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Japan trial to treat spinal cord injuries with stem cells …

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Japan trial to treat spinal cord injuries with stem cells

TOKYO: A team of Japanese researchers will carry out an unprecedented trial using a kind of stem cell to try to treat debilitating spinal cord injuries, the specialists said on Monday.

The team at Tokyos Keio University has received government approval for a trial using so-called induced Pluripotent Stem (iPS) cells, which have the potential to develop into any cell in the body, to treat patients with serious spinal cord injuries.

The trial, expected to begin later this year, will initially focus on four patients who suffered their injuries just 14 to 28 days beforehand, the university said. The team will transplant two million iPS cells into the spines of the patients, who will then go through rehabilitation and be monitored for a year.

The strict limitations on the number of participants is necessary because the process is an "unprecedented, world first clinical trial", the university added. "Its been 20 years since I started researching cell treatment. Finally we can start a clinical trial," Hideyuki Okano, a professor of physiology, said at a press conference.

"We want to do our best to establish safety and provide the treatment to patients," he added. The study will be carried out on patients aged 18 or older who have completely lost their motor and sensory functions.

There are more than 100,000 patients in Japan who are paralysed due to spinal cord injuries but there is no effective treatment. The primary purpose of the trial is to confirm the safety of the transplanted cells and the method of the transplant, the researchers said.

The research team hopes to test the efficacy and safety of the treatment for chronic injuries as well in the future if they can confirm the safety of the technique through the clinical trial. The announcement comes after researchers in Kyoto said in November they had transplanted iPS cells into the brain of a patient in a bid to cure Parkinsons disease. The man was stable after the operation and he will be monitored for two years.

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Kotton Lab – Boston University Medical Campus

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The Kotton labs goal is advancing our understanding of lung disease and developmental biology with a focus on stem cell biology and gene therapy. We believe that novel treatments for many lung diseases can be realized based on a better understanding of how the lung develops as well as regenerates after lung injury.

We are particularly interested in understanding how lung cells decide and remember who they are. To this end, one focus of our group is defining the genomic and epigenomic programs that regulate lung cell fate. A longer term goal is the de novo generation of the full diversity of lung lineages and transplantable 3D lung tissues from pluripotent stem cells. Our Principal Investigator, Dr. Darrell Kotton, also serves as the founding Director of the Center for Regenerative Medicine (CReM). Take a full tour of the CReM by clicking on our logo above.

Click on the menu to learn more about our research areas and our team

Have forty five minutes for an overview of our last decade? Listen here to Darrells ATS Discovery Series Lecture, Lung Regeneration: An Achievable Mission.

Open Source Works! Click here to access our:iPS Cell Lines, Lentiviral Vectors, Bioinformatics Datasets, or Detailed Protocols!

or read more about our Open Source Biology Philosophyor a recent interview on Darrells approach to sharing our cells

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Stem Cells Used in Cord Blood Treatments

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Stem cells are powerful, adaptable cells that can be used to promote healing and reverse damage. Stem cells are found in various places within the human body, but the purest stem cells are found in the umbilical cord.

Stem cells can be used in treatments for many different types of diseases. One of the main places young stem cells are found is in cord blood, which can be stored at birth and saved for future use if needed. Stem cells are also found in other places in the human body, including blood and bone marrow.

Regenerative transplants use stem cells from three main sources:

Bone marrow is tissue located in the center of your bones, making healthy blood cells that strengthen your immune system and fight off outside infections. A large amount of cells are located in bone marrow, and doctors frequently use hip bone marrow for most transplants, since the stem cells in this area are the most plentiful.

When doctors remove bone marrow, the patient receives anesthesia. This puts them to sleep and numbs any pain from the surgery. Doctors then insert a large needle, and pull the liquid marrow out. Once enough bone marrow is harvested, the solution is filtered and cryogenically frozen.

When a patient needs bone marrow for a transplant, stem cells are thawed and injected into the bloodstream. The cells then make their way to the bone marrow, and start producing new blood cells this process usually takes a few weeks.

While most people have a small amount of stem cells in their bloodstream, donors produce more stem cells after taking growth factor hormones. Doctors give these medications a few days before stem cell harvesting, which makes the bone marrow push more cells into the bloodstream.

During the harvesting procedure, doctors use a catheter to draw out blood. The blood moves through a machine, which separates stem cells and allows these cells to be put into storage. This process takes a few hours, and may be repeated over several days in order for doctors to get enough stem cells.

Stem cells are injected into the veins during a peripheral blood transplant, and naturally work their way to the bone marrow. Once there, the new cells start increasing healthy blood count. Compared to bone marrow transplants, cells from peripheral blood are usually faster, creating new blood cells within two weeks.

Umbilical cord blood contains a large amount of stem cells. If parents sign up for personalized storage or donation, medical staff will remove stem cells from the umbilical cord and placenta. The blood is then cryogenically frozen, and put into long-term storage.

While the stem cell count is smaller during a cord blood transplant, these cells multiply quickly, and researchers are studying new methods to increase cells naturally. Compared to bone marrow, cord blood cells multiply faster and dont require an exact match type to complete a successful transplant. Some techniques medical experts are testing to increase the amount of stem cells include:

While all three stem cell sources are used in similar procedures, they each have advantages and drawbacks. Bone marrow transplants are the traditional form of therapy, but peripheral blood cells are becoming more popular, since doctors often get more stem cells from the bloodstream.

The procedure for peripheral blood harvesting is easier on the patient than a bone marrow transplant, and stem cell transplants are faster. However, the chances for graft-versus-host disease, where donated cells attack the patients body, are much higher after a peripheral blood transplant.

Cord blood transplants are the least invasive, since they come from an external source the umbilical cord.

The biggest advantage for cord blood is the immaturity of the cells, which means transplants do not require an exact match. For bone marrow and peripheral blood transplants, donors need to match the patients cellular structure. However, cord blood cells can adapt to a wide variety of patients, and dont require donor matching. Chances for graft-versus-host disease are also much lower for cord blood transplants.

Patients and doctors can avoid graft-versus-host disease, and other dangerous side effects, by using HLA matching.

Multipotent stem cells develop into organ system cells, and are made from two different types of cells:

HSCs can become any type of blood cell or cellular blood component inside the body, including white blood cells and red blood cells. These cells are found in umbilical cord blood and are multipotent, which means they can develop into more than one cell type.

This cell type has been used in over 1 million patient transplants around the world.

MSCs can turn into bone, cartilage, fat tissue, and more. Although they are associated with bone marrow, these cells are also found in umbilical cord blood. These cells can function as connective tissue, which connects vital organs inside the body. Like HSCs, MSCs are multipotent.

Pluripotent cells can replace any type of cellular system in the body. Cord blood contains a rich variety of pluripotent stem cells, which allows treatment for a large amount of patients.

iPS cells are artificially-made pluripotent stem cells. This technique allows medical staff to create additional pluripotent cells, which will increase treatment options for patients using stem cell therapy in the near future.

ES cells are pluripotent, and similar to iPS cells, but come from an embryo. However, this kills the fertilized baby inside the embryo. This type of cell also has a high chance for graft-versus-host disease, when transplanted cells attack the patients body.

Your adult cells have one disadvantage to cord blood cells they cannot change their cell type. When stem cells from cord blood and tissue are transplanted, they adjust to fit the individual patient and replace damaged cells. Adult stem cells are also older, which means they have been exposed to disease, and may damage patients after the transplant. Compared to cord blood cells, adult cells have a higher chance for graft-versus-host disease.

Cord blood contains a wide variety of cell types, but there are different stem cell sources available to patients in need of a transplant.

Last Updated on February 15th, 2017

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Is donating bone marrow painful? | Anthony Nolan

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The myth that stem cell or bone marrow donation is painful is extremely common and worryingly, it often stops people from registering to donate.

In 2016, a YouGov survey found that a shocking 34% of young men who wouldnt sign up as a stem cell donor were just tooscared that the experience would be painful.

We urgently need that to change because it couldnt be further from the truth.

I would 100% recommend it to other people. Its comfortable, painless and so worthwhile.Zachary, stem cell donor

It was painless and thats coming from someone with a fear of needles! I remember being amazed at how simple it was.Sean, stem cell donor

90% of people now donate directly from their bloodstream, in a procedure known as peripheral blood stem cell donation (PBSC).

Youll receive a series of four hormone injections to make your stem cells multiply into the bloodstream. Then youll head to a clinic, where the stem cells will be extracted from one arm, and your blood returned to the other.

And thats it. Some people report flu-like symptoms from the hormone injections, but these are usually mild and vanish within a few days.

Ive felt worse after a few bruising encounters on the football pitch. Within a week of the donation, I was back on my feet and feeling much better; all in all, its a very small price to pay for what could be achieved.Liam, bone marrow donor

Some people have asked me if it was painful or difficult. It was actually quite simple and nothing compared to what the recipient is going through at the same time.Andrew, stem cell and bone marrow donor

Just 10% of people are asked to donate from the bone marrow itself.

This is the procedure that lies at the root of the bone marrow donation is painful myth but in reality, it takes place under general anaesthetic, so you wont feel any pain while its happening.

Afterwards, youll probably feel a bit tired and bruised, and we recommend that you take a short break from work to recover. But thats all and it makes a lifesaving difference.

Tackling the myth that stem cell or bone marrow donation is painful is one of our biggest priorities.

Thats why we often ask our donors to share their stories, to bust the myths and show the world what donation is really like.

For a wide variety of donation experiences, just check out the Anthony Nolan Facebook page we usually add one or two new stories every week!

If you're aged 16-30, sign up to our lifesaving register by clicking on the link below:

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Adult Stem Cells in Vascular Remodeling – Theranostics

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Theranostics 2018; 8(3):815-829. doi:10.7150/thno.19577


Dong Wang1*, LeeAnn K. Li1,2*, Tiffany Dai3, Aijun Wang4, Song Li1,5

1. Department of Bioengineering, University of California, Los Angeles, CA 90095, USA;2. David Geffen School of Medicine, University of California, Los Angeles, CA 90024, USA;3. Department of Bioengineering, University of California, Berkeley, CA 94720, USA;4. Surgical Bioengineering Laboratory, Department of Surgery, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA;5. Department of Medicine, University of California, Los Angeles, CA 90095, USA.* Equal contribution

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.

Understanding the contribution of vascular cells to blood vessel remodeling is critical for the development of new therapeutic approaches to cure cardiovascular diseases (CVDs) and regenerate blood vessels. Recent findings suggest that neointimal formation and atherosclerotic lesions involve not only inflammatory cells, endothelial cells, and smooth muscle cells, but also several types of stem cells or progenitors in arterial walls and the circulation. Some of these stem cells also participate in the remodeling of vascular grafts, microvessel regeneration, and formation of fibrotic tissue around biomaterial implants. Here we review the recent findings on how adult stem cells participate in CVD development and regeneration as well as the current state of clinical trials in the field, which may lead to new approaches for cardiovascular therapies and tissue engineering.

Keywords: Cardiovascular disease, Stem cell, atherosclerosis, vascular grafts, vascular smooth muscle cell.

Cardiovascular diseases (CVDs) such as ischemic heart disease, stroke, and peripheral artery disease are the leading cause of mortality and morbidity around the world: about 30% of global deaths and 10% of global disease burden a year are due to CVDs [1, 2]. In the past three decades, these diseases have been increasing in underdeveloped and developing countries. Although deaths from CVDs have declined in some developed countries with better healthcare interventions and systems and primary prevention, population growth and aging will drive up global CVDs in coming decades [1, 2].

Atherosclerosis is a chronic inflammatory disease resulting in clogged arteries or unstable plaque rupture [3, 4]. Currently, treatment of atherosclerosis includes reducing risk factors such as treatment of hypercholesterolemia and hypertension [1, 2] and, for advanced disease, surgery such as stent implantation and bypass surgery using autologous vessels or tissue-engineered vascular grafts [5]. However, thrombosis and secondary atherosclerosis are common complications following stent and graft implantation, particularly in small-diameter arteries and grafts [6]. New therapies are thus urgently needed for better prevention and treatment of atherosclerosis.

It is widely accepted that endothelial cell (EC) dysfunction, inflammatory cell recruitment, and vascular smooth muscle cell (SMC) de-differentiation contribute to atherogenesis [3, 4, 7]. In the past two decades, several types of vascular stem cells (VSCs), in addition to circulating progenitors, have been identified and characterized, with evidence that they are not only involved, but also play pivotal roles in blood vessel remodeling and disease development. VSCs or similar stem cells in mesenchymal tissues, for instance, also participate in the regeneration of blood vessels following the implantation of vascular grafts. Elucidating the regulatory mechanisms of these VSCs is fundamental to understanding vascular remodeling and may pave the way to developing novel, successful therapies for atherosclerosis. In this review, we analyze vascular remodeling through the lens of stem cells, and discuss the challenges we face in developing improved therapies for vascular diseases and regeneration.

Large and medium size blood vessels have three distinct layers: 1) the tunica intima, an inner lining of ECs, which may contain a small number of endothelial progenitor cells (EPCs) [8, 9]; 2) the tunica media, a thick middle layer composed of smooth muscle cells (SMCs) and a small number of stem cells; and 3) the tunica adventitia, an outer layer of connective tissue containing a heterogeneous population of cells, including fibroblasts, resident inflammatory cells (including macrophages, dendritic cells, T cells and B cells), microvascular (vasa vasorum) ECs around which pericytes reside, adrenergic nerves, and also stem cells (including multipotent mesenchymal stem cells, or MSCs) and progenitor cells (including those with macrophage, endothelial, smooth muscle, and hematopoietic potential) [10-18]. All these cells contribute, to varying extents, to the pathogenesis of atherosclerosis and vascular remodeling.

Atherosclerosis is thought to be initiated by dysfunctional or activated ECs [3, 7]. Various risk factors include genetic defects and environmental risks, behaviors like cigarette smoking and harmful use of alcohol, as well as disturbed blood flow, hypertension, hypercholesterolemia, infections, and other chronic conditions such as diabetes, obesity, autoimmune diseases, and aging [1, 2]. The injured endothelial area may be repaired by adjacent EC proliferation or EPCs from bone marrow or resident endothelium [19]. Disease begins when such endothelial repair does not occur properly.

Malfunctioning ECs secrete cytokines and upregulate expression of surface adhesive molecules to recruit circulating platelets, monocytes, T cells, neutrophils, dendritic cells, and mast cells to adhere to the site of endothelial injury and infiltrate into the subendothelial space. Within this space, monocytes differentiate into macrophages and scavenge lipid deposited from the circulation, becoming foam cells in the process [3, 20-22]. Notably, most of these foam cells are initially derived from preexisting intimal-resident myeloid progenitors rather than recently recruited blood monocytes [23]. In addition, the inflammatory cells activate medial SMCs and stem cells, prompting adventitial stem cells to proliferate and migrate into the intima, where they may differentiate and also obtain some properties of myofibroblasts and macrophages [3, 20-22, 24, 25]. Disease proceeds as the abnormal vascular wall processes prompt macrophages, together with leukocytes, activated ECs, and SMCs, to secrete increasing amounts of inflammatory cytokines to recruit more inflammatory cells from the circulation and resident adventitial tissues. This forms a cycle of inflammatory responses in local atherosclerotic lesions [3, 4, 26-28]. All these events lead to the development of fatty streaks, formation of neointima, and thickening of arterial walls seen at the early stages of atherosclerosis [3, 26]. The extracellular matrix, too, may play a role in lipid retention [29]. As these atherosclerotic lesions continue to grow and narrow the lumen, arteries may attempt to compensate by gradual dilation; however, this compensation reaches its limit beyond a certain size of atherosclerotic lesion.

