Mechanisms of a New Stem Cell Mobilizer

Jarcome-Galarza et al. J Bone Miner Res.

It is known that the bone marrow contains three main types of stem cells: a) hematopoietic stem cells, which make blood; b) endothelial progenitor cells, which maintain healthy blood vessels; and c) mesenchymal stem cells, which repair a variety of tissues and are capable of producing high amounts of growth factors. After major tissue injury or trauma all three of the bone marrow derived stem cells leave the bone marrow and enter systemic circulation in an attempt to heal the tissue damage. The original compound that was discovered to “mobilize” bone marrow stem cells was granulocyte colony stimulating factor (G-CSF). Studies in mice with lung injury in the late 1970s demonstrated that a lung-derived protein was capable of stimulating bone marrow to multiply and produce higher numbers of granulocytes. It was not until the late 1980s that scientists started injecting purified G-CSF into animals as a method of increasing the number of circulating stem cells. Why would people want to increase circulating stem cells? Commercially one of the main reasons is associated with the process of bone marrow transplantation. In bone marrow transplantation donors were historically required to undergo the painful procedure of bone marrow extraction, which requires an excess of 20 holes to be drilled into their hip bones. Compounds such as G-CSF could be administered to donors in order to make their stem cells enter circulation, and then the stem cells could be isolated from the blood instead of the bone marrow. This makes the procedure a lot less painful and arguably a lot safer. Additionally, the possibility of mobilizing stem cells by administration of a drug has the possibility of artificially increasing stem cell numbers in patients with degenerative diseases in order to attempt to naturally heal the condition.

The clinical use of G-CSF for mobilization and also for increasing granulocytes in the blood has resulted in multibillion dollars per year in sales for companies such as Amgen. Naturally, this has stimulated much interest in the process of how to make stem cells leave the bone marrow. G-CSF stimulates bone marrow stem cell release through several mechanisms. The main mechanism appears to be associated with stimulation of osteoclasts, which cause modulation of the bone marrow structure and physically release the stem cells from their environment. Other mechanisms exist such as breakdown of stromal derived growth factor (SDF-1). This protein is made by the bone marrow and literally keeps the hematopoietic stem cells stuck to the bone. When the bone marrow levels of SDF-1 decrease, the hematopoietic stem cells are no longer “stuck” to the marrow and as a result enter circulation. Yet another mechanism is that G-CSF activates neutrophils to produce various enzymes that cleave proteins on the bone marrow. These cleaved proteins are then recognized by pre-formed antibodies, which activate complement, which causes small holes in the bone marrow and thus releases stem cells.

The second “stem cell mobilizer” to be approved by the FDA is a drug called Mozibil which blocks the interaction between SDF-1 and its receptor CXCR4. This drug was sold by Anormed to Genzyme in a deal worth more than half a billion dollars. Mozibil is a superior stem cell mobilizer to G-CSF in many patients and as a result has rapidly been implemented clinically. Interestingly, it appears that Mozibil causes redistribution of different ratios of hematopoietic, mesenchymal and endothelial progenitor cells than G-CSF.

One of the most recent mobilizers under development is Parathyroid Hormone. This naturally –occurring substance has been demonstrated in clinical trials to mobilize stem cells, but apparently through a mechanism different than G-CSF and Mozibil. Specifically, both of these drugs appear to cause a temporary depletion of the stem cells in the bone marrow, whereas Parathyroid Hormone seems to preserve the stem cells inside of the bone marrow.

A recent paper (Jacome-Galarza et al. Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow. J Bone Miner Res. 2010 Dec 29) explored the activities of Parathyroid Hormone on osteoclasts in the bone marrow of mice. The authors found that treatment of mice with Parathyroid Hormone for 7 or 14 days increased the number of osteoclastic progenitors in the bone marrow as well as the absolute number of hematopoietic progenitors. These data suggest that the hormone acts not only as a means of stimulating redistribution of hematopoietic stem cells, but also may be involved in directly stimulating their multiplication, possibly through modulating activity of osteoclasts.

