February 22, 2011 by

PRECISE: Adipose-derived stem cells show utility as therapy

Cardiology Today

PRECISE is The Randomized Clinical Trial of Adipose-Derived Stem Cells in Treatment of Non Revascularizable Ischemic Myocardium, a double blind, placebo-controlled trial involving 27 patients with chronic ischemic heart disease with HF, angina or both, who were not eligible for percutaneous or surgical revascularization. The patients in the study underwent a liposuction to remove adipose tissue from their abdomen, the stem cells were separated and then reinjected directly into the heart. Placebo patients received the same treatment however were injected with placebo in place of stem cells. “These patients were not even able to be transplanted. So these were very high-risk, no-option patients,” said Francisco Fernández-Avilés, MD, with the department of cardiology, Hospital General Universitario Gregorio Marañón, Madrid, and PRECISE investigator.

The patients who were treated with stem cells had improved infarct size at 6 months and peak oxygen consumption compared to the placebo patients. “In my opinion, the results of the PRECISE trial are good enough to reconsider the possibility to start a larger scale randomized trial comparing cells to placebo in terms of left ventricular function, mainly clinical outcomes [like] mortality, HF and ischemia,” Fernández-Avilés said. For the years ahead, Fernández-Avilés said in patients with chronic HF and viability, the answer for stem cell therapy is adipose tissue, “and for patients with no viability, in my opinion, we need more basic investigation to find more effective cells.”

Filed Under: Adult Stem Cells, Heart Disease, News, Stem Cell Research, Stem Cell Therapy Tagged With: , , , , , ,
February 18, 2011 by

UCL Scientists Develop Magnetic Nanoparticles to Track Neural Stem Cells

Azo Nanotechnology

Neural stem cells have recently been shown to possess qualities that make them promising candidates for stem cell replacement therapy and spinal cord reconstruction. Researchers at University College London have recently discovered magnetic nanoparticles that could be used to track neural stem cells following their injection. This would allow for the stem cells to be followed throughout the treatment and repair process. Nguyen TK Thanh of the Davy Faraday Research Laboratory, UCL Physics and Astronoly and the Royal Institution believes that the hollow biocompatible cobalt-platinum nanoparticles that have been attached to stem cells will be a very efficient way of monitoring the progress of the cells.

Magnetic Resonance Imaging (MRI) parameters were designed in order to optimize the conditions of monitoring. After establishing these parameters, the nanoparticles were transplanted into organotypic spinal cord slices, and the efficacies of the parameters of MRI were confirmed. ‘The new method demonstrates the feasibility of reliable, noninvasive MRI imaging of nanoparticle-labelled cells,’ says Thanh.

‘Magnetic nanoparticles are emerging as novel contrast and tracking agents in medical imaging,’ says Samir Pal at the California Institute of Technology, US, an expert in biological-nanoparticle interactions. ‘When used as a contrast agent for MRI, the nanoparticles allow researchers and clinicians to enhance the tissue contrast of an area of interest by increasing the relaxation rate of water.’

Thanh is hopeful that these nanoparticles will contribute to stem cell replacement therapy for many central nervous system diseases. She is also working towards developing nanoparticles that can be used to diagnose and treat these diseases.

Filed Under: News, Stem Cell Research Tagged With: , , , , ,
February 17, 2011 by

World’s First Chemical Guided Missile Could Be the Answer to Wiping out Cancer

A research team at Deakin University has made a discovery that could have huge implications on the treatment and survival rates of cancer victims. The researchers, along with scientists in India and Australia have created the world’s first RNA aptamer, a chemical antibody that targets cancer stem cell marker epithelial cell adhesion molecule (EpCAM). This marker is overexpressed in cancer cells, thus allowing the RNA aptamer to bind directly to the cell before being internalized. The implications of this are that the aptamer has the potential ability to deliver drugs directly to the cancer stem cells and can also be used to develop a more effective cancer imaging system for early detection of the disease.