Advanced atherosclerotic plaques have developed a fibrous cap that sequesters the underlying inflammatory mixture, which includes foam cells and extracellular lipid droplets, infiltrated T cells, macrophages, and mast cells, and necrotic tissue [3, 26]. The cap itself is mainly comprised of SMCs and collagen matrix, which can be degraded and ruptured by metalloproteases released by macrophages and mast cells. Stability of plaques is thus defined by thickness of the fibrous cap. Severe thrombosis may occur upon fibrous cap rupture, leading to acute coronary artery disease (myocardial infarction) and stroke [3, 26].

Several groups provide direct evidence that smooth muscle myosin heavy chain (SM-MHC)+ SMCs are a major contributor to neointimal thickening and atherosclerotic lesions, using transgenic mice with tamoxifen-regulated CreER under the control of a SM-MHC promoter (SM-MHC-CreER) [22, 30-33]. Interestingly, some studies suggest that SMCs in human atherosclerotic lesions are monoclonal [34, 35], implying heterogeneity of the SMC population. By using multi-colored lineage tracing in ApoE-/-/SM-MHC-CreER/Rosa26-Confetti transgenic mice, a recent study demonstrates that only a small number of SMCs proliferate and contribute to atherosclerotic plaques [36]. This is consistent with our single-cell analysis of SMCs showing that only a small subpopulation of SMCs is capable of proliferation and differentiation (unpublished data). However it is worth noting that, in addition to medial SMCs, other non-SMCs such as stem cells and ECs also contribute to the SMCs of neointima and atherosclerotic lesions [22, 33, 37, 38], while lesional macrophage-like cells can also be derived from SMCs [39], suggesting alternative mechanisms may also account for vascular disease development.

Endothelial to mesenchymal transition (EndoMT) is one possible mechanism. Some studies utilized Tie2-Cre mice for lineage tracing ECs and found that ECs contribute to pulmonary artery neointimal formation by differentiating into cells positive for smooth muscle -actin (-SMA) [40, 41]. However, other researchers found a very low frequency, in contrast, of EndoMT in the neointima [38]. Similarly, using Tie2-Cre mice to trace ECs in carotid artery neointimal formation, we found that although ECs contributed to neointimal formation, they still maintained endothelial identities and expressed CD31 but no or low -SMA expression [37]. This discrepancy requires further investigation with different animal models and tissue locations, and still leaves open the possibility of additional mechanisms for neointimal pathogenesis.

In addition to vascular SMCs and ECs, vascular stem and progenitor cells have been isolated from the circulation and from different layers of the artery wall, and have been implicated in vascular disease development. Key examples found in or around the vasculature are summarized in Table 1. The list is organized based on differentiation potential and tissue(s) of origin, and is discussed in detail below.

Vascular stem cells and progenitors

Bone marrow cells were reported to differentiate into SMCs in neointima and atherosclerotic lesions in the early 2000s [42-45]. These findings, however, remain controversial, as later studies in vascular transplant and injury models countered by arguing that bone marrow-derived cells did not in fact differentiate into neointimal SMCs, although they did participate in the inflammatory response [46-48]. A mouse wire injury model, for instance, found that some bone marrow cells were recruited to the neointima and expressed -SMA, but never became positive for mature SMC marker SM-MHC. Rather, these bone marrow cells expressed markers of monocytes and macrophages [48].

Other bone marrow-derived cells - specifically, certain EPCs - have also been identified as important for endothelial regeneration. It should be noted that the term endothelial progenitor cell has been applied to many different cell types, and defining what precisely it means to be an EPC is a source of controversy. Classification traditionally is divided into two methods: antigen classification, and culture-based classification. Both have been used to identify vascular-relevant EPCs.

Using the first method, cell-surface antigens are examined typically with flow cytometry to quantify relevant populations. Putative EPCs were first isolated by Asahara et al. (1997) from human peripheral blood by flow cytometry using surface markers CD34 and vascular endothelial growth factor receptor 2 (VEGFR-2, also known as kinase insert domain receptor, KDR, or fetal liver kinase 1, Flk1), both of which are characteristically expressed by ECs [49]. These circulating cells could contribute to neoangiogenesis postnatally by homing to angiogenic sites and acquiring characteristics of endothelium. Thereafter, other groups reported that EPCs contribute to endothelial regeneration in rodent models after various arterial injuries including vein graft atherosclerosis and mechanical injury [50-52], as well as in human diabetic wound healing [53].

Studies further showed that EPCs are in fact a heterogeneous population comprised of different subpopulations with different cell surface markers. In addition to CD34 and VEGFR-2, in an attempt to distinguish between immature and mature endothelial cells, investigators also commonly use markers like CD133 (also known as AC133), which is lost during endothelial maturation [54]. For example, Peichev et al. (2000) identified a unique subpopulation of EPCs (CD34+/VEGFR-2+/AC133+) in human fetal liver and peripheral blood [55]; another subpopulation of Flk1+/AC133+/CD34-/VE-cadherin- cells were also identified as EPCs in human bone marrow [56]. Despite the advantages of having specific markers for lineage tracing and drawing ties between disparate populations, one can see here too how antigen-based definitions may still be somewhat nonspecific in phenotype. The more antigen markers utilized, the more specific the definition, but also the fewer the cells identified - particularly considering the inherently probabilistic nature of antigen carriage for given cell types.

In the second method of classification, cells are isolated based on in vitro culture. Given the difficulties of finding specific surface markers for EPCs, some research groups isolated EPCs by single-cell colony-formation assay (SCCFA) based on the high self-renewal and proliferation potential of stem cells. Some studies subdivided EPCs based on their time of appearance in culture into populations which, interestingly, have different differentiation potential: early EPCs cannot differentiate into ECs, but only differentiate into macrophages and contribute to angiogenesis through paracrine factors, and thus were named as myeloid angiogenic cells (MACs); and late EPCs can differentiate into ECs and contribute to de novo blood vessel formation, and were dubbed endothelial colony forming cells (ECFCs) [57-61].

In addition to circulation-derived EPCs, EPCs with similar properties have been derived based on colony-formation assay from the vascular endothelium of large human blood vessels, placenta, and adipose tissue [62-64]. Mouse ECFCs have also been isolated from endothelial culture by surface markers lin-CD31+CD105+Sca1+c-Kit+, with c-Kit expression found to be critical for the clonal expansion of these ECFCs [65].

Beyond the nature of EPC classification, their functions, too, remain controversial. The concept of bone marrow-derived EPCs playing a fundamental role in the mechanism of vascular repair and regeneration has acquired many proponents as we described, though it remains hotly debated [66]. Pre-clinical animal studies showed that transplanted human EPCs formed microvessels and promoted vascular regeneration in vivo [49, 55, 56, 67, 68]. In mouse models of vascular graft transplantation, for instance, bone marrow cells contributed to the regenerated ECs of the grafts [50, 69, 70]. Nevertheless, another study countered that bone marrow-derived EPCs do not contribute to vascular endothelium in mouse models of bone marrow transplantation, tumor formation, and a parabiotic system [71].

A role for bone marrow-derived EPCs in atherogenesis similarly has been inferred, but accumulation of solid evidence in this role is mixed and still work in progress [52]. In an ApoE-/- mouse model, bone marrow-derived Sca-1+/CD34+/Flk-1+/CD133+ EPCs were found in the lesion-prone area of endothelium, possibly for repairing the injured endothelium [72]. However, other studies have said that, although there may exist a population of bone marrow-derived EPCs, ECs derived from the vascular bed are instead responsible for the EC replacement and regeneration seen in transplant arteriosclerosis [73].

In the clinical context, the role of EPCs remains unclear. Large-scale clinical studies suggested that high levels of EPCs were associated with reduced risk of cardiovascular diseases [74, 75] and improved outcomes after acute ischemic stroke [76-78] (versus poorer stroke outcomes if blood EPCs failed to increase [79]), and that vascular trauma, acute coronary diseases, and stroke induced elevated level of EPCs [76, 80, 81], presumably for purposes of vascular repair and maintenance. However, some also found no clear correlation between EPC level and endothelial function [82].

To date, much ambiguity and controversy remains in regards to the existence of true EPCs that can differentiate into ECs, their marker expression, location, and contribution to endothelial regeneration. It is possible that EPCs are a rare but dynamic population that respond to specific stimuli such as severe endothelial injury of large arteries or vascular transplantation [50, 69, 70], but not to tumor growth, which involves microvessels [71].

Stem and progenitor cells resident to vasculature have been identified across the different vessel wall layers. Similar to the bone marrow-derived progenitor cells, isolation has relied on antigen selection or culture-based characterization. Although those derived from the adventitia are better characterized and supported - evidence which will be elaborated momentarily - a few groups of stem cells have also been characterized in the media.

A population of calcifying vascular cells (CVCs) was first isolated from human atherosclerotic lesions in the arterial medial layer by Bostrm et al. (1993) and Tintut et al. (2003) and found to differentiate into SMC, osteogenic, and chondrogenic lineages [83, 84]. CVCs were harvested by tissue explant culture and were identified as expressing CD29 and CD44, two non-specific mesenchymal cell markers (adhesion receptors). However, no specific transcriptional markers were identified.

Later, in 2006, Sainz et al. isolated a small population of Sca-1+, c-kit (-/low), Lin-, CD34-/low cells from the media layer (around 60.8% prevalence in tunica media) of healthy murine thoracic and abdominal aortas [85]. They used a Hoechst DNA binding dye method to identify non-tissue-specific stem/progenitor cells based on their ability to expel the dye via the transmembrane transporter ATP-binding cassette transporter subfamily G member 2 (ABCG2). These cells gave rise to ECs (as determined by VE-cadherin, CD31, and von Willebrand factor expression) and SMCs (determined by -SMA, calponin, and SM-MHC expression) when cultured with vascular endothelial growth factor (VEGF) and transforming growth factor 1 (TGF-1)/platelet-derived growth factor BB (PDGF-BB) respectively, similar to Flk-1+ mesoangioblasts found in the embryonic dorsal aorta, and also produced (VE-cadherin+ and -SMA+) vascular-like branching structures of cells [85, 86].

Another population of vascular progenitors were isolated by Zaniboni, et al. from the media by internal digestion of porcine aortas with collagenase [87]. These cells were described as similar to both MSCs and pericytes. Like MSCs, they had elongated, spindle-shaped, fibroblast-like morphology, and met minimum MSC criteria [88] for CD90 and CD105 positivity while lacking expression of CD34 and CD45. They also expressed additional MSC markers CD44 and CD56 and displayed classic MSC differentiation potential into adipocytes, chondrocytes, and osteocytes. At the same time, in behavior considered distinctive of pericytes, in coculture with human umbilical vein endothelial cells they were able to form network-like structures [87].

MSCs themselves have also been implicated in atherosclerosis [89]. MSCs expressing Oct-4, Stro-1, Sca-1, and Notch-1, for instance, were identified in the wall of a range of vessel segments such as the aortic arch, and thoracic and femoral arteries. These multipotent cells exhibited adipogenic, chondrogenic, and leiomyogenic potential [14, 15].

Our group, too, has identified a population of multipotent vascular stem cells (MVSCs) in the arterial medial and adventitial layers that could significantly contribute to the population of traditionally defined proliferative and synthetic SMCs in SMC culture and in neointima [25, 37]. Upon vascular injury (e.g., denudation injury), Sox10+ MVSCs are activated, become proliferative, and migrated from both medial and adventitial layers to contribute to neointima formation [25, 37]. In addition, some Sox10- cells became Sox10+, suggesting Sox10 may be a marker of activated cells (Fig. 1). In wound healing and scar formation, MVSC-like Sox10+ cells (which are also found in soft tissues around blood vessels and throughout the body) can differentiate into both myofibroblasts and SMCs [24]. Following the implantation of polymer vascular grafts for instance, these cells, rather than SMCs, are recruited to the outer surface of the grafts and gradually differentiate into SMCs [70], recapitulating some aspect of vascular development.

Of special note is that vessel-derived stem/progenitor cells as well as MSCs isolated from ApoE-/- mice respond to the inflammatory environment and undergo calcification in the form of significantly greater osteogenesis and chondrogenesis [90]. MVSCs can also differentiate mesenchymally into osteogenic, chondrogenic, and adipogenic cells in vitro [25] and in vivo (unpublished observation), suggesting a possible role for them in vascular fat accumulation and calcification. As CVCs, in contrast, can differentiate into osteogenic and chondrogenic cells but not adipogenic cells in vitro, it is possible that CVCs are derived from MVSCs that have partially differentiated. Because almost all VSCs share some characteristics of MSCs, it is also possible that MSCs are derived from one or multiple subpopulations of VSCs.

The adventitia is the outermost layer of a blood vessel and is composed of a collagen-rich extracellular matrix embedded with a mixture of cells. The complexity of cellular composition reflects the pivotal role of the adventitia in vascular remodeling. Indeed, of the three blood vessel layers, evidence for vascular stem/progenitor cell enrichment in the adventitia, specifically along its border with the media, is the most abundant and robust. Its significance makes physiological and anatomical sense. Proximity to the vasa vasorum, which connect to the peripheral circulation, enable vessel wall communication with otherwise removed stem cell niches including the aforementioned bone marrow [14, 15], and the pivotal role of vasa vasorum density, structural integrity, and expansion in atheroma development and complications is well documented [91].

In human arteries, in addition to the Sox10+ MVSCs we described in the previous section [25], a population of vascular wall-resident multipotent stem cells (VW-MPSCs) were isolated from the adventitia by Klein, et al. [92]. They expressed certain MSC surface markers (including Stro1, CD105, CD73, CD44, CD90 and CD29) and positivity for stem cell-associated transcription factors Oct4 and Sox2, and demonstrated lack of contaminating mature EC or EPCs and hematopoietic stem cells (HPCs) by negativity for CD31, CD34, CD45, CD68, CD11b, and CD19. These VW-MPSCs also demonstrated adipocyte, chondrocyte, and osteocyte differentiation in culture conditions. In vivo transplantation with human umbilical vein endothelial cells (HUVECs) into immunodeficient mice via Matrigel resulted in new vessel formation covered with VW-MPSC-derived pericyte- and smooth muscle-like cells, an effect enhanced by VEGF, FGF-2, and TGF1 stimulation [92]. These authors more recently identified that HOX genes may epigenetically regulate VW-MPSC differentiation into SMCs, potentially contributing to neointimal formation and tumor vascularization [93].

