "basically the life of the patient."

In an analysis accompanying the main article in Nature, Mariacelest Aragona and Cedric Blanpain wrote that this therapy appears to be one of the few examples of truly effective stem-cell therapies. The study "demonstrates the feasibility and safety of replacing the entire epidermis using combined stem-cell and gene therapy," and also provides important insights into how different types of cells work together to help our skin renews itself.

They said there are still many other lingering questions, including whether such procedures might work better in children than adults and whether there would be longer-term adverse consequences, such as the development of cancer.

There are also many challenges to translating this research to treating wounds sustained in fires or other violent ways. In the skin disease that was treated in the boy, the epidermis is damaged but the layer beneath it, the dermis, is intact. The dermis is what the researchers called an ideal receiving bed for the lab-grown skin. But if deeper layers of the skin are burned or torn off, it's possible that the artificial skin would not adhere as well.

"No matter how you prepare, it's a bad situation," De Luca said. For the time being, he says he's continuing to study the procedure in two clinical trials that involve genetic diseases.

Meanwhile, Hirsch and Rothoeft report that the boy is continuing to do well and is not on any medication for the first time in many years. Doctors are carefully monitoring the child for any signs that there may be some cells that were not corrected and that the disease may re-emerge, but right now that does not appear to be happening in the transplanted areas. However, the child does have some blistering in about 2 to 3 percent of his body in non-grafted areas and they are considering whether to replace that skin as well.

But for now, they are giving the boy time to be a boy, Rothoeft said: "The kid is now back to school and plays soccer and spends other days with the children."

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(CNN) - For the first time, doctors were able to treat a child who had a life-threatening rare genetic skin disease through a transplant of skin grown using genetically modified stem cells.

The grafts replaced 80% of the boy's skin.

The skin of his arms, legs, back and flanks, and some of the skin on his stomach, neck and face was missing or severely affected due to epidermolysis bullosa.

The compassionate-use experimental treatment is detailed in a case study published in the journal Nature on Wednesday.

Skin as fragile as a butterfly's wings -- that's how children with epidermolysis bullosa are described and why they're often called butterfly children.

The disease, of which there are five major types and at least 31 subtypes, is incurable. People with the condition have a defect in the protein-forming genes necessary for skin regeneration.

About 500,000 people worldwide are affected by forms of the disease. More than 40% of patients die before reaching adolescence.

Their skin can blister and erode due to something as simple as bumping into something or even the light friction of clothing, according to an email from Dr. Jouni Uitto, a professor and chairman of the Department of Dermatology and Cutaneous Biology at the Sidney Kimmel Medical College in Philadelphia. Uitto was not involved with this study.

Epidermolysis bullosa makes the skin incredibly susceptible to infections, and in the case of 7-year-old Hassan, whose treatment was detailed in Nature, those infections can be life-threatening.

A week after he was born in Syria, Hassan had a blister on his back, his father said through an interpreter in an interview provided by the hospital in Germany where the boy was treated.

Hassan's last name, as well as the first names of his family members, are not being disclosed to protect the privacy of the family.

In his first few weeks of life, Hassan was immediately diagnosed with epidermolysis bullosa, and their doctor in Syria told Hassan's family that there was no cure or therapy.

Over the years, their efforts to find help for their son's disease led the family to the Muenster University hospital in Germany in 2015, when Hassan was 7. His condition worsened, and he struggled with severe sepsis and a high fever. He weighed just over 37 pounds.

They didn't think he would make it, and doctors at Muenster decided in summer 2015 to transfer Hassan to the Ruhr-Universitt Bochum's University Hospitals, including the burn center -- one of the oldest in the country.

By the time Hassan arrived at Bochum, he had lost two-thirds of his surface skin.

"We had a lot of problems in first days just keeping him alive," said Dr. Tobias Rothoeft, consultant at the University Children's Hospital at Katholisches Klinikum Bochum.

Doctors tried to promote healing by changing his dressings and treating him with antibiotics, as well as putting him on an aggressive nutrition schedule, but nothing helped. They even tried transplanting skin from Hassan's father.