“Despite technological and medical advances, the survival rates for many cancers remain poor, due partly to the inability to detect cancer early and then provide targeted treatment,” said Professor Wei Duan, the Director of the Deakin Medical School’s Nanomedicine Program. “Current cancer treatments destroy the cells that form the bulk of the tumour, but are largely ineffective against the root of the cancer, the cancer stem cells. This suggests that in order to provide a cure for cancer we must accurately detect and eliminate the cancer stem cells.”

The aptamer is the first part of the ‘medical smart bomb’ the researchers have been developing. “What we have created is the ‘guided missile’ part of the ‘smart bomb’,” Professor Duan explained. “The aptamer acts like a guided missile, targeting the tumour and binding to the root of the cancer. “The aim now is to combine the aptamer with the ‘bomb’ (a microscopic fat particle) that can carry anti-cancer drugs or diagnostic imaging agents directly to the cancer stem cells, creating the ultimate medical smart bomb.”

“The cancer stem cell-targeting missile and the smart bomb could revolutionise the way cancer is diagnosed,” he explained. “The minute size of the aptamer means it could locate cancer cells in their very early stages. Attaching radioactive compounds to the aptamer could lead to the development of sensitive diagnostic scans for earlier detection, more accurate pinpointing of the location of cancer, better prediction of the chance of cure and improved monitoring of the response to treatment. More accurate identification of the type of cancer present would lead to more personalised treatment that is more successful and cost-effective. This could ultimately lead to better cancer survival rates and greatly improved quality of life for patients.”

Filed Under: News, Stem Cell Research Tagged With: , , , , , , ,
February 2, 2011 by

Injured Liver Calls in Bone Marrow For Help?

Li et al. Cells Tissues Organs

It is known that administration of bone marrow cells into patients with liver failure has the ability to improve enzyme function and overall health http://www.youtube.com/watch?v=DdH6Mm4w98I. Additionally, numerous animal models have demonstrated that injection of various types of stem cells can result in regeneration of injured liver tissue. For example, Manuelpillai et al demonstrated that injection of human mesenchymal stem cells derived from the amnionic membrane into immune competent mice whose livers were damaged by carbon tetrachloride results in reduction in liver injury http://www.ncbi.nlm.nih.gov/pubmed/20447339. Even more interesting, administration of compounds that “instruct” bone marrow cells to enter circulation such as G-CSF, have been demonstrated to improve liver function and actually prevent mortality after liver injury http://www.ncbi.nlm.nih.gov/pubmed/20881764. This is relevant because G-CSF is a medication that is FDA approved and possesses a favorable safety profile.

One of the main scientific questions in the area of liver failure is whether the liver is actually “calling in” bone marrow stem cells to try to heal it after liver damage, or whether the therapeutic effects of stem cells in liver failure are an epiphenomena. In situations of cardiac damage after an acute myocardial infarction it has been demonstrated that the injured tissue causes upregulation of the protein SDF-1, which recruits bone marrow stem cells into the heart in order to promote healing. Whether similar mechanisms are at play in liver injury is not known. Part of the puzzle has to do with the fact that liver injury is a more chronic process than heart attacks and therefore recruitment of stem cells may be occurring at a much lower level. Alternatively, it is also known that chronic inflammatory processes actually suppress stem cell activity. So it may be that in chronic liver failure the stem cells are actually inhibited from possessing regenerative function.

This question was addressed in a recent study in which the gene expression profile of bone marrow cells was examined in animals with liver failure induced by administration of the hepatotoxin D-galactosamine to rats. To assess gene expression the Affymetrix GeneChip Rat Genome 230 2.0 Array was used, which quantifies gene expression of every gene in the rat genome. The scientists found that more than 87.7% of the genes/probe sets that were upregulated more than 2-fold in the bone marrow cells of rats with liver failure were also expressed by the liver cells, including 12 genes involved in liver development, early hepatocyte differentiation and hepatocyte metabolism. The concurrent upregulation of these genes was verified by the technique of reverse transcriptase polymerase chain reaction (RT-PCR).

The scientists also found that 940 genes were expressed in both the bone marrow cells of rats with liver failure and the hepatocytes of rats with liver failure but not in control cells. Specifically, many of the genes that were uprgulated in both the bone marrow and the liver seemed to be involved in regeneration of damaged tissue.