2010-12-29T21:28:33+00:00 December 29th, 2010|News, Stem Cell Research|

What Works Better: Stem Cell Mobilization or Stem Cell Administration for Brain Injury

Bakhtiary et al. Iran Biomed J. 2010 Oct;14(4):142-9.

Bone marrow mobilization is used as part of hematopoietic stem cell transplantation in order to collect donor bone marrow stem cells without having to puncture the bone. The process of mobilization is induced by administration of the drug G-CSF, which is approved by the FDA. One interesting question is if instead of giving patients stem cell therapy, if one could simply give G-CSF and have their own stem cells “mobilize” and treated the area of injury. This would be simple and economical as compared to injection of stem cells.

In order to test this, a group from Iran used a rat model of traumatic brain injury and gave either G-CSF or bone marrow derived mesenchymal stem cells.

There were three groups of 10 rats used in the experiments. All rats were subjected to traumatic brain injury by use of a “controlled cortical impact device”. The first group received 2 million bone marrow derived mesenchymal stem cells. The second group received G-CSF to mobilize the bone marrow stem cells. The third group served as a control group. All injections were performed 1 day after injury into the tail veins of rats. The bone marrow derived mesenchymal stem cells were labeled with Brdu before injection into the tail veins of rats. Animals were sacrificed 42 days after TBI and brain sections were stained by Brdu immunohistochemistry.

As compared to controls, both the G-CSF mobilized and the bone marrow mesenchymal stem cell groups had a statistically significant improvement in behavior. When animals were sacrificed at 42 days the observation was made that labeled bone marrow mesenchymal stem cells homed into the area of injury and appeared to contribute to repair.

Although more date is needed when it comes to clinical application, it may be feasible to use G-CSF as part of therapy for traumatic brain injury. One caveat that we find with this is that G-CSF, as its name suggests (granulocyte colony stimulating factor), actually stimulates both increase in granulocyte number and function. While in a controlled laboratory environment brain damage may be relatively “sterile”, in the clinical setting it may be that increased granulocytes may contribute to a higher extent of inflammation and therefore more tissue damage. On the other hand it is possible that mesenchymal stem cells because of their known anti-inflammatory activity may function not only to regenerate the injured brain tissue but also to provide an anti-inflammatory effect.

2010-10-14T15:43:48+00:00 October 14th, 2010|Adult Stem Cells, Brain Injury, News, Stem Cell Research|

Scientists identify and isolate adult mammary stem cells in mice

(Times of India) It is well-known that stem cells exist in adult tissues. The most commonly known stem cell, the bone marrow stem cell, plays the physiological role of generating billions of blood cells per hour while being capable of making copies of itself. Subsequent to the discovery of the bone marrow stem cell in the 1960s by Till and McCulloch, other types of stem cells were subsequently identified in other tissues. For example, the brain contains a stem cell compartment term the “dentate gyrus” which is capable of creating new neurons at a basal rate, with acceleration of new neuron formation during pregnancy or after stroke. Other tissue specific stem cells include those found the in liver, the heart, and the spleen. One common characteristic amongst stem cells is their ability to efflux various drugs through expression of the multi-drug resistance (MDR) protein, as well as preferential state of quiescence in absence of growth factor activation.
One important reason to seek tissue-specific stem cells is that if they could be expanded in large numbers they may theoretically be superior to other stem cell types for therapeutic uses. For example, culture-expanded cardiac specific stem cells are superior to bone marrow stem cells at accelerating healing of the heart muscle after a myocardial infarction. These types of stem cells are actually in clinical trials at present.
The other reason for identifying tissue-specific stem cells is that they may be useful in identifying molecular events that occur in the process of normal tissue changing to cancer. This is of interest because cancer stem cells are believed to originate from tissue-specific stem cells acquiring numerous mutations.
Currently researchers from the Fred Hutchinson Cancer Research Center have identified a tissue-specific stem cell in the breast. The scientists developed genetically engineered mice in which the green marker protein GFP was used to identify only breast cells that express the stem cell phenotype. The findings appeared in peer-reviewed journal Genes and Development.
“Until now, we have not been able to identify stem cells in mammary tissue. They have never been detected before with such specificity. It is extraordinary. You can see these green stem cells under the microscope in their pure, natural state,” said Larry Rohrschneider of the Hutchinson Center.
It was demonstrated that the activity of the mammary stem cells is modulated during times associated with breast growth such as puberty and pregnancy.
“We have found that those transplanted green stem cells can generate new mammary tissue and this tissue can produce milk, just like normal mammary epithelial cells,” said co-author Lixia Bai.
“Identification of the exact stem cell and its location is the first critical and fundamental step toward understanding the regulatory mechanisms of these important cells,” she said.
The technology described in the publication may be useful in isolating and expanding human breast specific stem cells. If these studies are reproducible, it will be of great interest to see whether they still possess ability to home to injured tissue, which to date has been clearly demonstrated in bone marrow stem cells but not with too much clarity with cardiac –specific stem cells or other types of tissue-specific stem cells.