"By that time, he had lost 60% of his epidermis, the upper skin layer, and had 60% open wounds all over his body," said Dr. Maximilian Kueckelhaus of the Department of Plastic Surgery at Bochum's Burn Center.

Every approach failed, so the doctors prepared Hassan's family for what end-of-life care would entail. But the parents pleaded, asking the doctors to consult studies and research for experimental treatments that might help.

They found Dr. Michele De Luca at the University of Modena's Center for Regenerative Medicine in Italy. His publications described an experimental treatment transplanting genetically modified epidermal stem cells that healed small, non-life-threatening wounds in adults.

The medical team reached out to De Luca, asking whether he could help them replicate the procedure on a larger scale to help Hassan, and he agreed. De Luca told Hassan's parents that he believed there was a 50% chance of the treatment being successful.

They were more than willing to accept the risk, to do anything to help their son have a chance at a normal life.

Hassan "was in severe pain and was asking a lot of questions: 'Why do I suffer from this disease? Why do I have to live this life? All children can run around and play. Why am I not allowed to play soccer?' I couldn't answer these questions," his father said. "It was a tough decision for us, but we wanted to try for Hassan."

To obtain the skin's stem cells, the doctors took a small biopsy -- only accounting for 1 square inches -- from an unaffected part of Hassan's skin. The stem cells were processed by De Luca in Italy. A healthy version of the gene that is normally defective in epidermolysis bullosa patients was added to the cells, along with retroviral vectors: virus particles that assist the gene transfer.

This genetic transfer would essentially "correct" the cells.

The single cells were grown and cultivated on plastic and fibrin substrate, which is used to treat large skin burns, to form a large piece of epidermis. This method enabled the researchers to grow as much skin as they needed. The whole process took three to four weeks, Kueckelhaus said.

Once the sheets were ready, they were transferred from Italy to Germany and transplanted onto the well-cleaned wounds right away during two surgeries. The first procedure in October 2015 applied the sheets to Hassan's arms and legs. The second surgery, in November, grafted the sheets to Hassan's entire back and the other affected areas.

Hassan began to improve immediately. The researchers noticed that the grafts were not rejected; they bound to all of the areas they were transplanted.

"For everyone that was involved, taking off the bandages and seeing for the first time that this is working out, that the transplants are actually attached to the patient and growing skin, that's an incredible moment," Kueckelhaus said.

Hassan was discharged from the hospital in February 2016.

After steady followups over 21 months, the researchers found that Hassan's new skin healed normally, didn't blister anymore, and was resistant to stress. It was even growing hair. Unlike some skin graft patients, he doesn't require any ointment to keep his skin smooth and hydrated. And like any growing kid, he bruises and recovers normally.

They also learned that only a few stem cells contribute to the long-term maintenance of the epidermis, shedding light on cellular hierarchy in this regard.

"The investigators removed of small piece of patient's skin, isolated cells with stem cell potential for growth, introduced a normal copy of the mutated gene to the cells, propagated a large number of these cells in culture and then grafted them back to the skin," Uitto said. "This concept is not new, but what is remarkable here is that they were able to change essentially the entire skin of the patient with normal cells."

Hassan's family is currently living in Germany. Hassan, now 9, is able to go to school and play sports, but he maintains a schedule of frequent monitoring at the hospital to ensure that the initial success of the treatment continues. The area of his skin that was not treated sometimes shows small blisters, and if it worsens, he may receive transplants there as well.

"Seeing him 18 months after the initial surgery with an intact skin is incredible because he has been in the ICU for so long," Kueckelhaus said. "He had bandages all over his body except his hands, feet and face. He was on extremely strong pain medication. So the quality of life was really, really bad for him. Seeing him play soccer, play sports, play with other kids, that is just amazing because that's something he couldn't do before."

"It felt like a dream for us," the boy's father said. "Hassan feels like a normal person now. He plays. He's being active. He loves life."

Everything points to a good long-term outcome for Hassan.

The researchers will continue to monitor him for complications. Sometimes, genetic modifications can cause malignancies in cells.

"That is of course one thing we really have to be aware of," Kueckelhaus said. "However, analyzing the integration profile of that gene into the boy's DNA, which we did, we saw that it's mostly in areas that don't cause too much concern about developing malignancies."