Sox10+ MVSCs in aorta ring ex vivo culture. Aorta rings of Sox10-Cre/Rosa-RFP mice were cultured ex vivo, and imaged by two-photon microscopy. Arrows indicate the emerging Sox10+ cells. Scale bar, 100 m.

Progenitors have also been derived from human veins, dubbed saphenous vein-derived progenitor cells (SVPs) for their specific location of origin. Assessing endothelial markers CD34, CD31, and von Willebrand factor (vWF) in these cells showed CD34+, CD31-, vWF-. These highly proliferative cells were found to be localized around adventitial vasa vasorum, and expressed pericyte/mesenchymal antigens as well as stem cell marker Sox2. In an ischemic hindlimb model in immunodeficient mice, intramuscular injection of SVPs improved neovascularization and blood flow recovery, and the cells established N-cadherin-mediated physical contact with the capillary endothelium by day 14 post-transplantation [94]. These therapeutic benefits of vein-derived adventitial stem cells have been replicated in other studies using mouse models of ischemia, with one beginning to look towards manufacturing these cells for human angina therapy [95-97]. Spindle shaped MSCs (CD13+, CD29+, CD44+, CD54+) have also been isolated from human varicose saphenous vein intima. Displaying a similar gene expression profile to bone marrow-derived MSCs, these could differentiate into osteoblasts, chondrocytes, and adipocytes [98].

In rodents, another important progenitor population, Sca-1+ stem cells, has been described in the adventitia along the medial border. This population also expresses other stem cell markers including c-kit, CD34, and Flk1 and was first identified by Hu et al. in the aortic roots of ApoE-/- mice [99]. They had demonstrated capacity to differentiate into SMCs in vivo, with LacZ-labeled Sca-1+ cells found in vein graft atherosclerotic lesions after transplantation in the adventitial space, implying the migration of Sca-1+ cells from the adventitia to the neointima [99]. Years later, the same group illustrated the multipotency of the cells by demonstrating in a decellularized vessel graft mouse model the cells' in vitro differentiation into SMCs (with PDGF) and ECs (with VEGF) [100]. Implications to reduce neointimal thickness by applying VEGF to the adventitial layer, promoting stem cell differentiation into ECs rather than SMCs, were made clear as well [100].

Other studies have since further implicated Sca-1+ stem cells in atherosclerosis and adventitial remodeling [28, 101, 102]. The later stages of atherosclerosis, for instance, mainly involve resident proliferating macrophages rather than those differentiated from bone marrow monocytes [27]. These local resident proliferating macrophages were found to be derived from a subpopulation of Sca-1+ stem cells, resident macrophage progenitors, that also expressed CD45 [28]. In aging, Sca1+ adventitial cells enriched for monocyte/macrophage markers and CD45 were shown to be depleted by 3-fold in mature versus young mice, raising the question of whether age-related vascular degeneration may be due to such effects on progenitors in the vascular wall [103].

Recently, Majesky et al. used two in vivo SMC lineage-tracing approaches and showed that some Sca1+ vascular adventitial progenitors (CD34+) are derived from differentiated SMCs, potentially thereby contributing to maintenance of the resident vascular progenitor cell population [33]. In an earlier study, Shankman et al. had suggested that SMCs could de-differentiate into progenitor-like cells capable of differentiating into MSC- and macrophage-like cells [32]. Interestingly, in both cases, KLF4 was identified as a key modulator of cell phenotypic changes. This intriguing relationship between SMCs and VSCs (or VSC-like cells) warrants further investigation.

Overall, although a human ortholog of Sca-1 has yet to be identified, study of pathways and mechanisms surrounding these cells have been of great value, and results suggest that locally manipulating microenvironment is a possible angle for treating atherosclerotic disease [104].

Pericytes play important roles in regulating microvascular stability and dynamics [105]. They were first described over a century ago, and defined as another type of vascular mural cell that surround microvessels, forming an incomplete envelope around ECs and found within the microvascular basement membrane [106]. Pericyte-like cells have also been reported in the inner intima (mostly subendothelium) in human arteries of all sizes [107]. Several markers have been used to identify pericytes, including NG2 [108], CD146 [109, 110], PDGFR, and -SMA [111].

In recent years, accumulating studies have discovered important roles for pericytes in development and diseases. Pericyte-like cells were identified in atherosclerotic lesions and thought to be one of the sources of atherosclerotic cells [83, 112], which may come from the vasa vasorum, a specialized microvessel inside large vessel walls [91]. Cells histologically characterized as true pericytes were also found to comprise a second net-like subendothelial tissue layer, which combines with the endothelium to form the intimal barrier in healthy human and bovine microvasculature. In contrast with the endothelium, these pericytes were highly prothrombotic when exposed to serum and display overshooting growth behavior in endothelium-denuded vascular areas, making them potential key players in atherosclerosis, thrombosis, and thrombotic side-effects of venous coronary bypass grafting [92].

In the porcine aortic media, novel vascular progenitor cells with pericyte- and MSC-like properties were also found capable of differentiating into osteocytes, chondrocytes, and adipocytes [87]. Pericytes around microvessels in skeletal muscle are another type of myogenic progenitor cell distinct from satellite cells [113, 114].

Pericytes in multiple organs have been reported to have properties of MSCs [111]. Moreover, pericytes can differentiate into myofibroblasts and are another important cellular source of organ fibrosis [115-117]. It is likely that pericytes include subpopulations of stem cells or progenitors. In our recent work, we found Sox10+ stem cells in the stroma of subcutaneous connective tissues which had the same properties as MVSCs in large vessels [24, 25]. These Sox10+ stem cells are precursors of pericytes and fibroblasts, as described in the previous section, and contribute to both fibrosis and microvessel formation during tissue repair and regeneration [24]. Gli1+ stem cells had similarly wide distribution as the Sox10+ stem cells and were found in the perivascular space and also adventitial layer of large arteries. They could differentiate into myofibroblasts contributing to organ fibrosis, and neointimal SMCs contributing to atherosclerotic lesions and arterial calcification [115, 118].

Therapeutically, two separate studies examined the benefit of pericyte transplantation in mouse models of myocardial infarction. They found that pericytes from both saphenous vein [119] and skeletal muscle [120] attenuated left ventricular dilation, improved cardiac contractility and ejection fraction, reduced myocardial fibrosis and scarring, and improved neovascularization and angiogenesis. Saphenous vein-derived pericytes also reduced cardiomyocyte apoptosis, attenuated vascular permeability, and improved myocardial blood flow [119], while the skeletal muscle-derived pericytes significantly diminished host inflammatory cell infiltration at the infarct site as well [120]. Both studies attributed benefits to cellular interactions and paracrine effects [119, 120].

Dellavalle, et al. demonstrated the skeletal muscle-regenerating properties of both normal human pericytes and dystrophin-reprogrammed human Duchenne patient pericytes when transplanted into mouse models of muscular dystrophy [113]. In small-diameter tissue-engineered vascular grafts (TEVGs), exogenously seeded pericytes improved maintenance of patency after TEVG implantation into the aorta of rats (100% at 8 weeks, versus 38% unseeded controls) [121]. An endogenous approach has met with similar success, where promoting the differentiation of Sca-1+ stem/progenitor cells into the endothelial lineage has reduced neointimal thickness by up to 80% [100]. Altogether, these findings highlight stem cells as important players and potentially significant therapeutic targets in vascular remodeling, and underscore the multifactorial complexity of vascular disease pathogenesis.

The microenvironment plays important roles in regulating vascular cell function and the stem cell renewal and fate decision, and includes both biochemical factors (e.g., growth factors, cytokines) and biophysical factors (e.g., extracellular matrix, stiffness, flow shear stress and mechanical stretch).

Inflammatory cytokines, in addition to adhesion molecules, govern recruitment of relevant immune cells to the arterial wall in atherosclerosis. Beyond these traditional roles in regulating cell function and homeostasis, though, and notably for our discussion here, in recent years cytokines have also been found to regulate stem cell recruitment and activation during vascular remodeling [122, 123]. Cytokines like stromal cell-derived factor 1 (SDF-1), for example, has been shown to recruit bone marrow EPCs to form microvessels in hindlimb ischemic angiogenesis [124, 125] and to promote adventitial Sca1+ stem cells to migrate through vein graft walls and differentiate into neointimal SMCs [126]. In advanced atherosclerotic plaques, it is also believed that SDF-1 recruits SMC progenitor cells from bone marrow to the fibrotic cap [127]. Another cytokine, tumor necrosis factor- (TNF-), induces adventitial Sca1+ stem cells to differentiate into ECs, while suppressing SMC gene activation [128]. Growth factors like VEGF and PDGF-BB/TGF-1 can stimulate adventitial and medial stem cells to differentiate into ECs and SMCs, respectively [85, 100].

Among the biophysical factors found important for vascular cells, local disturbed flow is a major factor that induces EC dysfunction in the branches and curvatures of the arterial tree [129]. Disturbed flow shear stress can induce a series of intracellular signaling pathways in ECs and activate proliferative and inflammatory gene expression, initiating neointimal formation and atherosclerosis even in newborns [129, 130].

The extracellular matrix (ECM) is also important in regulating vascular dynamics. Subendothelial matrix proteoglycans are thought to contribute to lipid retention in the early stages of atherosclerosis [29]. ECM stiffness and embedded growth factors are critical in regulating cell functions. Our previous work has showed that stiff surfaces, together with TGF, promoted MSC differentiation into SMCs in vitro [131]. Collagen IV, too, has been reported to be critical in promoting embryonic stem cell differentiation into Sca-1+ stem cells, and to act together with aforementioned cytokines and growth factors to promote differentiation [132, 133]. Mechanical stretch and microtopography can regulate SMC differentiation and function as well [134, 135].

To date, the niche of VSCs has not been well defined. Although we know connection to the peripheral circulation via the vasa vasorum enables vessel niche communication with other stem cell niches like the bone marrow, how VSCs are activated by such communication, inflammatory signals, and local microenvironmental changes remains to be investigated.

As our understanding of the importance and mechanism of stem and progenitor cell involvement in human vascular remodeling has evolved, two therapeutic angles have arisen: 1) influencing endogenous VSC behavior to prevent initiation and progression of disease, and 2) exogenous stem cell delivery to promote disease reversal and healing of tissue injury. The application of more immature stem cells with greater differentiation potential such as embryonic and induced pluripotent stem cells to cardiovascular disease (including myocardial infarction, vascular regeneration in coronary and peripheral artery disease) has been reviewed elsewhere [136-138]. Adult stem cells such as those we have discussed pose multiple advantages in their accessibility (e.g., the stromal vascular fraction of adipose aspirates contain human blood vessel fragments; coronary bypass surgery makes pieces of aorta or segments of internal thoracic artery, radial artery, and saphenous vein readily available), decreased risk of uncontrolled differentiation (e.g., teratomas), and immune-privileged nature (in the case of MSCs and pericytes) that enables allogeneic use as well [139].

That said, clinical trials and therapies utilizing such VSCs are still sadly lacking. No human clinical trials to date have examined application of pericytes or resident VSCs for vascular disease. MSCs and EPCs, perhaps because of the broadness of their definition, have accumulated a more substantial body of clinically relevant evidence. The majority of clinical trials for atherosclerosis and diseases for which it is the primary cause - such as angina, myocardial ischemia, and ischemic stroke, all diseases primarily of the macrovasculature - utilize MSCs and EPCs instead. These trials focus, too, more on stem cell/progenitors for disease treatment rather than disease prevention. Limited evidence for underlying mechanisms suggests stem cell angiogenic roles play a large part in measurable therapeutic benefit; evidence for a therapeutic role in neointimal regression, in contrast, is lacking [140, 141]. It should be noted that MSCs and EPCs have also been utilized therapeutically to promote angiogenesis in diseases of the microvasculature such as diabetic ischemia-induced chronic wounds [53, 142] and peripheral occlusive disease [140, 141, 143], but we focus on macrovascular plaque-related diseases here instead.

In 2013, a phase III trial for refractory angina locally transplanted (G-CSF-stimulated) autologous blood cells positive for the EPC marker CD34 via percutaneous intramyocardial injection. The trial showed preliminary results consistent with those of earlier phase studies [144], although with higher placebo effects than previously detected, and animal studies lead us to believe benefit is derived from cell contribution to myocardial neoangiogenesis, and possible differentiation into cardiomyocytes and ECs [145-147]. If completed, it would have provided the requisite information for regulatory approval of the first cellular therapeutic for a cardiovascular indication [148]. Results may merit an expanded examination of therapeutic EPC transplantation, perhaps in combination with other vasculogenic mediators and scaffolds to improve EPC survival and function.

Other clinical trials have also attempted direct exogenous transplantation of adult bone-marrow-derived stem cells, but for myocardial ischemia (MI) and ischemic stroke patients. Several have found such intracoronary transplantation improves regional systolic function recovery and infarct size reduction in MI patients [149, 150], and a number of recent meta-analyses have confirmed improvements in not only left ventricular contractility after therapy [151-153] but also decreased mortality, acute MI recurrence, and readmission for heart failure [150, 152]. Still, effects of transplantation on infarct volume and remodeling are contradictory and inconclusive [150, 152-156]. BM cells, rather than incorporating, may prompt ischemic tissues to secrete paracrine signals (e.g., angiogenic factors); these signals in conjunction with transdifferentiation potential may underlie functional recovery [149, 156-158].

In stroke, promising results in experimental models [159] prompted clinical trials of intra-arterial or intravenous transplantation of autologous bone marrow mononuclear cells (including CD34+ progenitors). A phase I/II clinical trial in middle cerebral artery stroke patients transplanted 5-9 days after stroke found that changes in serum levels of GM-CSF, PDGF-BB, and MMP-2 associated with better functional outcomes were induced; however, varied impact on functional outcomes themselves was not measured [160]. Another phase II randomized control trial (RCT) found that cell therapy was safe, but had no beneficial effect on stroke outcome [161]. The first trial to explore dose-dependent efficacy of intra-arterial transplantation of bone marrow mononuclear cells in moderate-to-severe acute ischemic stroke patients is currently ongoing (IBIS trial, prospective phase II RCT) [162]. Despite promising animal studies, which suggest BM cell-based treatments can benefit endogenous neurorestoration by promoting contralesional pyramidal axon sprouting and preservation, increasing neurotrophic factor secretion, and possible synergistic effects between microvascular angiogenesis and neurogenesis, demonstrable long-term clinical therapeutic benefit of cell therapies for stroke is still being determined [141].

Secondary stimulation of endogenous progenitors has also been attempted. Granulocyte colony-stimulating factor (G-CSF) is one agent that can stimulate the bone marrow to release EPCs, in addition to release of granulocytes and hematopoietic stem cells [18]. Multiple clinical trials, encouraged by prior positive results in various animals [163], sought to assess its utility in upregulating endogenous EPC release in patients with ischemic heart disease. Results, however, have been mixed: although one study found an improvement of severe ischemia in severe MI patients [164] and a meta-analysis of seven RCTs including 364 acute MI patients found improvement of left ventricular ejection fraction (LVEF) [165], others (including an RCT and a meta-analysis of ten clinical trials including 445 patients) concluded no impact on infarct size, LV function, or coronary restenosis [166-168]. Interestingly, physical exercise, strongly established by many large-scale epidemiological studies as being robustly associated with decreased cardiovascular mortality and potent primary and secondary CVD prevention [169-173], has been found to mobilize EPCs from the bone marrow and is thought to exert its benefits mechanistically via the maintenance of an intact endothelial layer [174].