2010-09-01T15:50:49+00:00 September 1st, 2010|Adult Stem Cells, Bone Marrow, News, Stem Cell Research|

Stem cell therapy benefits patients with chronic heart failure—study

(Neharika Sabharwal) After a heart attack the myocardium (heart muscle) undergoes a period of damage during which cells of the body attempt to heal the injured tissue. This occurs through stem cells found in the heart itself, called cardiac specific stem cells (CSC) as well as bone marrow stem cells which seem to exit the bone marrow, enter circulation, and migrate towards the area of cardiac damage.

Given that the bone marrow stem cells seem to both directly become new heart cells, as well as stimulate formation of new blood vessels that accelerate the healing process, it may be theoretically beneficial to administer bone marrow stem cells to patients after a heart attack. Administration of stem cells is usually performed in these patients by means of a balloon catheter. This device temporarily occludes the artery that is feeding the blood vessel that provides circulation to the area of the injured muscle. While occlusion is occurring cells are administered. This allows the cells to enter the cardiac circulation in a highly concentrated manner. This type of stem cell therapy is termed “post-infarct intracoronary administration of stem cells”.

The use of intracoronary bone marrow transplantation has been published in many clinical trials with overall success in stimulating heart muscle function as judged by the left ventricular ejection fraction. Additionally, bone marrow stem cells have been demonstrated to reduce pathological remodeling by inhibiting the dilation of the ventricles that occurs after a heart attack.

While short-term effects of bone marrow stem cell administration are well-known, little is known about long term effects. A recent study, called the STAR Heart Study, aimed to compare bone marrow cells versus optimal conventional therapy in patients with heart failure due to healed myocardial infarction.

The study demonstrated that intracoronary bone marrow stem cell therapy not only improves ventricular performance and quality of life but also the long term rate of survival in patients with chronic heart failure, claims a new study.

According to researchers, the beneficial effects of stem cell therapy were perceived within three months of the treatment and the effect continued for well over five years. Lead scientist of the study, Bodo-Eckehard Strauer of Duesseldorf’s Heinrich Heine University in Germany said, “Our study suggests that, when administered as an alternative or in addition to conventional therapy, bone marrow cell therapy can improve quality of life, increase ventricular performance and increase survival.”

Currently several companies are developing devices that allow for the use of patient’s own stem cells for intracoronary administration post infarct. One such company is the Hackensack NJ based Amorcyte Inc, which uses standard bone marrow extraction procedures, isolates CD34 positive cells using the Baxter Isolex device, and subsequently infuses the isolated cells using a catheter based technique. The company Aldagen is also performing a similar procedure, however instead of purifying stem cells based on CD34 they are using aldehyde dehydrogenase expression as a means of isolating stem cells from non-stem cells from the bone marrow.