Epidermolysis bullosa patients can be at a very high risk of developing skin cancer simply because of the disease. Because Hassan now has intact skin and intact DNA, this risk might even decrease, but that will have to be proved through follow-up, Kueckelhaus said.

Given that this was one successful outcome for one patient, the experimental treatment can't be applied for other patients just yet. De Luca is conducting clinical trials using the treatment.

"This is one case with a distinct type of EB, and further studies will show whether this approach is applicable to other forms of EB as well," Uitto said. "It should be noted that in some severe forms of EB, the patients also suffer from fragility of the gastrointestinal and vesico-urinary tract, and some forms are associated with the development of muscular dystrophy. Obviously, gene therapy of the skin cannot correct them, and these issues have to be addressed in further studies."

Hassan's treatment also cost hundreds of thousands of dollars. Although the process could be optimized, doctors would still have to individually grow transplants for each patient, which could get very expensive.

But for patients' families, epidermolysis bullosa is already expensive.

"Standard maintenance treatment of patients with EB, including daily bandaging, antibiotics and special moisturizer, as well as frequent hospitalizations, can be extremely costly, and gene correction as described in this paper may well be cost-effective over the lifetime of these patients," Uitto noted.

Brett Kopelan, executive director of the Dystrophic Epidermolysis Bullosa Research Association of America, has a 10-year-old daughter, Rafi, with recessive dystrophic EB. Between January and August, $751,1778 for wound/burn dressings was charged to Kopelan's insurance company, he says. That doesn't account for drugs or hospital visits and surgeries.

Kopelan's nonprofit sends free supplies and bandages to families. The nonprofit can provide its employees with insurance that covers the medical equipment, but that isn't the case for everyone impacted by the condition, he said.

Kopelan is hopeful about the results of the study. The baths and bandage changes that are necessary for epidermolysis bullosa patients to stave off life-threatening infections can last hours and feel torturous.

"Do you remember the last time you got a paper cut and put Purell on it? It burned, right? Now think of 60% of body being an open wound, and opioids don't really work for this kind of pain," Kopelan wrote in an email. "This is what make EB kids and adults the strongest people on Earth."

The study "confirms our hopes that gene therapy is potentially the most efficacious path forward to providing a significant treatment option for those with epidermolysis bullosa," Kopelan said. "While it's important to remember that this is only one patient and more work needs to be done to demonstrate how effective this gene therapy platform may prove to be, I am very enthused."

"I wish that all children with the same disease could be treated in this way," Hassan's father said.

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Scientists replace skin using genetically modified stem cells

If you or a loved one will be having a bone marrow transplant or donating stem cells, what does it entail? What are the different types of bone marrow transplants and what is the experience like for both the donor and recipient?

A bone marrow transplant is a procedure in which when special cells (called stem cells) are removed from the bone marrow or peripheral blood, filtered and given back either to the same person or to another person.

Since we now derive most stem cells needed from the blood rather than the bone marrow, a bone marrow transplant is now more commonly referred to as stem cell transplant.

Bone marrow is found in larger bones in the body such as the pelvic bones. This bone marrow is the manufacturing site for stem cells. Stem cells are "pluripotential" meaning that the cells are the precursor cells which can evolve into the different types of blood cells, such as white blood cells, red blood cells, and platelets.

If something is wrong with the bone marrow or the production of blood cells is decreased, a person can become very ill or die. In conditions such as aplastic anemia, the bone marrow stops producing blood cells needed for the body. In diseases such as leukemia, the bone marrow produces abnormal blood cells.

The purpose of a bone marrow transplant is thus to replace cells not being produced or replace unhealthy stem cells with healthy ones.

This can be used to treat or even cure the disease.

In addition for leukemias, lymphomas, and aplastic anemia, stem cell transplants are being evaluated for many disorders, ranging from solid tumors to other non-malignant disorders of the bone marrow, to multiple sclerosis.

There are two primary types of bone marrow transplants, autologous and allogeneic transplants.

The Greek prefix "auto" means "self." In an autologous transplant, the donor is the person who will also receive the transplant. This procedure, also known as a "rescue transplant" involves removing your stem cells and freezing them. You then receive high dose chemotherapy followed by infusion of the thawed out frozen stem cells. It may be used to treat leukemias, lymphomas, or multiple myeloma.

