August 27, 2010 by

A Fall for Stem Cells Injunction Halting Stem Cell Research Funds May Have Far-Reaching Consequences

(STEPHEN BROZAK and LARRY JINDRA, M.D. ABC News) There is some anticipation that this fall will be an important season for the debate on embryonic stem cell research. On Aug 30, 2010 a Washington, DC district judge (Lamberth), issued a temporary injunction halting all federal funding for basic research into embryonic stem cell technology. The injunction states there is a legitimate basis for arguing the matter in court. A full hearing will soon decide the final outcome. If the decision is upheld, federal funding for embryonic stem cell research will cease, in a similar manner to the previous funding moratorium on this research during the Bush administration.

According to this article, Judge Lamberth’s decision “reflects the lack of awareness in the U.S. around research and development of embryonic stem cells”. This statement was made because subsequent to the ruling, the price of numerous stem cell company stocks fell, including of companies working in the area of adult stem cells. These companies in no way should be affected by the controversy surrounding embryonic stem cells.

The article highlights the important difference between these two stem cell types. Embryonic stem cells are generated from a fertilized egg in vitro. These stem cells are highly undifferentiated and form tumors when administered into immune deficient mice called teratomas. The other type of stem cells, adult stem cells, are derived from sources such as bone marrow, menstrual blood, cord blood, placenta, and fat. These cells do not generated tumors and have been used therapeutically in the treatment of many diseases. To date, the only use of embryonic stem cells in humans has been by the company Geron that is generating oligodendrocytes from embryonic stem cells for use in the treatment of patients with spinal cord injury.

Geron has spend years trying to attain FDA approval for its approach. A temporary approval was granted under the Obama administration which was rapidly rescinded. Subsequently the trial was allowed to continue, however no data has been reported at the time of writing.

Adult stem cell companies include Osiris, who are working on bone marrow derived mesenchymal stem cells for treatment of heart failure, graft versus host disease, and Crohn’s Disease, Pluristem, who are working on placental mesenchymal stem cells for treatment of critical limb ischemia, and Medistem Inc, who are using menstrual blood derived Endometrial Regenerative Cells (ERC) for treatment of the same condition.

The authors of the article are Stephen Brozak, president of WBB Securities, an independent broker-dealer and investment bank specializing in biotechnology, medical devices and pharmaceutical research and Dr. Lawrence Jindra who is director of research for WBB Securities.

Filed Under: Embryonic Stem Cells, News, Stem Cell Research Tagged With: , , , ,
August 27, 2010 by

Immunomodulation of Delayed-Type Hypersensitivity Responses by Mesenchymal Stem Cells Is Associated with Bystander T Cell Apoptosis in the Draining Lymph Node.

(Lim et al. J Immunol) Immune responses are quantified in many ways. Typically one thinks about immunity as the ability of an organism to overcome infection with another organism. However this test is impossible to perform in a reproducible, quantitative, and ethical way in humans. An alternative test was developed by immunologists called delayed type hypersensitivity (DTH) reaction. In this assay the patient is immunized with an antigen and subsequently the antigen is painted on the skin. The T cells that recognize the antigen then home to the skin, activate macrophages, which in term produce a swelling reaction that can be visualized easily.

Mesenchymal stem cells (MSC) have been described to be immune modulatory, however to our knowledge this is the first publication in which effects of MSC on DTH were examined.

In this paper the authors reported that subsequent to induction of a DTH response in which MSC were administered to the host, a small but significant number of MSCs accumulate in the secondary lymphoid organs and attenuate delayed-type hypersensitivity (DTH) response by inducing apoptotic cell death of surrounding immune cells in the draining lymph node (LN).

In order to visualize killing of immune system cells by the administered MSC, the scientists administered fluorescently-labeled MSC intravenously in mice after initiation of DTH. They observed that MSC preferentially accumulated at the boundary between the paracortical area and the germinal center in the lymph nodes, in close proximity to various types of immune cells including T, B, and dendritic cells in a dose-dependent manner.