Using G-CSF in stroke patients has been less studied. A phase IIb RCT concluded in 2012 that G-CSF successfully and safely increased CD34+ cells by 9.5-fold relative to placebo, with a trend of reducing ischemic lesion volume [175]. Further study, though, is necessary.

The majority of completed clinical trials (as reported on involving MSC transplantation for vascular disease focuses on treatment of myocardial ischemia, finding that treatment is tolerable and safe with improvements seen in metrics such as LVEF [176-178] and global EF [179], LV end-systolic [176, 178, 179] and diastolic volumes [178], and functional walk and cardiac tests [176] and global symptom scores [177]. A phase I/II clinical trial for patients with severe stable coronary artery disease and refractory angina transplanted autologous bone marrow-derived MSCs into their viable myocardium, and found similarly promising results. The trial showed sustained safety three years post-transplantation, significant clinical improvements in symptomatic and functional metrics, as well as reduced hospital admissions for CV disease [180].

Delivery route of MSCs, furthermore, was found by meta-analysis of six clinical trials involving 334 MI patients to shape efficacy of treatment. Greatest improvement in LVEF was seen if transendocardial injection and intravenous infusion, rather than intracoronary infusion, were used to deliver MSCs [181].

In 2015 an observational clinical study for coronary atherosclerosis examined outcomes of plasmonic resonance therapy using silica-gold nanoparticles that had been incubated with allogeneic mesenchymal CD73+ CD105+ stem-progenitor cells. Results showed highly safe, significant plaque regression relative to stenting controls (reduction of total atheroma volume up to 60mm3, or 37.8% of plaque burden, relative to current maximal success of conventional drugs of 6-14mm3) and late lumen enlargement without arterial remodeling [182].

Overall, although animal and preliminary clinical studies have revealed much promise, there remains much to be done in understanding the mechanism of VSC therapeutic benefits in order to appropriately target them for effective therapy.

Strong evidence has accumulated to demonstrate the involvement of various stem and progenitor cells in vascular regeneration and disease, including atherosclerotic neointimal formation. These stem cells display a nonuniform distribution both across the vessel wall as well as across different vascular territories, a distribution perhaps contributing to explanations of why different vascular segments may have variable susceptibility to vascular disease despite similar hemodynamics and environment [183]. Different populations of vascular cells, including SMCs, ECs, inflammatory cells (including macrophage and dendritic cell progenitors), and stem cells, may interact with and be subject to regulation by each other and by the local microenvironment during neointimal thickening. Recent studies show exosomes, nanometer lipid bilayer signaling particles secreted by cells with important roles in many physiological and pathological processes [184-187], have a hand in this regulation by mediating vascular calcification as found in atherosclerosis [188], atheroprotective communication between ECs and SMCs [189], and anti-inflammatory effects of MSCs [187]. Exosomes could thus be therapeutic targets of interest as well [190].

Identifying proper cellular targets (e.g., using screening methods such as RNA-sequencing and epigenetic profiling to characterize VSCs, along with other techniques such as laser microdissection and immunofluorescence to identify key VSC markers) and understanding the underlying regulatory mechanisms will facilitate the development of successful therapies for vascular disease. Given their differentiation potential into SMCs and ECs, these stem cells could also be good cellular sources for fabricating vascular grafts or otherwise promoting vascular regeneration.

Far as the field has come, several critical questions remain to be addressed. First, given the diversity of stem cells discovered by different research groups, confirming whether these cells are distinct populations and determining their relationship with proliferative/synthetic SMCs will be necessary. It will be helpful to obtain consensus on specific panels of markers to define different stem cell populations. Examining to what degree the difference in their marker expression profiles may be a result of different culture conditions in vitro, too, will be of importance.

Second, the niche of VSCs needs to be further characterized to define the macro and microenvironmental factors that maintain VSCs in a quiescent versus activated state, and how such factors promote healthy survival.

Third, stem cell fate needs to be determined in long-term in vivo experiments. However, stem cells may become activated and differentiated quickly at the early phase of neointimal thickening in vivo, which makes capture of the phenotype by immunohistology difficult. Genetic lineage tracing techniques would address this problem, if obstacles of selection of good markers and of availability of transgenic animal models can be surmounted. Such techniques could also address the relative contributions of different cell types, and multi-color reporter mice could be used to investigate heterogeneity within the same population.

Fourth, the behavior of VSCs under various pathological conditions should be elucidated. Stem cell activation and differentiation are regulated by various microenvironmental factors. Changes in biochemical and biophysical factors in a disease state and the effects of these factors, individually or in combination, may have profound effects on stem cell functions. Conversely, taking creative inspiration from current successful therapies for atherosclerosis and brainstorming approaches for cellular therapies to target their same mechanisms could yield therapies with fewer side-effects and more targeted results. For instance, any conversation on atherosclerosis would be incomplete without mention of statins, the current mainstay of treatment [191, 192]. Research has shown that, independent of cholesterol reduction, statins may exert their beneficial effects via EPC mobilization. This may be a promising direction for future therapies [52]. Similarly, piggybacking on the putative plaque-stabilizing mechanism of statins by use of the chemokine SDF-1 to recruit bone marrow-derived SM progenitor cells to the fibrous cap has yielded increases in cap thickness without altering artery diameter in mice [127]. This finding may prove useful for unstable atherosclerosis if further studies in large animals and humans continue to yield promising results.

Fifth, especially with sourcing of vascular wall MSCs becoming increasingly feasible [17], there is great promise in cell therapies if details on differences in identity and manufacturing based on specific vascular and cell source can be fleshed out. Despite their mechanistic significance, EPCs and other progenitors without immune-privilege, in contrast with MSCs and pericytes which do, may pose a challenge in clinical application if the goal is exogenous transplantation [139]. Endogenous recruitment and processes may be more feasible for these other progenitors. Although stem cell transplantation has been proven to be safe and benefit tissue regeneration, the mechanisms of benefit, too, are unclear at present. Overall, clinical trials certainly remain of value - as phenomena in humans are ultimately distinct from those in animals - but it is clear that such applications are yet in the early stages. The mixed results clearly indicate that an improved understanding of underlying mechanisms is necessary not only for effective design of therapeutic translation and study, but also for interpretation of results. Ongoing risk and safety assessment will continue to be necessary in parallel.

Finally, besides delivery of exogenous stem cells for therapies, the potential of endogenous recruitment or of using stem cells as novel targets of therapies needs to be further investigated in vitro and in vivo. In vitro isolated VSCs can be used for drug screening. A well-defined culture model, such as co-culture with SMCs, mechanical loading, and 3D culture that mimics the in vivo microenvironment, would be valuable. Blood vessel tissue ex vivo culture is better than cell culture as it mimics the niche of cell-cell interactions and native extracellular matrix, which may be useful when combined with tissue clarity techniques and transgenic animal models. All these new tools and technologies will continue to facilitate further discoveries in vascular stem cell biology, enabling development of diagnostic and therapeutic strategies with unprecedented efficacy and capability to combat vascular disease and promote regeneration.

CVD: cardiovascular disease; EC: endothelial cell; EPC: endothelial progenitor cell; SMC: smooth muscle cell; VSC: vascular stem cell; MSC: mesenchymal stem cell; MVSC: multipotent vascular stem cell; CVC: calcifying vascular cells; -SMA: smooth muscle -actin; SM-MHC: smooth muscle myosin heavy chain.

This work was supported by grants from the National Institutes of Health (HL117213 and HL121450 to S.L.) and the Medical Scientist Training Program at UCLA (NIH T32 GM008042 to L.L.).

The authors have declared that no competing interest exists.

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Adult Stem Cells in Vascular Remodeling - Theranostics

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Regenerative Medicine – AABB

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Regenerative medicine may be defined as the process of replacing or "regenerating" human cells, tissues or organs to restore or establish normal function. This field holds the promise of regenerating damaged tissues and organs in the body by replacing damaged tissue or by stimulating the body's own repair mechanisms to heal tissues or organs. Regenerative medicine also may enable scientists to grow tissues and organs in the laboratory and safely implant them when the body is unable to heal itself. Current estimates indicate that approximately one in three Americans could potentially benefit from regenerative medicine.

Regenerative Medicine refers to a group of biomedical approaches to clinical therapies that may involve the use of stem cells. Examples include cell therapies (the injection of stem cells or progenitor cells); immunomodulation therapy (regeneration by biologically active molecules administered alone or as secretions by infused cells); and tissue engineering (transplantation of laboratory grown organs and tissues). While covering a broad range of applications, in practice the latter term is closely associated with applications that repair or replace portions of or whole tissues (i.e., bone, cartilage, blood vessels, bladder, skin). Often, the tissues involved require certain mechanical and structural properties for proper functioning. The term has also been applied to efforts to perform specific biochemical functions using cells within an artificially-created support system (e.g., artificial pancreas or liver).

Cord blood stem cells are being explored in several applications including Type 1 diabetes to determine if the cells can slow the loss of insulin production in children; cardiovascular repair to observe whether cells selectively migrate to injured cardiac tissue, improve function and blood flow at the site of injury and improve overall heart function; and central nervous system applications to assess whether cells migrate to the area of brain injury alleviating mobility related symptoms, and repair damaged brain tissue (such as that experienced with cerebral palsy). Cord blood stem cells likely will be an important resource as medicine advances toward harnessing the body's own cells for treatment. Because a person's own (autologous) stem cells can be infused back into that individual without being rejected by the body's immune system, autologous cord blood stem cells have become an increasingly important focus of regenerative medicine research.

Regenerative medicine has made its way into clinical practice with the use of materials that are able to assist in the healing process by releasing growth factors and cytokines back into the damaged tissue (e.g., (chronic) wound healing). As additional applications are researched, the fields of regenerative medicine and cellular therapies will continue to merge and expand, potentially treating many disease conditions and improving health for a variety of diseases and health conditions.

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Regenerative Medicine - AABB

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Stem Cell Therapy For Knees | What You Need To Know …

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The main conditions treated by stem cell injections include knee osteoarthritis, cartilage degeneration, and various acute conditions, such as a torn ACL, MCL, or meniscus. Stem cell therapy may speed healing times in the latter, while it can actually rebuild tissue in degenerative conditions such as the former.

Thats a major breakthrough. Since cartilage does not regenerate, humans only have as much as they are born with. Once years of physical activity have worn it away from joints, there is no replacing it. Or at least, there wasnt before stem cell therapy.

Now, this cutting-edge technology enables physicians to introduce stem cells to the body. Thesemaster cells are capable of turning into formerly finite cell types to help the body rebuild and restore itself.

Although it may sound like an intensive procedure, stem cell therapy is relatively straightforward and usually minimally invasive. These days, physicians have many rich sources of adult stem cells, which they can harvest right from the patients own body. This obviates the need for embryonic stem cells, and thereby the need for moral arguments of yore.

Mesenchymal stem cells (MSCs) are one of the main types used by physicians in treating knee joint problems. These cells live in bone marrow, butincreasing evidence shows they also exist in a range of other types of tissue.This means they can be found in places like fat and muscle. With a local anesthetic to control discomfort, doctors can draw a sample of tissue from the chosen site of the body. The patient usually doesnt feel pain even after the procedure. In some cases, the physician may choose to put the patient under mild anesthesia.

They then isolate the mesenchymal stem cells. Once they have great enough numbers, physicians use them to prepare stem cell injections. They insert a needle into the tissue of the knee and deliver the stem cells back into the area. This is where they will get to work rebuilding the damaged tissue. Although the mechanisms arent entirely clear, once inserted into a particular environment, mesenchymal stem cells exert positive therapeutics effectsinto the local tissue environment.

Mechanisms of action of mesenchymal stem cells appear to include reducing inflammation, reducing scarring (fibrosis), and positively impacting immune system function.

Thats not quite enough to ensure a successful procedure, however. Thats why stem cell clinics may also introduce growth factors to the area. These are hormones that tell the body to deliver blood, oxygen,and nutrients to the area, helping the stem cells thrive and the body repair itself.

Physicians extract these growth factors from blood in the form of platelet-rich plasma (PRP). They take a blood sample, put it in a centrifuge and isolate the plasma, a clear liquid free of red blood cells, but rich in hormones needed for tissue repair.

So, what can a patient reasonably expect when it comes to stem cell therapy, in terms of time and cost outlay?

The answers to both of these questions differ depending on the clinic doing the procedure and the patients level of knee degradation. Some clinics recommend a course of injections over time. Meanwhile, others prepare the injection and deliver it back to the patient in only a matter of hours. Either way, the treatment is minimally invasive, with fast healing times and a speedy return to normal (and even high-intensity) activity.

Some quotes for stem cell knee treatment are as low as $5,000. Others cost up to $20,000 or more. Again, this depends on how many treatments a patient needs, as well as how many joints theyre treating at the same time. Because its easier to batch prepare stem cells, a patient treating more than one knee (or another joint) can address multiple sites for far less. The procedure would only cost an addition of about $2,000 or so per joint.

No treatment proves effective every time. However, insofar as patients reporting good results for stem cell injections, the overall evidence does lean in a beneficial direction.Studies at the Mayo Clinic, for instance, indicate that while further research is needed, it is a good option for arthritis in the knee. Anecdotal reports are positive as well. Patients report it as an effective alternative to much more invasive solutions, such as arthroscopic or knee replacement surgery.

Other studies point to the need for caution. Stem cell therapy and regenerative medicine, in general, are only now exiting their infancies. There arent enough high-quality sources from which to draw at this point, so hard and fast conclusions remain elusive. Of the studies that do exist, some contain unacceptably high levels of bias.

Of course, any new treatment will face these kinds of challenges in the beginning. For those who need an answer to knee pain, and havent yet found one that works, its likely worth the risk that it wont prove as effective as they hoped. But what about other risks?

The good news about this form of stem cell therapy is that the patient uses their own cells. That means they completely skip over the dangers that accompany donor cells. The main one of which is graft-versus-host disease (in which the donor cells initiate an immune response against the patients body). Because the cells have all the same antibodies, neither the body nor the reintroduced cells will reject one another.

Also, the relatively low-stakes outpatient nature of the procedure (versus, say, a bone marrow transplant) means that the chances of something going wrong are much reduced.

However, there do exist some risks wherever needles come into play. It is possible to get an infection at the site of the blood draw as well as at the injection site, but these risks are quite low. Other risks include discoloration at theinjection site or soreness. While some people fear the possible growth of stem cells at the site of injection into a tumor, it is unlikely for this to happen, because physicians utilize adult stem cells for these procedures that have a low proliferative capacity.