These data support the concept that the bone marrow stem cells can respond in similar ways to liver cells to injury. The hypothesis has been proposed by the authors that the bone marrow acts as a reservoir for the stem cells that are capable of regenerating liver. The mass amount of data in this publication is very interesting and requires detailed analysis to make sense of.

Filed Under: Adult Stem Cells, Liver, News, Stem Cell Research Tagged With: , , , ,
February 1, 2011 by

Scientists look to stem cells to mend broken hearts

Cardiac medicine has traditionally been associated with innovative procedures that sometimes where considered heretical to the present day dogma. For example, the first heart transplant, the use of the balloon catheter, the introduction of thrombolytics, all met substantial resistance from the “establishment” in their time. It appears that the next revolution in cardiac medicine is the use of stem cells. Aside from the obvious ethical and moral dilemmas surrounding embryonic tissues, the major controversy has been the belief that heart tissue does not repair itself after it has been lost. However, slowly but surely it appears that support behind the use of stem cells for heart conditions is gaining momentum.

One sign of this is the recent announcement that Britain’s leading heart charity, the British Heart Foundation (BHF), launched a 50 million pound ($80 million) research project into the potential of stem cells to regenerate heart tissue and “mend broken hearts”.

“Scientifically, mending human hearts is an achievable goal and we really could make recovering from a heart attack as simple as getting over a broken leg,” said Professor Peter Weissberg, medical director at the BHF.

One example of research in this area being performed in England is the work of Professor Paul Riley of the Institute of Child Health at University College London (UCL) who has identified a natural protein, called thymosin beta 4, that plays a role in developing heart tissue. He said his researchers had already had some success in using this protein to “wake up” cells known as epicardial cells in mice with damaged hearts. “We hope to find similar molecules or drug-like compounds that might be able to stimulate these cells further,” he told reporters at the briefing.

Currently the most advanced type of stem cell therapy for the heart involves administration of the patient’s own bone marrow cells into the area of heart damage after a heart attack. This work, which was performed in England and internationally, seems to suggest that cardiac muscle may be preserved when cells from the bone marrow produce various growth factors that stimulate stem cells that are already existing in the heart.

Other methods of administering stem cells into the heart include direct injection into the heart muscle during bypass surgery. This is performed experimentally in patients with severe angina on the hope that the injected stem cells will provide support for formation of new blood vessels, called collaterals, which are anticipated to increase the blood flow to the heart and thereby reduce angina.

Currently embryonic or fetal derived stem cells have not been used for treatment of heart conditions in humans. Therefore, at least for now, ethical issues do not seem to be a major obstacle to advancement of stem cell medicine for hearts.

Filed Under: Adult Stem Cells, Bone Marrow, Heart Disease, News, Stem Cell Research Tagged With: , , , , ,
January 31, 2011 by

Nine Patients with Crohn’s Disease Treated by Intravenous Administration of Mesenchymal Stem Cells

Marjolijn et al. Gut 59:1662

Mesenchymal stem cells are known to be suppressive to immune cells such as T cells, dendritic cells, and natural killer cells. Studies have demonstrated that patients suffering from the immune disease graft versus host enter remission after administration of donor or third party mesenchymal stem cells. One of the manifestations of graft versus host disease is inflammation of the colon, resembling autoimmune colitis and Crohn’s disease.

Some of the previous studies investigating this condition have demonstrated therapeutic effects of mesenchymal stem cells on colonic inflammation. Given this rationale, a recent paper examined the effects of autologous mesenchymal stem cells in the treatment of Crohn’s disease refractory to steroids, immune suppressants, and biologics.

50-100 ml of bone marrow cells were isolated from family members or third-party donors and expanded in vitro. Cells where grown to administer two doses, a week a part, of 1-2 x 10(6) cells per kg body weight. Patients were treated by intravenous administration and followed up for 6 months.

MSC infusion was without side effects, besides a mild allergic reaction probably due to the cryopreservant DMSO in one patient. Baseline median CDAI was 326 (224-378). Three patients showed clinical response (CDAI decrease ≥70 from baseline) 6 weeks post-treatment. Additionally, 3 other patient required surgery, presumably as a result of disease progression.