The Greek prefix "allo" means "different" or "other." In an allogeneic bone marrow transplant, the donor is another person who has a genetic tissue type similar to the person needing the transplant. Because tissue types are inherited, similar to hair color or eye color, it is more likely that you will find a suitable donor in a family member, especially a sibling. Unfortunately, this occurs only 25 to 30 percent of the time.

If a family member does not match the recipient, the National Marrow Donor Program Registry database can be searched for an unrelated individual whose tissue type is a close match. It is more likely that a donor who comes from the same racial or ethnic group as the recipient will have the same tissue traits.

Learn more about finding a donor for a stem cell transplant.

Bone marrow cells can be obtained in three primary ways. These include:

The majority of stem cell transplants are done using PBSC collected by apheresis (peripheral blood stem cell transplants.) This method appears to provide better results for both the donor and recipient. There still may be situations in which a traditional bone marrow harvest is done.

Donating stem cells or bone marrow is fairly easy. In most cases, a donation is made using circulating stem cells (PBSC) collected by apheresis. First, the donor receives injections of a medication for several days that causes stem cells to move out of the bone marrow and into the blood. For the stem cell collection, the donor is connected to a machine by a needle inserted in the vein (like for donating blood.) Blood is taken from the vein, filtered by the machine to collect the stem cells, then returned back to the donor through a needle in the other arm. There is almost no need for a recovery time with this procedure.

If stem cells are collected by bone marrow harvest (much less likely,) the donor will go to the operating room and while asleep under anesthesia, a needle will be inserted into either the hip or the breastbone to take out some bone marrow. After awakening, there may be some pain where the needle was inserted.

A bone marrow transplant can be a very challenging procedure for the recipient.

The first step is usually receiving high doses of chemotherapy and/or radiation to eliminate whatever bone marrow is present. For example, with leukemia, it is first important to remove all of the abnormal bone marrow cells.

Once a person's original bone marrow is destroyed, the new stem cells are injected intravenously, similar to a blood transfusion. The stem cells then find their way to the bone and start to grow and produce more cells (called engraftment.)

There are many potential complications. The most critical time is usually when the bone marrow is destroyed so that few blood cells remain. Destruction of the bone marrow results in greatly reduced numbers of all of the types of blood cells (pancytopenia.) Without white blood cells there is a serious risk of infection, and infection precautions are used in the hospital (isolation.) Low levels of red blood cells (anemia) often require blood transfusions while waiting for the new stem cells to begin growing. Low levels of platelets (thrombocytopenia) in the blood can lead to internal bleeding.

A common complication affecting 40 to 80 percent of recipients is graft versus host disease. This occurs when white blood cells (T cells) in the donated cells (graft) attack tissues in the recipient (the host,) and can be life-threatening.

An alternative approach referred to as a non-myeloablative bone marrow transplant or "mini-bone marrow transplant" is somewhat different. In this procedure, lower doses of chemotherapy are given that do not completely wipe out or "ablate" the bone marrow as in a typical bone marrow transplant. This approach may be used for someone who is older or otherwise might not tolerate the traditional procedure. In this case, the transplant works differently to treat the disease as well. Instead of replacing the bone marrow, the donated marrow can attack cancerous cells left in the body in a process referred to as "graft versus malignancy."

If you'd like to become a volunteer donor, the process is straightforward and simple. Anyone between the ages of 18 and 60 and in good health can become a donor. There is a form to fill out and a blood sample to give; you can find all the information you need at the National Marrow Donor Program Web site. You can join a donor drive in your area or go to a local Donor Center to have the blood test done.

When a person volunteers to be a donor, his or her particular blood tissue traits, as determined by a special blood test (histocompatibility antigen test,) are recorded in the Registry. This "tissue typing" is different from a person's A, B, or O blood type. The Registry record also contains contact information for the donor, should a tissue type match be made.

Bone marrow transplants can be either autologous (from yourself) or allogeneic (from another person.) Stem cells are obtained either from peripheral blood, a bone marrow harvest or from cord blood that is saved at birth.