The STAR study was reported at the ‘European Society of Cardiology (ESC) 2010 Congress. It tracked 391 patients with chronic heart failure because of ischemic heart disease following a heart attack. Out of 391 patients, 191 agreed to have the bone marrow stem cell treatment. The remaining 200 who refused therapy participated as the control group.

The patients were monitored for a period of five years after bone-marrow-cell therapy with results at 3 months, one year and five years showing a significant difference between the treatment and control group. At five years only 7 patients who received stem cells died, as compared to 32 in the control group. No treatment associated adverse events of a serious nature were observed.

Dr Mariell Jessup, medical director of the Penn Heart and Vascular Center at the University of Pennsylvania stated, “The hope is that by injecting stem cells into the scarred area, you will bring life back to that area and induce healthy muscle…There’s been ongoing excitement about using stem cells to treat heart disease for some time and this study certainly adds to it.”

2010-08-31T15:52:21+00:00 August 31st, 2010|Adult Stem Cells, Heart Disease, News, Stem Cell Research|

Pluristem to take part in EU stem cell study

(Shiri Habib-Valdhorn, Globes [online], Israel business news) Broadly speaking there are two types of adult stem cell therapies: Those that involve the use of the patient’s own stem cells, called autologous, and those that involve use of another patient’s cells, called allogeneic. There are pros and cons to both approaches.

In the autologous approach the main advantage is that because the cells come from the same patient, there is no issue of immunological rejection or fear of contamination from another person’s infectious agents. The drawbacks with autologous approaches include: a) the fact that stem cell extraction, manipulation, and re-administration requires expensive and laborious procedures, as well as the need for equipment that is not commonly available at most hospitals; b) patients with a variety of disease conditions often have defective stem cells that work suboptimally as compared to stem cells from healthy patients; and c) many times the procedure for extracting the patient’s own stem cells involves painful procedures such as bone marrow aspiration, or potentially dangerous procedures such as stem cell mobilization. This allows the procedure to be performed only for a limited number of times.

The allogeneic stem cell therapy approach has the advantage of using cells that have been generated in large quantities for a specific function and biological activity. This means that the cells used are of a certain quality standard. Additionally, the allogeneic approach does not require complex cell manipulation procedures since the cells are shipped frozen to the point of care. Allogeneic cells can be administered on multiple occasions to the patient if needed. The downside of allogeneic cell therapy is the potential for immunological rejection, as well as patient sensitization. The sensitization of the patient to allogeneic cells may not allow for future use of the stem cells, as well as preclude the patient from bone marrow transplantation.

Pluristem Therapeutics Ltd. (Nasdaq:PSTI; DAX: PJT) is an Israeli company that trades on NASDAQ which is focused on generating allogeneic, “off the shelf” cellular products from placental cells using a proprietary bioreactor device. Originally Pluristem was working on using these stem cells to accelerate bone marrow engraftment after transplantation.

The process of bone marrow transplantation involves administration of chemotherapy and/or radiation to patients with blood malignancies in order to destroy the abnormal cells of the recipient, followed by injection of healthy donor blood making cells (hematopoietic stem cells) in order to provide to the recipient a new immune system. While this procedure has saved thousands of lives, one of the major drawbacks is that the donor cells sometimes take weeks, if not months, to start producing new blood cells. The use of donor cord blood has also been tried in this context experimentally, however, cord blood takes even longer than bone marrow to “engraft” in the recipient. Pluristem believed that its cells produce various growth factors that accelerate the process of engraftment.

In 2009 Pluristem began using its cells for the treatment of critical limb ischemia. This disease is a manifestation of advanced peripheral artery disease characterized by non-ceasing pain, ulcers, and a high rate of amputation. Given that the Pluristem cells produce high amounts of various growth factors, the concept is that administration of these cells into the muscles of patients with critical limb ischemia will result in production of new blood vessels, which will provide increased circulation to the legs of these patients. Other companies such as Medistem Inc are also using allogeneic cells, albeit from different sources (menstrual blood endometrial regenerative cells), for the treatment of this condition.