These adult stem cells tend to be much safe than pluripotent stem cell types. Examples of pluripotent stem cells are embryonic stem cells (derived from embryos) and a type of lab-made stem cell known as induced pluripotent stem cell (iPS cell).

For those who think stem cell therapy could prove beneficial, its time to set up a consultation with your doctor. Multiple factors will influence whether or not its a good idea. These include age, health, andseverity of the condition and other available treatments. However, overall, this form of regenerative medicine is reasonably affordable, very low-risk, and typically effective.

Are you seeking a stem cell treatment for your knees or other joints?To support you,we have partnered withOkyanosa state-of-the-art facility providing patients with advanced stem cell treatments.

The group offers treatments for arange of chronic conditions, includingosteoarthritis and degenerative joint disease, which are leading causes of knee pain.

If you are seeking a stem cell treatment for knee pain or other chronic condition,contact Okyanos for a Free Medical Consultation.

What questions do you still have about stem cell therapy for knees? Ask them below and we will get you answers.

Stem Cell Therapy For Knees | What You Need To Know ...

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Adult stem cell – Wikipedia

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Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells (from Greek , meaning of the body), they can be found in juvenile as well as adult animals and humans, unlike embryonic stem cells.

Scientific interest in adult stem cells is centered on their ability to divide or self-renew indefinitely, and generate all the cell types of the organ from which they originate, potentially regenerating the entire organ from a few cells.[1] Unlike for embryonic stem cells, the use of human adult stem cells in research and therapy is not considered to be controversial, as they are derived from adult tissue samples rather than human embryos designated for scientific research. They have mainly been studied in humans and model organisms such as mice and rats.

A stem cell possesses two properties:

Hematopoietic stem cells are found in the bone marrow and umbilical cord blood and give rise to all the blood cell types.[3]

Mammary stem cells provide the source of cells for growth of the mammary gland during puberty and gestation and play an important role in carcinogenesis of the breast.[4] Mammary stem cells have been isolated from human and mouse tissue as well as from cell lines derived from the mammary gland. Single such cells can give rise to both the luminal and myoepithelial cell types of the gland, and have been shown to have the ability to regenerate the entire organ in mice.[4]

Intestinal stem cells divide continuously throughout life and use a complex genetic program to produce the cells lining the surface of the small and large intestines.[5] Intestinal stem cells reside near the base of the stem cell niche, called the crypts of Lieberkuhn. Intestinal stem cells are probably the source of most cancers of the small intestine and colon.[6]

Mesenchymal stem cells (MSCs) are of stromal origin and may differentiate into a variety of tissues. MSCs have been isolated from placenta, adipose tissue, lung, bone marrow and blood, Wharton's jelly from the umbilical cord,[7] and teeth (perivascular niche of dental pulp and periodontal ligament).[8] MSCs are attractive for clinical therapy due to their ability to differentiate, provide trophic support, and modulate innate immune response.[7] These cells have the ability to differentiate into various cell types such as osteoblasts, chondroblasts, adipocytes, neuroectodermal cells, and hepatocytes.[9] Bioactive mediators that favor local cell growth are also secreted by MSCs. Anti-inflammatory effects on the local microenvironment, which promote tissue healing, are also observed. The inflammatory response can be modulated by adipose-derived regenerative cells (ADRC) including mesenchymal stem cells and regulatory T-lymphocytes. The mesenchymal stem cells thus alter the outcome of the immune response by changing the cytokine secretion of dendritic and T-cell subsets. This results in a shift from a pro-inflammatory environment to an anti-inflammatory or tolerant cell environment.[10][11]

Endothelial stem cells are one of the three types of multipotent stem cells found in the bone marrow. They are a rare and controversial group with the ability to differentiate into endothelial cells, the cells that line blood vessels.

The existence of stem cells in the adult brain has been postulated following the discovery that the process of neurogenesis, the birth of new neurons, continues into adulthood in rats.[12] The presence of stem cells in the mature primate brain was first reported in 1967.[13] It has since been shown that new neurons are generated in adult mice, songbirds and primates, including humans. Normally, adult neurogenesis is restricted to two areas of the brain the subventricular zone, which lines the lateral ventricles, and the dentate gyrus of the hippocampal formation.[14] Although the generation of new neurons in the hippocampus is well established, the presence of true self-renewing stem cells there has been debated.[15] Under certain circumstances, such as following tissue damage in ischemia, neurogenesis can be induced in other brain regions, including the neocortex.

Neural stem cells are commonly cultured in vitro as so called neurospheres floating heterogeneous aggregates of cells, containing a large proportion of stem cells.[16] They can be propagated for extended periods of time and differentiated into both neuronal and glia cells, and therefore behave as stem cells. However, some recent studies suggest that this behaviour is induced by the culture conditions in progenitor cells, the progeny of stem cell division that normally undergo a strictly limited number of replication cycles in vivo.[17] Furthermore, neurosphere-derived cells do not behave as stem cells when transplanted back into the brain.[18]

Neural stem cells share many properties with haematopoietic stem cells (HSCs). Remarkably, when injected into the blood, neurosphere-derived cells differentiate into various cell types of the immune system.[19]

Olfactory adult stem cells have been successfully harvested from the human olfactory mucosa cells, which are found in the lining of the nose and are involved in the sense of smell.[20] If they are given the right chemical environment these cells have the same ability as embryonic stem cells to develop into many different cell types. Olfactory stem cells hold the potential for therapeutic applications and, in contrast to neural stem cells, can be harvested with ease without harm to the patient. This means they can be easily obtained from all individuals, including older patients who might be most in need of stem cell therapies.

Hair follicles contain two types of stem cells, one of which appears to represent a remnant of the stem cells of the embryonic neural crest. Similar cells have been found in the gastrointestinal tract, sciatic nerve, cardiac outflow tract and spinal and sympathetic ganglia. These cells can generate neurons, Schwann cells, myofibroblast, chondrocytes and melanocytes.[21][22]

Multipotent stem cells with a claimed equivalency to embryonic stem cells have been derived from spermatogonial progenitor cells found in the testicles of laboratory mice by scientists in Germany[23][24][25] and the United States,[26][27][28][29] and, a year later, researchers from Germany and the United Kingdom confirmed the same capability using cells from the testicles of humans.[30] The extracted stem cells are known as human adult germline stem cells (GSCs)[31]

Multipotent stem cells have also been derived from germ cells found in human testicles.[32]

To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter cells, both endowed with stem cell properties, whereas asymmetric division produces only one stem cell and a progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before finally differentiating into a mature cell. It is believed that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such as receptors) between the daughter cells.

Discoveries in recent years have suggested that adult stem cells might have the ability to differentiate into cell types from different germ layers. For instance, neural stem cells from the brain, which are derived from ectoderm, can differentiate into ectoderm, mesoderm, and endoderm.[33] Stem cells from the bone marrow, which is derived from mesoderm, can differentiate into liver, lung, GI tract and skin, which are derived from endoderm and mesoderm.[34] This phenomenon is referred to as stem cell transdifferentiation or plasticity. It can be induced by modifying the growth medium when stem cells are cultured in vitro or transplanting them to an organ of the body different from the one they were originally isolated from. There is yet no consensus among biologists on the prevalence and physiological and therapeutic relevance of stem cell plasticity. More recent findings suggest that pluripotent stem cells may reside in blood and adult tissues in a dormant state.[35] These cells are referred to as "Blastomere Like Stem Cells"[36] and "very small embryonic like" "VSEL" stem cells, and display pluripotency in vitro.[35] As BLSC's and VSEL cells are present in virtually all adult tissues, including lung, brain, kidneys, muscles, and pancreas[37] Co-purification of BLSC's and VSEL cells with other populations of adult stem cells may explain the apparent pluripotency of adult stem cell populations. However, recent studies have shown that both human and murine VSEL cells lack stem cell characteristics and are not pluripotent.[38][39][40][41]

Stem cell function becomes impaired with age, and this contributes to progressive deterioration of tissue maintenance and repair.[42] A likely important cause of increasing stem cell dysfunction is age-dependent accumulation of DNA damage in both stem cells and the cells that comprise the stem cell environment.[42] (See also DNA damage theory of aging.)

Adult stem cells can, however, be artificially reverted to a state where they behave like embryonic stem cells (including the associated DNA repair mechanisms). This was done with mice as early as 2006[43] with future prospects to slow down human aging substantially. Such cells are one of the various classes of induced stem cells.

Adult stem cell research has been focused on uncovering the general molecular mechanisms that control their self-renewal and differentiation.

Adult stem cell treatments have been used for many years to successfully treat leukemia and related bone/blood cancers utilizing bone marrow transplants.[47] The use of adult stem cells in research and therapy is not considered as controversial as the use of embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo.

Early regenerative applications of adult stem cells has focused on intravenous delivery of blood progenitors known as Hematopetic Stem Cells (HSC's). CD34+ hematopoietic Stem Cells have been clinically applied to treat various diseases including spinal cord injury,[48] liver cirrhosis [49] and Peripheral Vascular disease.[50] Research has shown that CD34+ hematopoietic Stem Cells are relatively more numerous in men than in women of reproductive age group among spinal cord Injury victims.[51] Other early commercial applications have focused on Mesenchymal Stem Cells (MSCs). For both cell lines, direct injection or placement of cells into a site in need of repair may be the preferred method of treatment, as vascular delivery suffers from a "pulmonary first pass effect" where intravenous injected cells are sequestered in the lungs.[52] Clinical case reports in orthopedic applications have been published. Wakitani has published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.[53] Centeno et al. have reported high field MRI evidence of increased cartilage and meniscus volume in individual human clinical subjects as well as a large n=227 safety study.[54][55][56][57] Many other stem cell based treatments are operating outside the US, with much controversy being reported regarding these treatments as some feel more regulation is needed as clinics tend to exaggerate claims of success and minimize or omit risks.[58]

The therapeutic potential of adult stem cells is the focus of much scientific research, due to their ability to be harvested from the parent body that is females during the delivery.[59][60][61] In common with embryonic stem cells, adult stem cells have the ability to differentiate into more than one cell type, but unlike the former they are often restricted to certain types or "lineages". The ability of a differentiated stem cell of one lineage to produce cells of a different lineage is called transdifferentiation. Some types of adult stem cells are more capable of transdifferentiation than others, but for many there is no evidence that such a transformation is possible. Consequently, adult stem therapies require a stem cell source of the specific lineage needed, and harvesting and/or culturing them up to the numbers required is a challenge.[62][63] Additionally, cues from the immediate environment (including how stiff or porous the surrounding structure/extracellular matrix is) can alter or enhance the fate and differentiation of the stem cells.[64]

Pluripotent stem cells, i.e. cells that can give rise to any fetal or adult cell type, can be found in a number of tissues, including umbilical cord blood.[65] Using genetic reprogramming, pluripotent stem cells equivalent to embryonic stem cells have been derived from human adult skin tissue.[66][67][68][69][70] Other adult stem cells are multipotent, meaning they are restricted in the types of cell they can become, and are generally referred to by their tissue origin (such as mesenchymal stem cell, adipose-derived stem cell, endothelial stem cell, etc.).[71][72] A great deal of adult stem cell research has focused on investigating their capacity to divide or self-renew indefinitely, and their potential for differentiation.[73] In mice, pluripotent stem cells can be directly generated from adult fibroblast cultures.[74]

In recent years, acceptance of the concept of adult stem cells has increased. There is now a hypothesis that stem cells reside in many adult tissues and that these unique reservoirs of cells not only are responsible for the normal reparative and regenerative processes but are also considered to be a prime target for genetic and epigenetic changes, culminating in many abnormal conditions including cancer.[75][76] (See cancer stem cell for more details.)

Adult stem cells express transporters of the ATP-binding cassette family that actively pump a diversity of organic molecules out of the cell.[77] Many pharmaceuticals are exported by these transporters conferring multidrug resistance onto the cell. This complicates the design of drugs, for instance neural stem cell targeted therapies for the treatment of clinical depression.

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StemCell Maxum Longevity Support | Make America Well

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A Natural formula designed to prevent premature aging. Feel better and look younger! Your cells lose function as you age. Adult stem cells rejuvenate old damaged tissues, but adult stem cells are also aging. Now you can do something about it. StemCell Maxum supports adult stem cells and their functions.

Scientific research is constantly finding new anti-aging discoveries. Biological aging does not need to be our destiny. People will eventually live long, healthy lives while maintaining younger characteristics. A lifetime that of centuries or longer will eventually be a reality. Maintaining the body of a 21 year old for a lifetime that could stretch to centuries or longer will be a reality. We are developing products and therapies to extend lifespan. Progress will continue indefinitely. Your best strategy is to use dietary supplements, exercise and a healthy diet and lifestyle to extend your lifespan.

StemCell Maxum is designed to prevent premature aging. This can help you feel better and look younger. Your cells lose function as you age. Adult stem cells rejuvenate damaged and old tissues, but adult stem cells are also aging. Now you can do something about it. StemCell Maxum supports adult stem cells and their functions.

Millions of people suffer from chronic disease conditions. We have hope that conditions afflicting mankind will eventually be remedied using stem cell regenerative medicine. Improve the effectiveness of your adult stem cells by using our StemCell -Longevity.

Ingredients in StemCell Maxum have been proven to support:

As a child, we rapidly recover from injury or illness because of the ability of our young regenerative stem cells to regenerate damaged tissues. As we age, our stem cells slowly lose their repairing capacity. This natural progression occurs slowly, but we start to notice the body changes especially after age 50. StemCell Maxum helps you regain your youthful regenerative potential.

Premature aging can be defeated by maximizing your longevity genes.

Users may expect a reduction in blood pressure, blood sugar, total cholesterol, LDL and triglycerides and an increase in HDL (good cholesterol) after a few months of taking StemCell Maxum.

All the organs and tissues of the body have adult stem cells for regenerating cells in case of injury or disease. As we age, adult stem cells gradually lose the ability to differentiate into functional tissue-specific cells. For example, cardiac muscle stem cells exist but elderly people have only one half the number of cardiac stem cells found in young people. Thus, adult stem cells become more dysfunctional as we age, causing progressively increased organ and tissue dysfunction.

An example of the aging role of adult stem cells is your skin continually losing dead cells, so that adult stem cells must continuously replenish the dying skin cells. With age, there are progressively fewer functional skin stem cells. Skin cell turnover slows, leading to thinner, dryer, less elastic skin that loses its youthful beauty. Hair thins and turns grey as functional hair follicle stem cells decline. Vision, hearing, smell, taste, and touch slowly decline with age, as the declining stem cell populations responsible for maintaining these functions are unable to fully rejuvenate.

Stimulating adult stem cell populations is not a simple task. If the proliferation of adult stem cells is over stimulated, then you may get overgrowth of tissues or a potential tumor. StemCell Maxum is a dietary supplement designed to improve the function of your existing stem cells. When an organ or tissue is damaged, it emits natural signals that new cells are needed to replace old or damaged cells. StemCell Maxum supports the adult stem cells that respond to provide new replacement cells.

Everyone can benefit from StemCell Maxum. Younger persons will enjoy the wellness endurance boost during sports or exercise. Older persons will notice increased energy, youthful appearance, wellness and better weight management.