It was reported that accumulated MSCs markedly attenuated DTH response in proportion to the number of MSCs infused. During the DTH response, the infiltration of T cells in the challenged site was significantly decreased, whereas a number of apoptotic T cells were remarkably increased in the draining lymph node.

Killing of immune cells seemed to be restricted to activated T cells since apoptosis was observed only in the BrdU stained (proliferating) cells. Additionally it appeared that T cell death was mediated by MSC secretion of nitric oxide.

Filed Under: Adult Stem Cells, News, Stem Cell Research Tagged With: , , , ,
August 27, 2010 by

Platelet-Rich Plasma Releasate Promotes Differentiation of Tendon Stem Cells Into Active Tenocytes.

(Zhang et al. Am J Sports Med. ) Platelet rich plasma (PRP) contains products of activated platelets which include numerous growth factors such as fibroblast growth factor, hepatocyte growth factor, insulin like growth factor, etc. Conventionally, PRP is used to promote various healing processes. In the area of sports medicine PRP has been used for the treatment of cartilage injuries and to accelerate their repair.

Given that numerous repair processes have been associated with stem cells, in the current study researchers sought to determine whether PRP may yield an effect on stem cell populations found in the joint called tendon stem cells (TSC).

The scientists found that treatment of TSC with PRP led to the cells taking on a large, well spread, and highly elongated shape. Furthermore, treatment with PRP results in a decrease of nucleostemin expression, which is associated with TSC activation. Treatment with PRP also enhanced TSC proliferation, tenocyte-related gene and protein expression, and total collagen production, all of which indicated that PRCR treatment induced differentiation of TSCs into activated tenocytes.

The possibility that PRP stimulates TSC may be examined in vivo in future experiments. For example, it would be interesting to see which of the many growth factors actually is responsible for the high proliferative response of the TSC.

One other area of interest is whether PRP may be used in absence of tissue culture media for stem cell expansion. Currently one of the major limiting factors in the area of cell therapeutics has been the lack of appropriate supply of fetal calf serum for en masse cell manufacturing. If the growth factors released by PRP are strong enough to stimulate cell proliferation in vitro, then this may be a solution to a big hurdle.

Filed Under: Adult Stem Cells, News, Stem Cell Research Tagged With: , , , ,
August 2, 2010 by

Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study.

Liang et al. Ann Rheum Dis. 2010 Aug;69(8):1423-9.

Mesenchymal stem cells are unique in that on the one hand they are capable of differentiating into a variety of tissues, but on the other hand they also are potently anti-inflammatory and immune modulatory.

Evidence of immune modulation comes from studies that show mesenchymal stem cells: a) directly suppress ongoing mixed lymphocyte reaction; b) produce immune suppressive cytokines such as IL-10; c) produce immune suppressive enzymes such as indolamine 2,3 deoxygenase; d) inhibit natural killer and CD8 cytotoxic T cell activity; e) inhibit dendritic cell maturation; and f) stimulate production of T regulatory cells.

Animal studies covered on our youtube channel www.youtube.com/cellmedicine have shown that mesenchymal stem cells inhibit collagen induced arthritis and experimental allergic encephalomyelitis, which represent human rheumatoid arthritis and multiple sclerosis, respectively.

Since these cells are such potent immune modulators, they have been used with some success in the treatment of immunological diseases such as graft versus host disease (GVHD). Medistem and Cellmedicine have previously used fat derived stem cells, which contain high concentrations of mesenchymal stem cells, in order to treat rheumatoid arthritis. In the current paper mesenchymal stem cells from the bone marrow where used to treat the autoimmune disease systemic lupus erythematosus.

Scientists at the Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, in Nanjing, China, reported a clinical trial of allogeneic (universal donor) mesenchymal stem cells in the treatment of patients with treatment-refractory systemic lupus erythematosus (SLE).

Fifteen patients with SLE who did not respond to conventional treatments where administered bone marrow derived mesenchymal stem cells isolated from allogeneic donors. No chemotherapy or immune suppression was used. Administration of stem cells was performed intravenously.