These data demonstrate that intravenous administration of bone marrow mesenchymal stem cells appears to be safe for treatment of Crohn’s disease, however larger studies are necessary to determine whether statistically significant efficacy exists.

Filed Under: Crohn's Disease, News, Stem Cell Research Tagged With: , , , , ,
January 4, 2011 by

Male-Pattern Baldness Found Rooted in Stem Cells

Amanda Chan, MyHealthNewsDaily Staff Writer

A new discovery regarding the presence of stem cells in males with androgenetic alopecia (male-pattern baldness) has led to hope that the disease may be treatable. It was previously believed that people who suffered from baldness also had a depleted number of hair follicle stem cells, meaning that new hair growth would not be possible. However, this new discovery has shown that the number of stem cells present in bald areas and non-bald areas is equal; the difference is a depleted number of hair follicle progenitor cells.

The implication for this discovery are if scientists are able to coax the present stem cells into developing into hair follicle progenitor cells, they would be able to regrow hair. The only FDA approved baldness treatments; Rogaine and Propecia do not have the ability to regrow cells. Propecia works by inhibiting testosterone’s effect on hair follicles, disrupting its ability to decrease the size of hair follicles.

http://www.livescience.com/health/male-pattern-baldness-stem-cells-110104.html

Filed Under: Adult Stem Cells, News, Stem Cell Research Tagged With: , , , , ,
January 1, 2011 by

Study Shows Patient’s Own Stem Cells Help Stroke Recovery: 16 Treated Patients Improve in Comparison to 36 Controls