Expected benefits of taking StemCell Maxum:

Caution: Normal blood glucose and/or blood pressure may result from taking StemCell Maxum. Please consult with your doctor and regularly monitor yourself if you are on medication for these disorders. StemCell Maxum is not recommended for pregnant or lactating individuals.

The statements above have not been reviewed by the FDA. StemCell Maxum is not meant as a preventive or treatment for any disease.

StemCell Maxum

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StemCell Maxum Longevity Support | Make America Well

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The Cost Of Stem Cell Therapy And Why It’s So Expensive …

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How much is stem cell therapy? As stated by CBC Canada,the cost of stem cell therapy is $5,000 to $8,000per stem cell treatment for patients. According to a Twitter poll by BioInformant, the cost can be even higher. Our May 2018 poll found that stem cell treatments can cost as much as $25,000 or more. This article explores the key factors that impact the cost of stem cell therapy, including the type of stem cells used within the protocol, the number of treatments required, and the site of theclinic. It also provides pricing quotes from stem cell clinics within the U.S. and worldwide.

In this article:

Stem cell therapy is the use of living cells as therapeutics to treat disease or injury. Read on to learn about the cost requirements of these procedures.

CBC Canadas pricing involves Cell Surgical Network (CSN) following its protocol to remove fat tissue and process it before re-injecting [adipose-derived stem cells] either directly or intravenously into the same patient. Unfortunately, the U.S. FDA and Department of Justice (DOJ) sent this network of stem cell treatment providers a permanent injunction notice in May 2018. Therefore, patients should not seek treatments from the group at this time.Although Cell Surgical Network (CSN) is based in California, it has a network of approximately 100 U.S. treatment centers. They also have three Canadian clinics located in Vancouver, Sudbury,andKamloops.

The controversy such as the one above stirs up questions about the safety of stem cell procedures. Anyone considering stem cell therapy from any tissue or source will benefit from understanding the possible consequences of stem cell therapy and the factors driving costs.

For the patient, a stem cell transplant involves multiple steps, including:

There are also real costs for the doctors who provide stem cell treatments. They have overhead costs, including:

There is also time and expertise required toperform the procedure and offer post-operative care. In some cases, the physician must pay licensing fees to access stem cell sourcing, processing, or delivery technologies.

Stem cell treatment has gained more and more traction over the last decade. It has been helped along by considerable advances in research. In 2017, the number of scientific publications about stem cells surpassed 300,000. The number of stem cell clinical trials has also surpassed4,600 worldwide.

However, stem cell therapy is still expensive. Among the cheapest and easiest options is to harvest adipose-derived stem cells (ADSCs) those that exist in adult fat layers and re-deliver them to the patient. Unlike harvesting from bone marrow or teeth, providers can feasibly remove fat, separate stem cells, then re-inject them into a patient the same day. This approach is typically less expensive than those that require more invasive procedures for harvesting. Because of its practicality in terms of cost, it has become a common approach to stem cell treatment.

Relatively easy harvesting stilldoesnt translate to inexpensive cost, although some are certainly more affordable than others. For orthopedic conditions, the costof stem cell therapy is typically lower, averaging between $5,000 and $8,000. Examples of these types of medical conditions include:

Note that these prices are typically out-of-pocket costs paid by the patientbecause most insurance companies will not cover them. They are considered experimental and unapproved by the FDA. This means patients needing stem cell treatment will need to use their own savings.

Although fat is a frequently utilized source for stem cells, it is also possible for physicians to utilize stem cells from bone marrow. Regenexx provides this service in the U.S. and Cayman Islands. With theRegenexxstem cell injection procedure, a small bone marrow sample is extracted through a needle, and blood is drawn from a vein in the arm. These samples are processed in a laboratory, and the cells it contains are injected into an area of the body that needs repair. On June 19, 2018, ACAP Health, a leading provider in innovative, clinical-based solutions partnered with Regenexx to reduce high-cost musculoskeletal surgeries.ACAP Health is a national leader in employer healthcare expense reduction. It is one of the first healthcare groups to partner with a stem cell treatment group to support insurance coverage to patients.

A recent Twitter poll conducted by BioInformant reported that, on average, patients can expect to spend $25,000 or more on stem cell therapies. According to the poll,

Most likely, those paying lower stem cell treatment costs under $5,000 were pursuing treatment for orthopedic or musculoskeletal conditions. In contrast, those paying higher treatment costs were likely getting treated for systemic or more complex conditions, such as diabetes, multiple sclerosis (MS), neurodegenerative diseases (such as Alzheimers disease or dementia), psoriatic arthritis, as well as the treatment for autism.

In the U.S., treatment protocols vary depending on the clinic and the treating physician. A one-time treatment that utilizes blood drawn from a patient can cost as little as $1,500. However, protocols that utilize a bone marrow or adipose (fat) tissue extraction can run as much as $15,000 $30,000. This is because bone marrow extraction is an invasive procedure that requires a penetrating bone and adipose tissue extraction requires a medical professional trained in liposuction.

For treatments that require a systemic or whole-body approach, the cost tends to be in the higher range, often averaging from $20,000 to $30,000. Examples of the diseases or conditions requiring this type of stem cell treatment include:

These higher costs reflect the complexity of treating these patients and the fact that multiple treatments are often required.

Founded by Dr. Neil Riordan, a globally recognized stem cell expert, theStem Cell Institutein Panama is one of the worlds most trusted adult stem cell therapy centers. Over the past 12 years, the center has performed more than10,000 procedures, making it a widely recognized destination for stem cell treatments.

Working in collaboration with universities and physicians worldwide, its stem cell treatment protocols utilize combinations of allogeneic human umbilical cord blood stem cells and autologous bone marrow stem cells to treat a wide variety of conditions.

A reader of BioInformant was recently treated for psoriatic arthritis at the Stem Cell Institute in Panama in early 2018. The price of his stem cell treatment was $22,000. With travel and lodging included, the total expenses were approximately $30,000.

Because of its proximity to the U.S., Mexico is increasingly becoming a destination for medical tourism.Before choosing a stem cell treatment provider in Mexico, ensure the clinic is fully authorized by COFEPRIS, the Mexican equivalent to the FDA.

One patient who recently shared stem cell treatment quotes with BioInformant found that the treatment for glycogen storage disease, a metabolic disorder that often onsets in infancy and continues into adulthood, would cost $23,900 throughGIOSTAR Mexico.

In contrast, the patient was quoted$33,000 throughCelltex, a U.S.-based company that treats patients in Cancun, Mexico.Celltex follows FDA regulations concerning the export of cells to Mexico and is compliant with the standards and procedures of COFEPRIS. Celltex also has an alliance with a certified hospital in Mexico, which is approved to receive cells and administer them to patients by a licensed physician.

In contrast, the patient was quoted $10,000 from Stem Cell Therapy of Las Vegas and Med Spa, an American clinic. This price difference may reflect regulatory restrictions that prevent U.S. providers from expanding cells. It may also reflect the therapeutic approach used by the clinic, as well as the quality of their expertise.

In Mexico, where certain types of stem cell expansion are allowed that are restricted within the U.S., treatment protocols vary depending on the clinic and the treating physician. A one-time treatment that utilizes peripheral blood from a patient can cost as little as $1,000. In contrast, protocols that utilize more invasive sources of stem cells can run as much as $15,000 $35,000. Examples of invasive procedures includebone marrow and adipose tissue extraction. In some cases, hospitalization may be required, which raises costs. The location of a stem cell facility can factor heavily into thecost of the procedure.

Not every cost associated with treatment gets billed to the patient at the time of the procedure. Hidden costs such as reactions to the treatment, graft-versus-host disease, or disability derived from the treatment can all result in more money to the patient, to insurance, or to the government.

For example, in the case of someone with cancer, it frequently isnt viable to harvest the patients own stem cells because they may contain cancerous cells that can reintroduce tumors to the body. Instead, the patient would receive stem cells by transplant. Treatments that involve cells from another person are called allogeneic treatments. The danger here is that the body may see those cells as invaders and attack them via the immune system, a condition known as graft-versus-host disease (GvHD). The body (host) and the introduced stem cells (graft) then battle rather than coexist.

Transplanted cells often face the risk of being rejected by their host; this article discusses the effect of plasma exchange on acute graft vs. host disease

Katie Bunde (@kbuns76) May 29, 2018

In addition to making the stem cell treatments less effective or ineffective, GvHD can be deadly. Roughly30 to 60 percent ofhematopoieticstem cell and bone marrow transplantationpatients sufferfrom it, and of those, 50 percent eventually die. The hospital costs associated with it are substantial.

Another hidden cost is the potential to disrupt a system that formerly functioned adequately. The best current example of this isthe case of Doris Tyler, who received bilateral stem cell injections in her eyes from Drs.RobertHalpernand JamieWalraven of Stem Cell Center of Georgia. According to her, while her vision was failing, it was still good enough to perform various tasks, and now it is not. That means the cost increases for her, as well as potential insurance or disability claims (though again, insurance is unlikely to cover the specific consequences of this action).

Because of tight regulations surrounding stem cell procedures performed in the United States, many stem cell treatment providers provide both on-shore (U.S.-based) and offshore (international) treatment options.Depending on where a treatment is received, patients may have to pay travel, lodging,and miscellaneous expenditures.

For example, Regenexx offers treatments at a wide range of U.S. facilities using non-expanded stem cells. However, it also offers a laboratory-expanded treatment option at a site in the Cayman Islands, which can administer higher cell doses to patients by expanding the cells in culture within a laboratory.

Similarly, Okyanos (pronounced Oh key AH nos) offers treatments to patients at its Florida location and provides more involved stem cell procedures at its offshore site inGrand Bahama. It was founded in 2011 and is a stem cell therapy provider specializing in treatments for congestive heart failure (CHF) and other chronic conditions. It is fully licensed under the Bahamas Stem Cell Therapy and Research Act and adheres to U.S. surgical center standards.

Similarly, Celltex is headquartered in Houston, Texas, but offers stem cell treatments in Cancun, Mexico. Celltex specializes in storing a patients mesenchymal stem cells (MSCs) for therapeutic use.

While no hard evidence yet points to stem cell clinics raising their rates as a result of lawsuits, that is a typical response in industries whose products or services the public perceives as a high risk.

An additional danger to stem cell treatment providers,points out Nature, is the reduction of bottom-line profits through former patients winning suits. If clinics have to pay out the money they earned and then some to individuals suing for damages, they may soon become faced with an unviable business model. That is a definite concern for those hoping to leverage these treatments now and in the future.

As with any other area of medicine, patient evaluations of stem cell providers and treatments run the gamut from extremely satisfied to desolately unhappy. Those like Doris Tyler who have lost their eyesight exist at the negative end of the spectrum. However, many others praise stem cell treatments for their power to heal diseases, boost immunity, fight cancer, and more.

For example, BioInformants Founder and President, Cade Hildreth, had a favorable experience with stem cell therapy. Cade had bone marrow-derived stem cells collected and then had them re-injected into the knee to treat a devastating orthopedic injury. Cade was able to reverse pain, swelling, and scarring to reclaim an elite athletic ability.

As of now, this much is clear. There exists enough interest in America and across the world that stem cell providers are continuing to offer a wide range of treatments. Stem cell treatments also offer the potential to reverse diseases that traditionally had to be chronically managed by drugs. Like most medical practices, stem cell treatments will require further testing to reveal merits and faults. Until then, the public will likely continue to pursue services when medical needs arise.

Although the cost of stem cell therapy is pricey, some patients choose to undergo the treatment because it is more economical than enduring the costs associated with chronic diseases.

Although most stem cell therapy providers do not provide FDA-approved procedures, the Food and Drug Administration (FDA) continues to encouragepatients to pursue approved therapies, even if there is a higher associated treatment cost.

Providers rarely post their prices for stem cell treatments in print or digital media because they want patients to understand the benefits of therapy before making a price decision. Additionally, the price of stem cell treatments varies by condition, the number of treatments required, and the complexity of the procedure, factors that can make it difficult for medical providers to provide cost estimates without a diagnostic visit for the patient. However, in many cases, it is not in the patients best interest to make treatment decisions based on the cost of stem cell therapy. The best way to know whether to pursue stem cell therapy is to explore patient outcomes by condition and compare the healing process to other surgical and non-surgical treatment options.

The cost of stem cell therapy is indeed expensive, especially because the procedures are rarely covered by health insurance. However, with the right knowledge and a clear understanding of the treatment process, the risk of undergoing stem cell therapy can be worth it, especially if it removes the requirement for a lifetime of prescription medication. Although stem cell therapy has associated risks, it has improved thousands of lives and will continue to play in a key role in the future of modern medicine.

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Are you seeking a stem cell treatment? If so, we have partnered with GIOSTAR to help you acccess medical guidance and advice.

In alignment with what we believe at BioInformant, GIOSTARs goal is to offer cutting-edge, extensively researched stem cell therapy options designed to rejuvenate and improve a patients quality of life.

Click here to Schedule a Consultation or ask GIOSTAR a question.

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Cost Of Stem Cell Therapy And Why Its So Expensive

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Stem Cell Therapy in Thailand – Beike Biotech – Hospitals

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TREATMENT:hRPE stem cells implantation (human Retinal Pigment Epithelial cells, (adult stem cells) by stereotactic brain injection + nutritious stem cell cocktail treatment (intravenous).


BEFORE THE TREATMENT: Lindas main symptoms were rigidity and stiffness in the left side of her body. She had mild tremors mainly in her left hand and had difficulty grasping small objects or holding things with her fingers. She would drag her left leg while walking and while at rest the

muscles in her leg and tows would contract. During the night her muscles would contract constantly keeping her regularly from having more than few hours sleep. Her muscles were very weak and she would tire very quickly, her posture was stooped and she suffered from a general tenseness and stiffness in her face, neck and back.

Without the affect of the medications she could not turn her neck and should turn her whole body in order to look back. Every morning, before the medications started to influence, it was difficult getting dressed, getting out of bed or taking a shower.

Before the treatment Linda took her medications every 2-3 hours (Contam 250mg x 8 times a day). One hour after taking the medications Lindas symptoms were hardly noticed, but the medications influence wear out quickly and Lindas every activity was dependant on her next dose of medications.

During the last few years Lindas short term memory was affected up to a level that she quit her job in human resources. Her hand writing was affected too even after taking the medications, it was still very scratchy and hard to read.

Linda also suffered from general anxiety and depression.


Lindas first notable change after the surgery was a full night sleep - the first one in 5 years. Within 5 weeks after the stem cell implantation most of Lindas symptoms were gradually gone. Her fingers got their flexibility back and the tremors were gone she could now grasp things, open a door and articulate more precise movements with her fingers.

The cramps in her leg were gone and she stopped dragging her left leg.

I dont need to think anymore about every movement, as I did before she says.

Her muscle tension was significantly reduced, she felt more relaxed and stronger than before.

Her posture became more open and she could now turn her neck more easily. Before leaving the hospital Linda still had some weakness in her muscles but she felt that she is getting stronger every day.