Recently Pluristem was chosen as one of 19 companies from 12 countries that will participate in a placenta stem cell study financed by EU Seventh Framework Progamme for Research and Development.

The study will be conducted concurrently at 12 European medical centers to examine the effect of placenta stem cell treatments on several kinds of heart cells that are damaged by high blood glucose levels caused by diabetes. The study will examine whether placenta stem cell-based anti-inflammatory agents can prevent or delay the onset of diastolic heart failure (DHF) among diabetics.

This is a new indication for Pluristem’s PLX (PLacental eXpanded) cell therapy product. The company will be allotted $150,000 from the Seventh Framework Progamme for R&D to cover the cost of the research and to develop the stem cells for the program.

Pluristem chairman and CEO Zami Aberman said, “There has been a growing interest in the potential of PLX cells to treat a variety of clinical indications following the release of the PLX-PAD clinical study interim results, which demonstrated safety and shows a trend of efficacy. The decision to use our PLX cells in this DHF study is further verification of the uniqueness of Pluristem’s PLX cells as an off-the-shelf product that requires no tissue matching prior to administration. There is a significant unmet medical need for the treatment of DHF, not only in Europe but also globally, and Pluristem’s placenta-derived cell therapy may provide patients and physicians with an effective and safe treatment option for this disease.”

The use of mesenchymal stem cells for treatment of cardiac diseases has previously been reported by Medistem Inc and Osiris Therapeutics.

2010-08-30T16:31:42+00:00 August 30th, 2010|News, Stem Cell Research|

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

2010-05-20T17:02:58+00:00 May 20th, 2010|Adult Stem Cells, News, Stem Cell Research|

Success Stems From Adult Cells

The use of adult stem cells for conditions besides bone marrow transplant is most prevalent in the area of heart failure. Since the original study of Strauer et al in 2001 in which a 46-year old patient was administered bone marrow stem cells after a heart attack and experienced a profound improvement in cardiac function, more than a thousand patients have received adult stem cells for cardiac-associated conditions.

Today the story of Eddie Floyd, a small business owner from Austin, Texas was highlighted in an article describing his presentation to the Texas Alliance for Life. Mr. Floyed suffered a heart attack three years ago. The heart attack caused profound damage so as to make him eligible to participate in a clinical trial being conducted at the Texas Heart Institute using his own bone marrow stem cells. The trial involves administration of the stem cells using a special catheter to the blood vessels supplying the heart muscle.

Three years later, Mr Floyd is happy with the results. He explains that he has been able to resume normal daily activities. "There really isn’t anything that I can’t do because of my heart, that I’m aware of. [But] there are a few things I can’t do because of my belly…,"

Since the stem cells are from the patient’s own body, there is no possibility of rejection. He stated "They did not cause any kind of rejection, so I didn’t have to have any rejection-preventive medicine or anything like that…They were just generic stem cells that became heart."

In his talk Mr. Floyd explained that despite all of the media publicity and controversy around embryonic stem cells, these cells produced no benefit to patients like himself. There was one clinical trial in embryonic stem cells that was approved, which was Geron’s spinal cord injury protocol. The approval, however, was retracted before any patients were treated.

In contrast, adult stem cells such as the ones derived from the bone marrow have been used successfully not only in the treatment of heart failure, but other diseases such as liver failure, type 2 diabetes, and prevention of amputation in patients having poor circulation in the legs.