For a donor, the process is relatively easy. For the recipient, it can be a long and difficult process, especially when high doses of chemotherapy are needed to eliminate bone marrow. Complications are common and can include infections, bleeding, and graft versus host disease among others.

That said, bone marrow transplants can treat and even cure some diseases which had previously been almost uniformly fatal. While finding a donor was more challenging in the past, the National Marrow Donor Program has expanded such that many people without a compatible family member are now able to have a bone marrow/stem cell transplant.

Sources:

American Society of Clinical Oncology. Cancer.Net. What is a Stem Cell Transplant (Bone Marrow Transplant)? Updated 01/16. http://www.cancer.net/navigating-cancer-care/how-cancer-treated/bone-marrowstem-cell-transplantation/what-stem-cell-transplant-bone-marrow-transplant

U.S. National Library of Medicine. MedlinePlus. Bone Marrow Transplant. Updated 10/03/17. https://medlineplus.gov/ency/article/003009.htm

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bone marrow/stem cell transplant - verywell.com

The following was written withProf. Gerold Riempp, a professor of information systems who was diagnosed with Parkinsons disease 16 years ago at age 36. He is co-founder of a charitable organization in Germany that supports the development of therapies that aim to cure PD.

The idea behind cell replacement therapy(CRT) for PD is pretty simple: lack of mobility in PD is the result of the dysfunction and death of a specific kind of cell in the midbrain. While there are a few other things that go wrong in PD, the progressive loss of motor skills is the biggest problem most diagnosed face. Since we are reasonably sure that this lack of mobility results from the impairment and death of dopamine producing cells in an area of the midbrain called the substantia nigra,why not try to replace those cells?

A group of iPS cells grown from human skin tissue at Osaka University

Replacing those cells is one of three core problems that each person diagnosed with PD needs to address. They are:

1. Keeping remaining cells healthyOnce diagnosed, most people have already lost production of 50-80% of dopamine in their midbrain. The problem then is to stop further disease progression by figuring out how to get rid of everything that might be harming the remaining 20-50% of cells while giving their body everything it needs to keep those cells alive and active.

2. Clearing clogged cellsOf those 50-80% of non-dopamine producing cells, a portion are still alive, they are just not doing their job, producing dopamine. This impairment is a result of a range of interrelated factors that harm the cells and eventually lead to their death. Most researchers believe the problem can be boiled down to the clumping of a misfolded protein called alpha-synuclein. Many different methods are being tried in labs around the world to clear these clumps and stop more from accumulating. But this might only be part of the story since a wide variety of other factors also lead to cell death.

3. Replacing dead cellsThen we come to what to do about all of those dead cells. A couple of different options are being considered to get the brain tostimulate the production of new neurons orreplace the function of dead ones. However, the most promising therapy being developed is stem cell therapy, now commonly referred to as cell replacement therapy. It works by placing new dopamine producing neurons into the part of the brain where the dead neurons used to release dopamine.

If a patient manages to address problems one and two they might have no need for CRT. The reason for this is that he or she can likely rescue a considerable portion of the damaged but still living cells and thereby bring dopamine production back to a level that allows for normal movement. CRT will generally be for people who have had PD for a longer time and whose remaining healthy cells plus the rescued ones together are not capable of providing enough dopamine.

The late 80s and 90s saw a number of CRT trials for Parkinsons disease with mixed results. But we nowhave a much better understanding of what kind of cells to use, how to culture and store those cells, how to implant them, and who this therapy would be best for.

We also now have iPS cells (induced pluripotent stem cells). Discovered in 2006, these are cells that have been chemically reprogrammed, usually from adult skin tissue, back into pluripotent stem cells. (Pluripotent means they are capable of becoming almost any cell in the body). Using these cells for transplantation has two major advantages. One, it eliminates the need for potentially harmful immuno-suppressors. Two, it has none of the ethical issues that come with using fetal stem cells. But iPS cells are much more expensive and technically difficult to produce.

Despite all the progress made, cell replacement therapy is still very controversial and fraught with all sorts of technical issues. Luckily, CRT for PD is one of the only fields of medical science where the top labs around the world are cooperating with each other. An international consortium of labs has come together under a name that sounds like it was ripped out of a Marvel comic, the GForce-PD. Each lab in the GForce-PD aims to bring CRT for PD to clinical trial within the next few years.