Mean patient follow up was 17.2+/-9.5 months with 13 patients have been followed for more than 12 months. 15/15 patients presented with clinical improvements subsequent to stem cell therapy. At 12-month follow-up, SLEDAI scores dropped from 12.2+/-3.3 to 3.2+/-2.8 and proteinuria decreased from 2505.0+/-1323.9 to 858.0+/-800.7 mg/24 h. At 1-year follow-up in 13 patients, 2 had a relapse of proteinuria, while the other 11 continue to have decreased disease activity on minimal treatment. Anti-dsDNA levels decreased. Improvement in glomerular filtration rate was noted in two patients in which formal testing was performed. Non-renal-related manifestations also improved significantly. No serious adverse events were reported.

This study demonstrated that mesenchymal stem cells are capable of not only inhibiting the pathological processes in SLE (eg production of anti-dsDNA antibodies) but also reversing renal damage that has occurred as a result of the disease process. The fact that some of the patients relapsed may mean that there is a rationale for multiple administration of mesenchymal stem cells.

Filed Under: Adult Stem Cells, Lupus, News, Stem Cell Research Tagged With: , , , , ,
August 1, 2010 by

Pluripotent stem cell-derived natural killer cells for cancer therapy.

Knorr et al. Transl Res. 2010 Sep;156(3):147-154. Epub

Immune therapy of cancer is an exciting prospect given the possibility of treating cancer without the side effects associated with conventional treatments such as chemotherapy or radiotherapy. Additionally, the use of the immune system to target tumors offers the possibility of eradicating micrometastasis, which often cannot be treated by conventional means.

Early work in the immunotherapy of cancer involved taking out patient lymphocytes that were infiltrating the tumor, expanding them outside of the body, and subsequently re-injecting them with the hope that expanded numbers of tumor-specific killer cells would destroy the tumor. Unfortunately this approach was very expensive and did not yield positive results to justify the complexity and expense of the procedure. One possible reason for the failure of this approach is that the cells used where already “old” and “exhausted”. In other words, previous encounters of the T cells with cancer antigens seems to have programmed them so as to inhibit ability to mount a proper immune response.

The use of natural killer cells as an alternative to T cells was considered. These cells, called lymphokine activated killers (LAK) displayed specific ability to kill tumors and were more effective than T cells alone. Unfortunately this approach too also required substantial manipulation of the cells outside of the body and was not practical.

In a recent paper, the group of Knorr et al discussed how to use stem cells to solve the problem of generating anti-cancer immune cells out of the body. They discuss how they have successfully used embryonic stem cells to generate “universal donor” natural killer cells. This approach is highly promising since NK cells do not need to be matched with the recipient in order to mediate anti-cancer activity. Additionally, since the cells are generated “brand new” in the laboratory, the problem of “exhaustion” is no longer relevant. Unfortunately there are still several obstacles to overcome such as the potential of embryonic stem cells forming leukemias/tumors, and the possibility of host anti-graft responses.

The paper also describes the future possibility of using inducible pluripotent stem (iPS) cells as a method of generating autologous T cells with any given TCR specificity.

Filed Under: Cancer, News, Stem Cell Research Tagged With: , , ,
July 31, 2010 by

Stem Cells for Spinal Cord Injury

The use of mesenchymal stem cells for a variety have
diseases has been published. This includes conditions such as heart failure,
liver failure, stroke, and lupus. One of the attractive features of mesenchymal
stem cells is that they can differentiate into numerous tissues while at the
same time exerting anti-inflammatory activities.

In the situation of spinal cord injury, mesenchymal stem
cells are thought to produce various growth factors that contribute to
regeneration of the damaged nerve. In the paper by Park et al the question was
asked whether Schwann Cells that are differentiated from mesenchymal stem cells
may be a more potent source of therapeutic growth factors. This question was
raised in part because the natural function of Schwann Cells is to produce
factors that accelerate new neuron formation.