Currently adult stem cells are in clinical trials in the US and Western Europe. The most advanced adult stem cell types are in Phase III of trials, meaning that
if successful they will be sold as a drug within the next 1-3 years. Because Phase III trials have a placebo control arm, some patients do not want the risk
of being in a placebo group and therefore choose to go to clinics outside the US that offer this treatment. Once such clinic, Cellmedicine, has published
results on patients, such as a recent heart failure patient who underwent a profound recovery in heart function after treatment. The patient is described
in the peer reviewed journal International Archives of Medicine which is freely accessible at
www.intarchmed.com/content/pdf/1755-7682-3-5.pdf.

2010-05-17T17:11:53+00:00 May 17th, 2010|Adult Stem Cells, Heart Disease, News, Stem Cell Research|

Stem Cells Have GPS to Generate Proper Nerve Cells

One of the main questions in stem cell therapy is how the
injected cells "know" to find their way into the specific parts of the body
where they are needed. The most common example of stem cells homing is during
bone marrow transplant. In this situation donor stem cells are administered to
the recipient intravenously, but somehow they find their way to the bone marrow
of recipient, and once in the bone marrow start producing new blood cells. It
was discovered that specific cells in the bone produce a chemical signal called
stromal derived factor (SDF)-1 that acts as a homing beacon for the stem cells,
causing them to be localized in the bone marrow regardless of where they are
injected. This is explained in the video
www.youtube.com/watch?v=VJaQkYWdJ8w.

By knowing the signals involved in keeping stem cells in
the bone marrow, drugs have been made that can temporarily release them from the
bone into circulation. One example of such a drug made by Genzyme called
Mozibil. This is a small molecule that has been synthesized to act as an agent
that blocks the interaction between SDF-1 and its receptor. By blocking this
interaction, stem cells are "mobilized" to exit the bone marrow and enter
systemic circulation. Once the drug exits circulation by normal metabolism, the
stem cells home back to the bone marrow, or if there is injury in the body, some
of them localize to the damaged area.

Mozibil and similar agents are useful in situations where
one wants to collect patient stem cells without having to perform a bone marrow
aspiration, which is a painful procedure involving drilling numerous holes in
the bone of the donor. Another use of such "mobilizers" is to increase the
number of stem cells in circulation, to accelerate recovery in conditions such
as stroke or heart attack. In both of these conditions an increase in
circulating stem cells is associated with better recovery. Thus if one
artificially increases the number of stem cells in circulation by administering
agents such as Mozibil, it may be possible to see a therapeutic benefit.

While the control of stem cell homing for the bone marrow
is relatively well-known, the brain is a completely different matter. A
previously unknown factor that regulates how stem cells produce different types
of cells in different parts of the nervous system has been discovered by Stefan
Thor, professor of Developmental Biology, and graduate students Daniel Karlsson
and Magnus Baumgardt, at Linköping University in Sweden.

The scientists studied a specific stem cell in the nervous
system of the fruit fly. This stem cell is present in all segments of the
nervous system, but outside of the nervous system it is found only in the
thorax. To investigate why this cell type is not created in the stomach or head
region they manipulated the Hox genes’ activity in the fly embryo. The
investigators found out that the Hox genes in the stomach region stop stem cells
from splitting before the specific cells are produced. In contrast, the specific
nerve cells are actually produced in the head region, but the Hox genes turn
them into another, unknown, type of cell. Hox genes can thus exert their
influence both on the genes that control stem cell division behaviour and on the
genes that control the type of nerve cells that are created.

"We constantly find new regulating mechanisms, and it is
probably more difficult than previously thought to routinely use stem cells in
treating diseases and repairing organs, especially in the nervous system", says
Thor.

The regulation of stem cell homing by Hox genes has previously been demonstrated in
other systems, however this is the first time that it was found in relation to
development of the nervous system. These findings may lead to strategies for
"rewiring" neurons after injury has occurred in situations such as cerebral
palsy or stroke.