Linda also noticed that her sense of smell and taste that were greatly weakened during the last years were coming back.

A major change in her quality of life was that now her symptoms were unnoticeable with almost half the dosage of the medications she used to take before. Linda is now taking medications 4 times a day (Sinemet 200mg X4 times a day) instead of 8 times of double dosage that she used to take before the treatment.

I was a watch keeper, I used to watch at the clock all the time, I stopped swimming riding bicycle and other activities because I never knew when the medications affect will wear out she says.

Linda hopes that her medications could be gradually reduced even more, and she will keep a close contact with her doctors in China in order to follow up with her condition.

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Types of Stem Cells A Closer Look at Stem Cells

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Tissue-specific stem cells

Tissue-specific stem cells (also referred to assomaticoradultstem cells) are more specialized than embryonic stem cells. Typically, these stem cells can generate different cell types for the specific tissue or organ in which they live.

For example, blood-forming (orhematopoietic) stem cells in the bone marrow can give rise to red blood cells, white blood cells and platelets. However, blood-forming stem cells dont generate liver or lung or brain cells, and stem cells in other tissues and organs dont generate red or white blood cells or platelets.

Some tissues and organs within your body contain small caches of tissue-specific stem cells whose job it is to replace cells from that tissue that are lost in normal day-to-day living or in injury, such as those in your skin, blood, and the lining of your gut.

Tissue-specific stem cells can be difficult to find in the human body, and they dont seem to self-renew in culture as easily as embryonic stem cells do. However, study of these cells has increased our general knowledge about normal development, what changes in aging, and what happens with injury and disease.

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What Do Stem Cells Have to Do with a Spinal Cord Injury?

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You may have heard of stem cells in the news and that they are being used in medical research. This can be a controversial topic for many, but the fact is that the research is happening in specialties across the medical industry. Lets start with the basics to clarify how stem cells are being used in research for spinal cord injuries.

This is the bundle of nerve fibers that transmits information between the brain and rest of the body, protected by the hard vertebrae spinal column. Made up of millions of nerve cells, when connected to the brain, this forms the central nervous system. Injury to the spinal cord can cause paralysis or even death, and there is currently no effective treatment.

Following an injury, the nerve cells and motor axons, which make up the spinal cord, are crushed and torn, and the insulating sheath around the axons begins to die. Any exposed axons begin to degenerate, which means the neuron connection is disrupted, and the flow of information between thebrain and the spinal cord is subsequently blocked.

When this happens, the body is unable to replace lost cells from a spinal cord injury. As a result, their function becomes permanently impaired, leading to severe movement and sensation disability which doctors measure on various scales, including the American Spinal Injury Association Impairment Scale (AIS).

Although the research is still in its infancy, professionals believe stem cells are an ideal answer to contribute to spinal cord treatment and repair. The two main characteristics of stem cells, which make them so well-suited for this use, is

Stem cells, come from two main sources- embryonic stem cells from an embryo and somatic stem cells found throughout the body.

Studies in animals demonstrated that transplantation of stem cells contributed to the repair of spinal cord material. It did so in various ways, and these included the replacement of dead nerve cells; the generation of new cells to re-form the aforementioned insulating sheath around the axons, to stimulate the regrowth of damaged axons. It also acted to protect cells at the site of the injury from any further damage.

In prior testing situations, stem cells have been removed from brain tissue, nasal cavity lining, and tooth pulp for applications. This has only ever resulted in partial recovery of function, however, and remains in experimental stages.

There is controversy over this type of treatment at the moment; due to the fact stem cells need further research into how they behave and how they could work in a form of treatment. Stem cell behavior is directed by chemical signals, some of which are internal, and others of which are external and depend on the environment they find themselves in. These chemical signals would need to be created in the spinal cord environment in order to encourage relative growth and development.

Although stem cell treatment continues to be in testing stages, it is still a possible solution for repairing spinal cord injuries at some point in the future.

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What Do Stem Cells Have to Do with a Spinal Cord Injury?

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Spinal Cord Injury Research Advances with New Stem Cells

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At Spinal Cord, were excited to share that researchers at the University of California, San Diego successfully created spinal cord neural stem cells (NSCs) that could have clinical applications in spinal cord injury and disorder treatments.

The spinal cord injury research, conducted by postdoctoral scholar Hiromi Kumamaru and Professor of Neuroscience and Director of the UCSD Translational Neuroscience Institute Mark Tuszynski, grafted the cultured cells into the spinal cords of rats with spinal cord injuries (SCIs).

Kumamaru says about the spinal cord injury research:

In grafts, these cells could be found throughout the spinal cord, dorsal to ventral. They promoted regeneration after spinal cord injury in adult rats, including corticospinal axons, which are extremely important in human voluntary motor function. In rats, they supported functional recovery.

These diverse cells are derived from immature self-replicating human stem cells known as human pluripotent stem cells (hPSCs), which morph into different types of stem cells that could disperse throughout the spinal cord. According to the researchers, these pluripotent cells could serve as a scalable source of replacement cells for individuals with spinal cord injuries.

In the Universitys press release, Tuszynski says that the new cells could serve as source cells for human clinical trials in three to five years. First, however, it first needs to be determined whether the cells are safe over long-time periods via studies on rodents and non-human primates and that the results are replicable.

According to the Universitys press release on the new stem cell research:

The achievement, described in the August 6 online issue of Nature Methods, advances not only basic research like biomedical applications of in vitro disease modeling, but may constitute an improved, clinically translatable cell source for replacement strategies in spinal cord injuries and disorders.

The hope is that the cultured spinal cord neural stem cells from this stem cell research will benefit people with other spinal cord dysfunction disorders via modeling and drug screening. According to UCSD, such disorders would include amyotrophic lateral sclerosis, progressive muscular atrophy, hereditary spastic paraplegia and spinocerebellar ataxia, a group of genetic disorders characterized by progressive discoordination of gait, hands and eye movement.

Although significant research has been done to explore the potential use of hPSC stem cells in creating new cells to repair diseased or damaged spinal cords, historically, progress has been slow and limited.

It is one of the goals of the Spinal Cord team to help keep you and your family informed about the newest medical advances in spinal cord injury research. We recently shared about exciting advances in gene therapy research that helped to restore hand function in rats with SCIs, as well as the use of olfactory ensheathing cells (cells from the bodys system that enables you to perceive smells) to trigger spinal cord nerve regeneration.

Please be sure to subscribe to our blog to get the latest updates on stem cell and other spinal cord injury research.

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Stem Cell Therapy for ALS Patients

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Learn about what stem cells are, why they are important and how they are going to revolutionize healing and medical care in Canada.

Not all conditions are effectively treated by PRP injections or stem cell therapy, and with ongoing clinical trials its important to realize what stem cells can and cannot help with. Weve built a comprehensive list of the different types of conditions that stem cell therapy shows promise for, however if you dont find it listed wed recommend checking outDanish health website Regular maintenance of health is key to making sure long-term issues dont arise as we age, and part of that is a rich, balanced diet and careful supplementation.

Research on human embryos in general, and stem cell research in particular, has been the subject of public debate in Canada since the late 1980s. In 2002, the Canadian Institute of Health Research (CIHR) issued guidelines for research on human embryonic stem cell lines, which have been revised and reissued several times since 2005 (most recently in 2007). These guidelines regulate the allocation of state funds in the field of research on human embryonic stem cells and concern both the handling of existing stem cell lines and the establishment of new stem cell lines.

The guidelines specify a number of important conditions that must be fulfilled in order for research projects to be eligible for funding. These include, but are not limited to:

The Stem Cell Oversight Committee (SCOC) was set up to ensure that research projects comply with the provisions of the Directive and to address the complex ethical issues surrounding research projects. Any project applying for government funding in the field of stem cell research must first be positively evaluated by the SCOC.

In addition to the regulation of state funding, the Assisted Human Reproduction Act came into force in 2004, which broadly regulates the field of reproductive medicine. Unlike the guidelines of the CIHR, it is not merely a guideline for state funding of certain research activities, but a law that places certain activities under state control and generally prohibits others. Research on human embryos is one of the controlled activities of the Assisted Human Reproduction Act. According to 8 Para. 3, the approval according to 10 Para. 2 requires the consent of the donor after clarification of the intended use. The Assisted Human Reproduction Agency of Canada (AHRAC), established by law, is responsible for granting authorisations and monitoring research activities.

The extraction of ES cells also falls under this section and is therefore permitted in Canada. The use of in vitro embryos for research purposes, including the derivation of stem cells, is subject to the following conditions under the Assisted Human Reproduction Act:

The production of a human clone is prohibited according to 5 a Assisted Human Reproduction Act. This provision also includes so-called therapeutic cloning by nuclear transfer. According to 5 b, the creation of embryos for purposes other than the creation of a human being or the improvement of artificial reproduction procedures is also prohibited. The law does not apply to the handling of already established human embryonic stem cell lines.

The CBC news network and other media responded to Twitter posts and a YouTube live video about unapproved treatments that lately came up. Patients that suffer from chronic pain or disease could benefit from stem-cell therapies. Canadians who have been treated more open by their federal and other regulatory laws about unlicensed stem cell therapies are asking for the legalization or this procedure.

A new company now made it their mission to offer direct-to-customer opportunities for trainees and people in general which can mean a big advantage for a patient. Unproven stories about this training in marketing and science services are offering support for approved stem-cell professionals.

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Spinal Cord Injury Center – Treatments, Research …

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Spinal Cord Injuries Are Not JustCaused by Trauma

When you think of spinal cord injury (SCI), traumatic events like a serious car accident may come to mind. While its true that car accidents are the leading cause of traumatic SCI, you may be surprised that non-traumatic diseasessuch as a spinal tumorcan also cause SCI.

SCI involves damage to the spinal cord that temporarily or permanently changes how it functions. SCI is divided into 2 categories: traumatic or non-traumatic. Even if the cause of SCI is non-traumatic, that doesnt lessen its impact or severitythe aftermath of SCI can have devastating effects on a persons life.Falls are the second most common cause of traumatic spinal cord injury. Photo Source: Spinal Cord Injury

Traumatic SCI occurs more often in men than womennearly 80% of cases affect men. People of all ages may experience SCI, but certain activities tend to affect different age groups more. For example, high-impact events like car accidents and sports injuries tend to occur more often in younger people. On the other hand, traumatic SCI caused by a fall is more common in adults over age 60.

Regardless of the cause, traumatic SCI occurs most frequently in the cervical spine (about 60% of cases involve the neck), followed by thoracic spine (32% involve the mid-back). Only 9% of cases occur in the lumbosacral spine, or low back and tailbone.

Understanding the Traumatic Spinal Cord Injury CascadeA traumatic SCI doesnt simply damage your spinal cord at the point of initial impact. In traumatic SCI, the primary injury (that is, the initial traumatic event that caused the SCI) may damage cells and dislocate your spinal vertebrae, which causes spinal cord compression. The primary injury also triggers a complex secondary injury cascade, which causes a series of biological changes that may occur weeks and months after the initial injury.

During the secondary injury cascade, the following processes occur:

This cascade changes the spinal cords structure and how it normally operates. Ultimately, this secondary injury cascade may interfere with the spinal cords ability to recover itself. This means a person with traumatic SCI may experience permanent nerve pain and dysfunction because of their injury.

Non-traumatic Spinal Cord InjuryTraumatic events arent the only causes of spinal cord damageSCI can also be caused by non-traumatic diseases in the spine. Spinal tumors are the leading cause of non-traumatic SCI, but infections and degenerative disc disease can also damage your spinal cord.

Though most people connect traumatic events to SCI, non-traumatic causes of SCI are a much more likely cause. To highlight just how common non-traumatic cases are versus their traumatic counterparts, consider the incidence of traumatic SCI in North America: 39 cases per million people. On the other hand, the incidence of non-traumatic SCI is 1,227 cases per million people for Canada alone (data for the rest of North America is not available).

A Healthy Research Outlook to Improve Spinal Cord Injury OutcomesOver the past 30 years, spine researchers have made great strides in developing successful protective and regenerative therapies to improve the health of the spinal cord and the survival rate of people with SCIbut the work is far from over. Current studies and clinical trials are examining innovative medical, surgical and cell-based treatments to further the medical communitys understanding of SCI, which will improve the quality of life and preserve a brighter future for people who experience these injuries.

Suggested Additional ReadingA special issue of the Global Spine Journal set forth guidelines for the Management of Degenerative Myelopathy and Acute Spinal Cord Injury, which is summarized on SpineUniverse in Summary of the Clinical Practice Guidelines for the Management of Degenerative Cervical Myelopathy and Traumatic Spinal Cord Injury.

Sources:Ahuja CS, Wilson JR, Nori S, et al. Traumatic spinal cord injury. Nature Reviews Disease Primers. 3, 17018. Accessed January 10, 2018.

Spinal Cord Injury. Facts and figures at a glance. National SCI Statistical Center (NSCI SC). 2017. Accessed January 10, 2018.

Updated on: 01/27/19

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C3, C4, & C5 Vertebrae Spinal Cord Injury |

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The C3, C4, and C5 vertebrae form the midsection of the cervical spine, near the base of the neck. Injuries to the nerves and tissue relating to the cervical regionare the most severe of all spinal cord injuries because the higher up in the spine an injury occurs, the more damage that is caused to the central nervous system. Depending on the how severe the damage to the spinal cord is, the injury may be noted as complete or incomplete.

The C2 - C3 junction of the spinal column is important, as this is where flexion and extension occur (flexion is the movement of the chin toward the chest and extension is the backward movement of the head). Patients with spinal cord damage at the C3 level will have limited mobility in both their flexion and extension.

Symptoms of a spinal cord injury corresponding toC3 vertebrae include:

The portion of the spinal cord which relatesto the C4 vertebra directly affects the diaphragm. Patients with C4 spinal cord injuries typically need 24 hour-a-day support to breathe and maintain oxygen levels.

Symptoms of a spinal cord injury corresponding toC4 vertebrae include:

Damage to the spinal cord at the C5 vertebra affects the vocal cords, biceps, and deltoid muscles in the upper arms. Unlike some of the higher cervical injuries, a patient with a C5 spinal cord injury will likely be able to breath and speak on their own.

Symptoms of a spinal cord injury corresponding to C5 vertebrae include:

The most common causes of cervical spinal cord injuries are:

Unfortunately, there is no treatment which will completely reverse the damage frominjuries to the spinal cord at the C3 - C5 levels. Medical care is focused on preventingfurther damage to the spinal cord and utilization of remaining function.

Current treatments available for patients are:

It is an unfortunate truth that there are not many options to date to completely recover from a cervical spinal cord injury. Medical researchers are continuously looking into new drug therapies to help regain sensory and motor function. The use of stem cells is seen more and more in research as these cells are specialized enough to possibly regenerate damaged spinal cord tissues. Lab study results show greater sensory and motor function in those patients treated with stem cells for spinal cord damage.

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Bone Marrow for Spine and Orthopaedic Stem Cell Treatment …

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Stem cells are the next frontier in the treatment of orthopaedic and spinal disorders, and the Cary Orthopaedics team is leading the way.