The researchers used a growth factor-based differentiation
media to induce the transformation of mesenchymal stem cells into cells that
resemble Schwann Cells. The resulting cells developed a morphology similar to
Schwann Cells and expressed proteins that are specific to this cell type such as
the p75 neurotrophin receptor.

It was found that the Schwann Cells generated from the
mesenchymal stem cells expressed higher amounts of the growth factors hepatocyte
growth factor (HGF) and vascular endothelial growth factor (VEGF) when compared
with non transformed mesenchymal stem cells. When the newly generated cells
were cultured with a neuronal cell line called Neuro2A, a large increase in the
proliferation of the cell line was noted with a decrease in spontaneous cell
death. Transplantation of the artificially generated Schwann Cells into an ex
vivo model of spinal cord injury dramatically enhanced axonal outgrowth. This
was blocked by antibodies to HGF and VEGF.

The authors propose that artificially generated Schwann
Cells without genetic modification are useful for autologous cell therapy to
treat nervous system injury.

One
important question that was not addressed is to what extent are the Schwann
Cells generated from mesenchymal stem cells seen by the immune system. In other
words, is it possible to use Schwann Cells in a universal donor fashion the same
way that mesenchymal stem cells can be used.

Filed Under: Adult Stem Cells, News, Spinal Cord Injury, Stem Cell Research Tagged With: , , , ,
July 29, 2010 by

Protein Found on Endometrial Regenerative Cells Inhibits Immune Attack

Medistem Inc. (PINKSHEETS: MEDS) announced today publication of a peer reviewed paper identifying a molecule found on the company’s lead product, the universal donor Endometrial Regenerative Cell (ERC), as a key component of cellular escape from immune attack. The study, entitled “Resistance of neonatal porcine Sertoli cells to human xenoantibody and complement-mediated lysis is associated with low expression of alpha-Gal and high production of clusterin and CD59” was published in the journal Xenotransplantation as a collaboration between Medistem and the Institute of Organ Transplantation, Tongji Hospital, in Wuhan, China.

The study found that CD59, a molecule made by ERC, plays an important role in protecting cells from immune rejection when placed in contact with immune components from another species. The ERC is a mesenchymal-like stem cell that Medistem discovered in 2007 capable of generating heart, lung, brain, muscle, blood vessel, pancreas, liver, fat and bone tissue. The original description of this cell, which won the “Publication of the Year Award” may be found at http://www.translational-medicine.com/content/pdf/1479-5876-5-57.pdf.

“One of the fundamental aspects of Medistem’s lead product, the Endometrial Regenerative Cell (ERC), is its ability to function without the need for tissue matching. In other words, the ERC stem cells act as universal donors. We have previously published that human ERC are effective in treating mice having a condition that resembles critical limb ischemia (see paper http://www.translational-medicine.com/content/pdf/1479-5876-6-45.pdf ). We now believe that expression of the molecule CD59 on ERC may be one of the mechanisms by which these human cells can be used not only as a universal donor for humans, but also for the treatment of numerous diseases across a variety of animal species.” Said Thomas Ichim, CEO of Medistem.

Medistem has filed an IND with the FDA for treatment of critical limb ischemia (severe obstruction of the arteries that leads to decreased blood flow to the extremities) with ERC. Currently the company is in the process of completing additional experiments requested by the FDA before clinical trials can commence. Through physician-initiated compassionate use mechanisms Medistem has already published on human use of ERC in treatment of heart failure, Duchenne Muscular Dystrophy, and multiple sclerosis. A recent peer-reviewed paper describing ERC in treatment of heart failure may be found at http://www.intarchmed.com/content/pdf/1755-7682-3-5.pdf.

Filed Under: Adult Stem Cells, Endometrial Stem Cells, News, Stem Cell Research Tagged With: , ,
July 2, 2010 by

Eradication of brain tumor stem cells with an oncolytic adenovirus.

Jiang et al. Discov Med. 2010 Jul;10(50):24-8.