Lee et al Stem Cells 28:1099
Stroke is caused by blocked circulation to parts of the brain usually as a result of a blood clot. Outcomes of stroke are generally proportional to the length of time the circulation was blocked and to the amount of brain tissue injury and death. Although the introduction of “clot busters” has improved outcomes in these patients, substantially morbidity and mortality still occurs. Numerous pharmaceutical approaches have been attempted in the treatment of stroke, both from the perspective of inhibiting tissue damage, and more recently trying to stimulate regeneration of injured brain tissue. To date clinical progress in this area has been relatively insignificant. In fact, in the pharmaceutical industry the condition of stroke has been referred to as a “graveyard for biotechs”.
One potentially promising treatment for stroke would be to augment the body’s own repair processes through activation of stem cells that are either pre-existing in the body, or through administration of stem cells either directly into the damaged brain tissue or areas associated with the damaged brain tissue. Rationale for this includes observations that stem cells from the bone marrow called endothelial progenitor cells are known to enter circulation in patients with stroke. A study from Dunac et al in France demonstrated that patients who have a higher degree of stem cells in circulation after a stroke have a better neurological outcome in comparison to patients who have lower numbers of circulating stem cells. In rats which are given a stroke experimental by ligation of one of the arteries that feeds the brain, called the middle cerebral artery, administration of human or rat stem cells reduces the size of brain damage, as well as causes regeneration of new neurons. Additionally, animal studies have demonstrated that administration of stem cells causes improved behavior as compared to animals receiving control cells or saline.
One reason why there exists a belief in the field that bone marrow derived cells may be capable of generating new neurons is that in female recipients of bone marrow transplant nerve cells have been found that express the Y-chromosome (Weimann et al. Contribution of transplanted bone marrow cells to purkinje neurons in human adult brains Proc Natl Acad Sci USA 100:2088).
In a recent paper (Lee et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28:1099) a group from Korea reported what to date is the largest clinical trial of stem cells in stroke. The investigators used mesenchymal stem cells generated from the bone marrow of the stroke patients. These cells are believed to be capable of generating new neurons, as well as producing growth factors that stimulate the brain to heal itself. Mesenchymal stem cells are currently used in clinical trials in the US and internationally for treatment of graft versus host disease, heart failure, and critical limb ischemia (an advanced form of peripheral artery disease that causes 100-200,000 amputations per year). Advantages of mesenchymal stem cells include: a) ability to be expanded in tissue culture; b) Well-known safety profile; and c) Ability to use between individuals without need for matching.
In the study discussed, the investigators selected 52 patients with a defined type of stroke (non-lacunar infarction within the middle cerebral artery territory). Patients were selected 7 days after the stroke in order to have a standardized level of dysfunction. It was previously published that before 7 days the patient may have a sudden increase or decrease in neurological function, but after 7 days post-stroke the neurological function remains stable.
The investigators extracted 5 ml of bone marrow from 16 patients and expanded the mesenchymal stem cells over a 4 week period. The mesenchymal stem cells were defined as cells expressing the markers CD105 (SH-2) and SH-4. Cells were grown as adherent cells in media containing fetal calf serum. The 16 patients received two administrations of 50 million cells intravenously spread apart by a week.
Patients were followed for an average of 117 weeks, with some patients followed as long as 5-years after the stroke. There was a statistically significant difference in overall survival in the patients that received the mesenchymal stem cells as compared to controls. Specifically, 4 of the 16 patients who received the mesenchymal stem cells passed away during the follow-up period as compared to 21 of the 36 control patients.
In studies of embryonic or fetal stem cells, one of the major concerns is development of tumors. This stems from the fact that administration of embryonic stem cells into immune deficient animals causes tumors called teratomas, and in humans there is at least one documented case of a brain tumor developing in a patient who received fetal derived stem cells. Of the patients administered mesenchymal stem cells, no tumors were detected. This is important because this study has one of the longest follow up periods.
Functional improvements as quantified by the modified Rankin Score were noted in patients receiving stem cells, whereas controls overall suffered a decline in function. Specifically, function was assessed at a median of 3.5 years in the control group and 3.2 years in the mesenchymal stem cell treated group. Function was assessed by doctors where were “blinded” to which patient received stem cells and which patient was in the control group. In the control group 13 of 26 patients had a negative rank, which indicates an improved functional outcome for each patient, whereas 21 patients had a positive rank, which means worse outcome. In contrast, in the treatment group 11 of the 16 patients had a negative rank. The difference between groups reached statistical significance.
In 9 patients of the group that received stem cells, a correlation was studied between the cytokine SDF-1 and functional outcome. Functional outcome was determined both by the modified Rankin score as well as by the Barthel index. A positive correlation was found between levels of SDF-1 at the time of MSC treatment and functional outcome in the patients studied. This protein is known to be involved in recruiting stem cells to the site of injury. Given that in this study the stem cells were administered intravenously and not locally (eg by sterotactic injection), it would be logical that a correlation exist between chemotactic signaling and improved outcome. Currently there are companies such as Juvantis, that are administering plasmids expressing SDF-1 in order to induce homing of endogenous stem cells into cardiac infarcts. It is interesting that the same priniciple may be valid in situations of ischemic stroke. To date no studies have been performed clinically using co-administration of stem cells and SDF-1, however, myoblasts transfected with SDF-1 have been used in a clinical trial in Jordan by the company BioHeart for treatment of heart failure.
One other interesting finding of the study besides lack of ectopic tissue or tumor formation is that no adverse effects were associated with using stem cells grown in fetal calf serum. There has been concern in the literature, particularly the academic literature, that fetal calf serum may induce autoimmunity or sensitization upon second MSC administration. This did not appear to be the case.

Filed Under: Adult Stem Cells, Bone Marrow, News, Stem Cell Research, Stroke Tagged With: , , , , ,
December 31, 2010 by

Differences between Stem Cells from the Placenta and Bone Marrow

Fazekasova et al. Mesenchymal stem cells were historically isolated from the bone marrow as an adherent stem cell population capable of “orthodox” differentiation, meaning that they have ability to become bone, cartilage, and fat. Further research revealed that these cells are also capable of “non-orthodox” differentiation, that is, becoming neurons, hepatocytes, insulin producing cells, and lung cells. Given the high number of growth factors secreted by mesenchymal stem cells, numerous companies have sought to develop therapeutic products from mesenchymal stem cells. For example, Osiris Therapeutics has been developing bone marrow mesenchymal stem cells as a treatment for Graft Versus Host Disease. Athersys has been using bone marrow derived mesenchymal-like cells for treatment of heart disease, and Mesoblast has been using these cells for treatment of bone injury.