Using stem cells harvested from an adult patients own bone marrow,Dr. Sameer Mathurand Dr. Nael Shanti both board-certified orthopaedic spinal surgeons have developed a minimally invasive remedy for those suffering from degenerative disc disease, back pain and spinal arthritis. Applying a similar approach, Cary OrthosDr. Douglas Martini a fellowship-trained, board-certified orthopaedic surgeon specializing in sports medicine has crafted a pain-relief solution for patients living with osteoarthritis and soft tissue injuries.

Multiple research studies have shown a significant reduction in low back and joint pain and improved function after stem cell injections. While these treatments are new, 80% to 90% of patients are already reporting improvement in their symptoms after orthopaedic stem cell treatments.

Many patients suffering from degenerative disc diseases or low back pain are often not ideal candidates for surgery, and some who have chosen to undergo surgery have had unsatisfactory results. Therefore, the typical remedy for chronic orthopaedic conditions is extensive physical therapy combined with oral anti-inflammatory medications. The result: The majority of patients still had to live with pain.

Physicians at Cary Orthopaedics are utilizing orthopaedic stem cell treatment using the patients own bone marrow, the soft, spongy tissue found in the center of bones. Bone marrow in adults contains a rich reservoir of multipotent stem cells also known as Mesenchymal Precursor Cells (MPCs) that can be extracted from the patients pelvis or hip bone. Due to their unique, regenerative composition, these cells can become various types of tissues including soft tissue, bone or cartilage, which make them an excellent resource for repairing and rebuilding damaged tissue, accelerating the healing process and improving overall function.

Thanks to advancements in technology, the removal and harvesting process has become easier and less expensive. Since this is a minimally invasive procedure, it has fewer side effects compared to traditional surgery, and it causes minimal discomfort to the patient.

Bone marrow injections are a breakthrough for patients in pain. Dr. Martini, a sports medicine physician at Cary Orthopaedics, has been active in the sports medicine community, previously serving as team physician for the Carolina Hurricanes, numerous colleges, and local high schools. After 25 years of experience in sports medicine, he realizes the need for improved treatment options for the greying athlete. He has begun incorporating bone marrow aspirate concentrate (BAC) into the treatment of both acute and chronic soft tissue and joint-related injuries. I believe this will be equally helpful to the patient who needs to exercise for overall health benefits as it would be for those who need to stay at their peak athletic performance, says Dr. Martini.

We have found based on our research and experience that stem cell therapy can be very safe and effective when used with the appropriate patient population, said Kevin G. Morrison, PA-C, a member of Dr. Martinis team. All the feedback to this point has been quite positive, both on the process of having the procedure done as well as the early response. But ultimately long-term data will need to be compiled and critically examined.

Much of the previous research into stem cells has centered around placental stem cells, which can also adapt into other types of tissues. However, these have not performed well when put to the test for orthopaedic treatment. Bone marrow aspirate concentrate provides MPCs that can transform into osteocytes, chondrocytes and adipocytes, all of which are important in treating orthopedic conditions.

The latest research around mesenchymal stem cells, specifically bone marrow aspiration, is certainly promising. Dr. Martini will continue to collect more data and review patients responses.

Dr. Mathur has been an instrumental force in elevating the level of patient care at Cary Orthopaedic Spine Center since joining the practice in 2008. Dr. Mathur completed his medical school at the University of Pennsylvania and spinal reconstructive fellowship at the Rush University Medical Center in Chicago. He also taught at Dana Farber Cancer Institute in Boston. Over the last 10 years, in conjunction with the National Institutes of Health, he has conducted significant study of disc degeneration and analysis of the expression of genes that may damage the disc.

In the past decade, there have been several advancements in spinal surgery, but regenerative medicine is the next frontier, said Dr. Mathur. I see so many patients that have low back pain and leg pain from degenerative disc disease. For many, there is no good surgical treatment, and stem cell injections may be a viable option.

As an orthopaedic spine specialist, Dr. Mathur is not only an expert in spinal surgery but also in the diagnosis and treatment of a wide range of spinal problems. His depth of experience allows him to best determine whether a patient would benefit from physical therapy, stem cell injections or surgical intervention. When providing stem cell treatment, Dr. Mathur performs a single injection for all patients, whereas other clinics typically require multiple injections over several weeks.

There is currently extensive, ongoing research on the application of stem cell therapy and tissue regeneration, including an application for spinal cord injury and disc pathology, which is very exciting, said Dr. Shanti, who has dedicated a great deal of time researching the potential impact stem cell therapy can provide for his patients. Dr. Shanti believes stem cell therapy is the next great advancement in healthcare with an application for a wide spectrum of medical conditions.

Recently recognized as Top Orthopaedic Doctor by The Leading Physicians of the World for the outstanding patient care, Dr. Shantis in-depth experience and understanding of the spine allows him to guide his patients especially those with chronic back pain to the most appropriate path of treatment with the shared collaborative goal of pain relief. Dr. Shanti completed his spine surgery fellowship training at the prestigious New England Baptist Hospital, Tufts University program with an emphasis on minimally invasive spine surgery, and he has authored and presented multiple papers and textbooks on the advancement of minimally invasive spine surgery.

Orthopaedic stem cell treatment is an excellent solution for patients with degenerative disc disease and also those suffering from arthritis of the spine, bulging disc, low back pain, facet joint pain or disc with annular tears.

The stem cell injection is a same-day procedure that generally takes one hour to perform. The actual extraction of bone marrow takes up to 10 minutes. The bone marrow extraction site typically the back of the patients hip or pelvis bone is numbed using a mixture of local anesthetics. A suctioned syringe is attached to a long needle that reaches the posterior aspect of the hip. The patient may experience a minimal amount of discomfort during the extraction.

The sample is collected, transferred through a filter, and then placed into a centrifuge for spinning. The speed separates the stem cells and platelets from the bone marrow. This concentration of stem cells is then reintroduced into the degenerative or painful area under image guidance with fluoroscopy to confirm accurate placement.

The harvesting site will be numb for 1 to 2 hours after the procedure, so the patient will need to have transportation home. It is permissible to fly after the treatment, but this may cause increased pain or discomfort.

Stem cell therapy relies on the bodys own regenerative process to heal, which takes time. Patients have seen the benefits in two to three months after treatment; however, many have noticed improvements in symptoms sooner.

The recommended age range for the treatment is 20 to 70 years old. As the body ages, the quality and quantity of stem cells slowly decline. After age 70, patients may experience a sharper decline in stem cells, resulting in less beneficial outcomes.

If you think you might be a candidate for orthopaedic stem cell therapy treatment, contact Cary Orthopaedics to schedule a consultation.

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Become a Donor | The Bone Marrow Foundation

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Jack, diagnosed with Acute Myelogenous Leukemia (AML), and his donor Kristy

To become a donor it just takes a small vial of blood or swab of cheek cells to be typed as a bone marrow/stem cell donor. There are many patients who are desperately waiting to find a donor match. You may be able to save someones life. There are donor registry sites throughout the country.

You must be between the ages of 18 and 60 and in general good health. You should be committed to helping any patient. A simple blood test or cheek cell swab that is given through an authorized National Marrow Donor Program Donor Center or Recruitment Group is needed to obtain your HLA tissue type so it can be entered into the National Registry. You will have to complete a short health questionnaire and sign a form stating that you understand what it means to be listed in the Registry.

The cost for HLA tissue typing ranges from $45 to $96 depending on the Donor Center, the level of testing performed, and the laboratory that analyzes the test results. There may be funding available to offset this cost through the Donor Center. After the initial testing, all medical expenses are covered by the recipient or the recipients insurance. Please contact your local Donor Center for further information.

To find out more information and to become a donor:

Delete Blood Cancer |

The National Marrow Donor Program/Be The

The American Bone Marrow Donor

The Gift of

The Icla da Silva Foundation, Inc.Helping Children and Adults with Leukemia(866)

Every 15 minutes, someone in the United States is diagnosed with a medical condition (over 35,000 people a year) such as leukemia, anemias, myelodysplastic disorders and other life-threatening diseases that require treatment with bone marrow/stem cell transplants. Nearly 70 percent of these patients must rely on an unrelated donor to offer them this precious gift of life. Unfortunately, many patients who are in need of a bone marrow/stem cell transplant cannot find a suitable donor no relatives that match and no match among volunteer donors.

Fortunately, there is an alternative that has been researched and is now proving to be a good option for many of these patientsstem cells from a newborns placental and umbilical cord blood. A newborns umbilical cord and placenta contains stem cells that are the building blocks for mature blood and immune system cells. Umbilical cord blood is collected at the time of birth under controlled conditions, shipped to a blood bank where it is tested, typed and stored.

Two studies published in The New England Journal of Medicine, Volume 351:2276-285 and an editorial by Miguel A. Sanz, M.D., Ph.D. in the same issue, concluded that cord blood should be considered as an acceptable source of stem cells in the absence of a matched bone marrow donor. For many gravely ill patients (who do not have an available donor who is a match), the immediate availability of typed cord blood units is a compelling reason for its use. And for ethnic minorities, who may have unique combinations of HLA types, the chances of finding a donor match with cord blood is greater than from the existing bone marrow donor pool.

If you have a family history of certain diseases you might choose to save your babys cord blood with a private bank. Alternatively, you can donate the cord blood to a public bank. The Bone Marrow Foundation encourages you to direct any questions you have concerning the use and storage of cord blood to your physician or other appropriate health care professional. The following are further resources for more information on public and private banking:

Public Banking National Marrow Donor

National Cord Blood ProgramNew York Blood Center310 East 67th StreetNew York, NY 100211-866- 767-NCBP (6227)

Parents Guide to Cord Blood

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Overview of Spinal Cord Disorders – Brain, Spinal Cord …

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Causes of spinal cord disorders include injuries, infections, a blocked blood supply, and compression by a fractured bone or a tumor.

Typically, muscles are weak or paralyzed, sensation is abnormal or lost, and controlling bladder and bowel function may be difficult.

Doctors base the diagnosis on symptoms and results of a physical examination and imaging tests, such as magnetic resonance imaging.

The condition causing the spinal cord disorder is corrected if possible.

Often, rehabilitation is needed to recover as much function as possible.

The spinal cord is the main pathway of communication between the brain and the rest of the body. It is a long, fragile, tubelike structure that extends downward from the base of the brain. The cord is protected by the back bones (vertebrae) of the spine (spinal column). The vertebrae are separated and cushioned by disks made of cartilage.

The spine (spinal column) contains the spinal cord, which is divided into four sections:

Each section is referred to by a letter (C, T, L, or S).

The vertebrae in each section of the spine are numbered beginning at the top. For example, the first vertebra in the cervical spine is labeled C1, the second in the cervical spine is C2, the second in the thoracic spine is T2, the fourth in the lumbar spine is L4, and so forth. These labels are also used to identify specific locations (called levels) in the spinal cord.

Nerves run from a specific level of the spinal cord to a specific area of the body. By noting where a person has weakness, paralysis, sensory loss, or other loss of function, a neurologist can determine where the spinal cord is damaged.

The spine is divided into four sections, and each section is referred to by a letter.

Within each section of the spine, the vertebrae are numbered beginning at the top. These labels (letter plus a number) are used to indicate locations (levels) in the spinal cord.

Along the length of the spinal cord, 31 pairs of spinal nerves emerge through spaces between the vertebrae. Each spinal nerve runs from a specific vertebra in the spinal cord to a specific area of the body. Based on this fact, the skins surface has been divided into areas called dermatomes. A dermatome is an area of skin whose sensory nerves all come from a single spinal nerve root. Loss of sensation in a particular dermatome enables doctors to locate where the spinal cord is damaged.

The surface of the skin is divided into specific areas, called dermatomes. A dermatome is an area of skin whose sensory nerves all come from a single spinal nerve root. (Sensory nerves carry information about such things as touch, pain, temperature, and vibration from the skin to the spinal cord.)

Spinal roots come in pairsone of each pair on each side of the body. There are 31 pairs:

There are 8 pairs of sensory nerve roots for the 7 cervical vertebrae.

Each of the 12 thoracic, 5 lumbar, and 5 sacral vertebrae has one pair of spinal nerve roots.

In addition, at the end of the spinal cord, there is a pair of coccygeal nerve roots, which supply a small area of the skin around the tailbone (coccyx).

There are dermatomes for each of these nerve roots.

Sensory information from a specific dermatome is carried by sensory nerve fibers to the spinal nerve root of a specific vertebra. For example, sensory information from a strip of skin along the back of the thigh is carried by sensory nerve fibers to the 2nd sacral vertebra (S2) nerve root.

A spinal nerve has two nerve roots (a motor root and a sensory root). The only exception is the first spinal nerve, which has no sensory root.

Motor root: The root in the front (the motor or anterior root) contains nerve fibers that carry impulses (signals) from the spinal cord to muscles to stimulate muscle movement (contraction).

Sensory root: The root in the back (the sensory or posterior root) contains nerve fibers that carry sensory information about touch, position, pain, and temperature from the body to the spinal cord.

The spinal cord ends in the lower back (around L1 or L2), but the lower spinal nerve roots continue, forming a bundle that resembles a horses tail (called the cauda equina).

The spinal cord is highly organized (see figure How the Spine Is Organized). The center of the cord consists of gray matter shaped like a butterfly:

The front "wings" (anterior or motor horns) contain nerve cells that carry signals from the brain or spinal cord through the motor root to muscles.

The back (posterior or sensory) horns contain nerve cells that receive signals about pain, temperature, and other sensory information through the sensory root from nerve cells outside the spinal cord.

The outer part of the spinal cord consists of white matter that contains pathways of nerve fibers (called tracts or columns). Each tract carries a specific type of nerve signal either going to the brain (ascending tracts) or from the brain (descending tracts).

Spinal nerves carry nerve impulses to and from the spinal cord through two nerve roots:

Motor (anterior) root: Located toward the front, this root carries impulses from the spinal cord to muscles to stimulate muscle movement.

Sensory (posterior) root: Located toward the back, this root carries sensory information about touch, position, pain, and temperature from the body to the spinal cord.

In the center of the spinal cord, a butterfly-shaped area of gray matter helps relay impulses to and from spinal nerves. Its "wings" are called horns.

Motor (anterior) horns: These horns contain nerve cells that carry signals from the brain or spinal cord through the motor root to muscles.

Posterior (sensory) horns: These horns contain nerve cells that receive signals about pain, temperature, and other sensory information through the sensory root from nerve cells outside the spinal cord.

Impulses travel up (to the brain) or down (from the brain) the spinal cord through distinct pathways (tracts). Each tract carries a different type of nerve signal either going to or from the brain. The following are examples:

Lateral spinothalamic tract: Signals about pain and temperature, received by the sensory horn, travel through this tract to the brain.

Dorsal columns: Signals about the position of the arms and legs travel through the dorsal columns to the brain.

Corticospinal tracts: Signals to move a muscle travel from the brain through these tracts to the motor horn, which routes them to the muscle.

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