Philosophically, tumor cells have an advantage to humans in the “War on Cancer”. That is, the tumors have the ability to rapidly mutate, so that when drugs are given to fight the tumor, the tumor can “mutate around” the drug and become resistant. This occurs in several ways: a) the tumor starts expressing drug efflux pumps, such as the multi-drug resistance (MDR) protein that actively transports chemotherapeutics out of cancer cells; b) the tumor mutates the kinase or molecular target that the drug is inhibiting; and c) the tumor increases expression of other oncogenes that are not inhibited by the drug.

One interesting method of dealing with the problem of tumor mutation is to use agents against the tumor that are actively mutating. One approach has been the use of viruses that have a selective ability to infect tumors and to kill them. These are called “oncolytic” viruses. One of the most well-known oncolytic virus is the Reovirus, which only replicates in cells that express high concentrations of the oncogene RAS. This virus is in clinical trials by the Canadian company Oncolytics.

Delta-24-RGD is an oncolytic adenovirus that is capable of infecting glioma cells and preferentially inducing their death. It is being developed at the Brain Tumor Center, The University of Texas MD Anderson Cancer Center and is the subject of an ongoing Phase I clinical trial in the treatment of patients with therapy-resistant glioma.

One of the key issues surrounding any cancer therapeutic is whether the treatment is targeting tumor stem cells, or only the tumor progeny cells. This is very important because tumor stem cells are usually resistant to chemotherapy or other interventions that require cells to be metabolically-active and hyperproliferating. The majority of tumor cells are metabolically-active and fast multiplying, these cells are usually destroyed by conventional drug approaches, however, subsequent to their destruction the tumor stem cells exit quiescence and start making a new tumor. This has been one of the primary reasons for the poor success rate of cancer therapeutics that are currently under development.

In the current paper scientists found that the Delta-24-RGD virus is capable of infecting and causing death of glioma stem cells. This is a very important finding because it implies the possibility of attaining tumor cure by administration of such an oncolytic virus. Other advantages of the oncolytic virus approach is that the process of tumor cell death likely releases numerous antigens which cause activation of systemic immunity towards micrometastasis. Unfortunately one of the drawbacks of cancer therapy using oncolytic viruses is that the host develops an immune response to the virus which does not allow for long term continual administration. Patients interested in this treatment should contact Dr. Jiang at hjiang@mdanderson.org .

Filed Under: News, Stem Cell Research Tagged With: , , , , ,
June 21, 2010 by

Medistem Reports Rheumatoid Arthritis Patient Success Using Adult Stem Cell Protocol

SAN DIEGO, CA – (Marketwire – June 21, 2010) – Medistem Inc. Medistem Inc. together with the Stem Cell Institute reported today publication in the peer reviewed journal Cellular Immunology its paper titled “Autologous stromal vascular fraction cells: A tool for facilitating tolerance in rheumatic disease,” which describes the first use of a patient’s own fat stem cells for treatment of rheumatoid arthritis.

How Fat Stem Cells May Work on Autoimmune Diseases

In collaboration with the company Vet-Stem Inc, the University of Western Ontario, and The University of California San Diego, Medistem scientists detailed the scientific rationale for use of patient’s own fat derived stem cells for “reprogramming” the immune system of patients with autoimmune diseases such as rheumatoid arthritis. A case report of a 67-year-old American woman who recovered from rheumatoid arthritis after intravenous treatment with adult stem cells is provided.

“We have been treating companion animals for osteoarthritis and rheumatoid arthritis for over five years, achieving and publishing excellent efficacy data,” said Robert Harman, CEO of Vet-Stem. “Medistem’s identification of potential mechanisms of action, as well as translation of this technology into the clinic, supports the importance of our findings.”
Medistem previously identified and filed intellectual property covering the co-purification of high concentrations of T regulatory cells using protocols that enrich for adipose derived stem cells, a finding that was later confirmed and published by Diane Mathis’s group from Harvard University (Feuerer et al. Nat Med. 2009 Aug;15(8):930-9). T regulatory cells are used by the body to control autoimmunity, which is explained in this video by Thomas Ichim, the CEO of Medistem.