Infographic made by PhD neuroscientist Kayleen Schreiber at kayleenschreiber.com

The GForce-PD

New York City Run by Dr. Lorenz Studer out of the Rockefeller research labs in New York City. Dr. Studer pioneered many of the reprogramming techniques being used around the world to convert pluripotent stem cells into dopamine producing neurons. His lab wasrecently announced to be part of a huge funding initiative from Bayer Pharmaceuticals to help speed up development of CRT. Studers lab is aiming to start transplantation of embryonic stem cells in human trials in early 2018.

Kyoto, Japan Dr. Jun Takahashis lab in Kyoto is working on producing several iPS lines for the Japanese population. One advantage they have is the relative homogeneity of Japanese people allows them to use a dozen or so iPS lines for almost everyone in the country. The lab recently made headlines with results from monkey trials that showed human iPS cells graft safely, with no signs of malignant growth, two years after transplantation.

Cambridge, England Dr. Roger Barkers lab has been working on cell replacement therapy for Parkinsons disease for a number of years through the Transeuro project. His lab is pushing forward with more embryonic stem cell transplantations expected to begin in 2020. They also work very closely with the team in Sweden.

Lund, Sweden The lab in Lund has been working on CRT for PD since the 80s and has been part of a number of human trials. The lab is now run by Dr. Malin Parmar whose team has also pioneered many of the techniques used in direct programming that will one day allow researchers to skip the stem cell phase all together and produce dopamine cells directly in the brain.

San Diego, California The team is moving rapidly towards iPS cell transplantation under Dr. Jeanne Loring at the Scripps research center. They are the only lab that uses patients own cells for transplantation. Another unique feature of this lab is that it has been a community funded initiative under theSummit For Stem Cellsfoundation.

(Dr. Roger Barker talking about CRT for PD)

Though there is a lot of excitement building around cell replacement therapy, we need to proceed carefully. The field has potential for setbacks from some of the less rigorous trials being conducted in places like Australia and China where regulatory standards are more lax. Researchers in these areas are already going ahead with trials that do not meet the standards set by the GForce-PD. These have the potential to put a black-eye on all cell replacement therapies.

Also, producing pure batches of dopamine neurons is still a highly technical process that only a few labs in the world are capable of doing safely and effectively. Thankfully a few other labs around the world are joining the efforts of the GForce-PD, such as Dr. Tilo Kunaths lab in Edinburgh, which is working on techniques to better differentiate and characterize the cell lines used for transplantation.

(The pictures above show human embryonic stem cells being differentiated into dopamine cells at days 2, 4 and 7. Courtesy of Dr. Tilo Kunaths lab at the University of Edinburgh)

The Future of Cell Replacement Therapy

These therapies being developed for Parkinsons disease will, in essence, be version 1.0 of CRT. Clinical trials are set to begin next year and the therapy is expected to be widely available to people diagnosed with Parkinsons disease within the next 5-10 years.

Version 2.0 will be CRISPR-modified, disease resistant grafts, with genetic switches to modulate dopamine production and graft size.

Version 3.0 will make use of an emerging field called in vivo direct programming where viruses are inserted into the brain and transform other existing cells into dopamine producing cells.

(Edit: Credit to Dr. Tilo Kunath for correcting versions 2.0 and 3.0)

Dopamine neurons grown from iPS cells at 40 times magnification, from the Gladstone Institute

CRT for PD is one of the most exciting areas of research on the planet. It is a powerful demonstration of the progress we as a species have made in our attempt to gain mastery over the forces of biology.It has the potential to improve the lives of the millions living with PD, and the millions yet to be diagnosed. Once the transplanted cells have connected with their surroundings and start delivering dopamine to the right places, it should allow patients to gradually reduce their medication. Being able to move normally and not deal with the side effects of all the drugs and other therapies is what PD patients around the world are dreaming of.

Click here for more information on the future of cell replacement therapy for Parkinsons disease and the work of the GForce-PD.

And if you want to be part of bringing CRT to the clinic you can do so by supporting organizations like Summit For Stem Cells.

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