A new generation of companies has been focusing other mesenchymal-like cells derived from other tissues. For example, Medistem Inc has identified endometrial regenerative cells (ERC), a type of mesenchymal-like stem cell that is found in the endometrium and appears to have higher ability to produce growth factors that stimulate new blood vessel production as compared to other sources of mesenchymal stem cells. General Biotechnology LLC has been developing tooth derived mesenchymal stem cells for treatment of neurological disorders. Celgene has been using placental-derived mesenchymal stem cells for treatment of critical limb ischemia, a disorder associated with poor circulation of the legs.

Given that there appear to be various sources of mesenchymal stem cells, an important question is how do these cells compare when they are used in experiments side by side. In a paper published this month, placental derived and bone marrow derived mesenchymal stem cells were compared. The scientists found that higher numbers of mesenchymal stem cells could be isolated from the placenta as compared to the bone marrow. Interestingly, placental mesenchymal stem cells were found to be comprised of both fetal and maternal origin.

One of the critical features of mesenchymal stem cells is that they are able to be used without need for matching with the recipient. This is because mesenchymal stem cells are historically known to be “immune privileged”. One of the experiments that the scientists did was to examine whether there is a difference between the bone marrow and placentally derived mesenchymal stem cells in terms of immunogenicity.

Placentally derived mesenchymal stem cells expressed lower levels of the immune stimulatory molecule HLA class I and higher levels of the immune suppressive molecules PDL-1 and CD1a, compared to bone marrow derived mesenchymal stem cells. However, when both cell types were treated with interferon gamma, the placentally derived mesenchymal became much more immune stimulatory as compared to the bone marrow cells. Furthermore it appeared that direct incubation with T cells resulted in higher T cell stimulation with the placental mesenchymal stem cells as compared to the bone marrow cells. Thus from these data it appears that bone marrow derived mesenchymal stem cells are more immune privileged as compare to placental derived cells.

Filed Under: Adult Stem Cells, Bone Marrow, Endometrial Stem Cells, News, Stem Cell Research Tagged With: , , , , , ,
December 30, 2010 by

Men with Type 1 diabetes eventually may have a way to grow their own pancreas transplants

Thomas H. Maugh II, Los Angeles Times

Researchers from Georgetown University Medical Center in Washington DC reported today at the Annual Meeting of the American Society of Cell Biology that sperm contains stem cells capable of becoming beta cells. The beta cells are the insulin producing cells of the pancreas which are damaged/destroyed in patients with Type 1 diabetes.

Conventionally adult stem cells are found in the bone marrow, fat tissue, and cord blood. Recent studies have identified stem cells in places such as menstrual blood (endometrial regenerative cells), hair follicles, and baby teeth. The finding that stem cells from sperm are capable of generating insulin-producing cells has several major implications. For one, males could theoretically bank their own stem cells and use them in the future. Currently transplants with beta cells or pancreatic transplants have the drawback that there are not enough donors and also that the recipient is required to receive life-long immune suppression.

The lead scientist of the finding is biochemist G. Ian Gallicano of Georgetown and his colleagues obtained tissue from human testes from recently deceased donors and placed them in a special growth medium in the laboratory, where they began producing insulin. “These are true pluripotent stem cells,” he said in a statement. When transplanted into the backs of immune-deficient mice, the cells cured diabetes for about a week before dying. More recent results, Gallicano said, show that the researchers are able to produce more insulin-producing cells and keep them alive longer. The challenge, he noted, is to make them survive for very long periods of time in the recipient.

Dr. Gallicano and his team previous published in the peer reviewed journal Stem Cells and Development (Golestaneh et al. Pluripotent stem cells derived from adult human testes Stem Cells Dev. 2009 Oct;18(8):1115-26) that the testes contains spermatogonial stem cells (SSCs) which are capable of converting to embryonic stem (ES)-like cells which can differentiate into all three germ layers and organ lineages.

The importance of the current research is that these stem cells can actually exhibit function when administered to animals. It will be interesting to see if other organ functions may be restored by use of these stem cells.

Filed Under: Diabetes, News, Stem Cell Research Tagged With: , , , ,
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