“We are very excited that Medistem’s protocol for isolation of a patient’s own fat derived stem cells and T regulatory cells, which produced promising results in multiple sclerosis, appears to be useful in rheumatoid arthritis, another autoimmune disease,” said Neil Riordan, Chairman of Medistem.

In a 2009 paper Medistem together with Vet-Stem and University of California San Diego reported substantial clinical improvement in a small group of multiple sclerosis patients treated using a similar protocol. The paper is available at www.translational-medicine.com.

About Medistem Inc.

Medistem Inc. is a biotechnology company developing technologies related to adult stem cell extraction, manipulation, and use for treating inflammatory and degenerative diseases. The company’s lead product, the endometrial regenerative cell (ERC), is a “universal donor” stem cell being developed for critical limb ischemia. A publication describing the support for use of ERC for this condition may be found at www.translational-medicine.com.

Cautionary Statement

This press release does not constitute an offer to sell or a solicitation of an offer to buy any of our securities. This press release may contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified. Future events and actual results could differ materially from those set forth in, contemplated by, or underlying the forward-looking information. Factors which may cause actual results to differ from our forward-looking statements are discussed in our Form 10-K for the year ended December 31, 2007 as filed with the Securities and Exchange Commission.

Filed Under: Adult Stem Cells, News, Rheumatoid Arthritis, Stem Cell Research, Stem Cell Therapy Tagged With: , , ,
May 20, 2010 by

Pluristem’s Off-The-Shelf Placenta-Derived Cell Therapies

Pluristem announced that its "off the shelf" placental stem
cells will be the focus of upcoming talking at investor and medical
conferences. The company Pluristem is currently in Phase I trials assessing its
unique bio-reactor expanded placental stem cells for the treatment of critical
limb ischemia. In contrast to other therapies that use the patient’s own stem
cells (called autologous), the advantage of the "universal donor" or
"allogeneic" approach is that large numbers of cells can be generated according
to defined conditions. Additionally, universal donor cells can be administered
several times at a number that is limited only by the desire of the physician to
escalate the dose. In the autologous situation stem cells are usually taken
from the bone marrow, making it difficult to perform multiple extractions.

Pluristem will present at the International Society for
Cellular Therapy’s (ISCT) 16th Annual Meeting in Philadelphia some updates on
its ongoing programs.

"We recently reported interim top-line results from our
Phase I clinical trials demonstrating that PLX-PAD is safe, well tolerated and
had improved the quality of life of CLI patients in the studies," said Zami
Aberman, Pluristem’s chairman and CEO. "With PLX-PAD, we have the unique
opportunity to utilize a single source of cells, the placenta, to treat an
unlimited number of CLI patients. Our presentations at the ISCT Annual Meeting
and other conferences will highlight the potential of PLX-PAD as well as our
core technology that enables the cost-effective development of cell therapies
derived from the human placenta."

There are several other companies pursuing "universal
donor" stem cells. Medistem, the licensor of technologies used by Cellmedicine
has developed such a cell from the endometrium, called "Endometrial Regenerative
Cells" that are currently subject of an IND application for use in critical limb
ischemia. Athersys is using bone marrow derived universal donor stem cells for
treatment of heart failure. The most advancement in this area comes from the
company Osiris Therapeutics which also uses bone marrow derived cells to treat a
variety of conditions, although all are still in clinical trials.

In
the majority of cases universal donor cells are related directly or indirectly
to mesenchymal stem cells. These cells, originally discovered by Dr. Arnold
Caplan, express low levels of proteins that are seen by the immune system, thus
allowing them to be transplanted without matching. Additionally, they also
produce proteins that actively suppress the immune system from killing them. In
diseases associated with abnormal immunity mesenchymal stem cells have shown
promise. Cellmedicine has published on use of mesenchymal stem cells in
treatment of multiple sclerosis

Filed Under: Adult Stem Cells, News, Stem Cell Research Tagged With: , , ,
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