2010-05-12T17:23:40+00:00 May 12th, 2010|News, Stem Cell Research|

Stem Cells Don’t have to be Alive to Be Beneficial

The use of stem cells in patients who have poor circulation
is well-known.  In fact, the first use of stem cells for conditions other than
blood disorders was in patients who were undergoing bypass surgery.  Usually
patients undergo bypass because of advanced atherosclerosis that is inhibiting
the flow of blood to the heart muscle.  Despite success of bypass surgery, the
underlying problem of thickened blood vessels remains.  Japanese scientists (Hamano
et al. Local implantation of autologous bone marrow cells for therapeutic
angiogenesis in patients with ischemic heart disease: clinical trial and
preliminary results. Jpn Circ J. 2001 Sep;65(9):845-7
) in 1999 treated 5
patients with ischemic heart disease with their own bone marrow cells injected
into the heart muscle during bypass.  Of these 5 patients, 3 demonstrated
increased blood flow at the area where the stem cells were injected.  Subsequent
to this numerous clinical trials have been conducted using bone marrow stem
cells for increasing circulation both to the heart and also to legs that lack
proper blood flow (particularly in patients with critical limb ischemia see
video

http://www.youtube.com/watch?v=dcCwZ4CsiKc
). 

One of the major questions has always been how the injected
stem cells improve circulation.  Originally the idea was that the stem cells
become new blood vessels, and that these new blood vessels take over the
function of the older blood vessels.  However, recent data suggests that the
stem cells injected actually collaborate with the stem cells that are already in
the patient.  For example, it was demonstrated that in patients lacking oxygen
in their legs who receive bone marrow stem cell therapy, the responders actually
have increased levels of their own circulating stem cells.  Here is a video
describing this

http://www.youtube.com/watch?v=OwIOL13vXQ4
.

It is believed that bone marrow stem cells, particularly
mesenchymal stem cells, are capable of producing proteins that stimulate the
body’s own stem cells into making new blood vessels.  These proteins include
IGF-1, VEGF, and HGF. 

A recent study from Stanford University (Hoffmann et al.
Angiogenic Effects Despite Limited Cell Survival of Bone Marrow-Derived
Mesenchymal Stem Cells under Ischemia. Thorac Cardiovasc Surg. 2010
Apr;58(3):136-142
) should to investigate the cellular and molecular
interactions which are associated with formation of new blood vessels after
administration of bone marrow mesenchymal stem cells.

The investigators first began by assessing production of
the protein VEGF from bone marrow mesenchymal stem cells under conditions of
normal oxygen, and under reduced oxygen conditions.  The idea being that if
mesenchymal stem cells are responsible for producing growth factors, then it
would make sense that production of these factors would increase in response to
needs of the body (eg reduced oxygen).  As a control, fibroblast cells were
assessed side by side with the mesenchymal stem cells.  It was found using in
vitro experiments that mesenchymal stem cells produced much higher levels of
VEGF under hypoxia as compared to fibroblasts, however, mesenchymal stem cells
died faster than fibroblasts in response to hypoxia.

To determine whether mesenchymal stem cells or fibroblasts
cause formation of new blood vessels in animals, a model of critical limb
ischemia was developed in which the artery feeding the leg of mice was ligated. 

One week after induction of ischemia in the leg, 1 million
mesenchymal stem cells, or fibroblasts were injected into the muscles of the
animals.  The cells were labeled genetically so that the injected cells could be
distinguished from the endogenous cells. 

Substantially elevated levels of new blood vessels, and
improved circulation, was observed in the mice that received mesenchymal stem
cells as compared to fibroblasts.  Interestingly, at 3 weeks after
administration, despite improved circulation, the mice receiving mesenchymal
stem cells had much lower numbers of injected cells as compared to mice that
received fibroblasts.

This study suggests that mesenchymal stem cells seem to use
the natural mechanisms of the body in order to generate new blood vessels. 
Something else of interest from this study is that fibroblasts live longer in
hypoxia as compared to mesenchymal stem cells.  Hypothetically it may be
possible to transfect fibroblasts with genes that stimulate production of new
blood vessels.  Unfortunately, the proper combination of growth factors and
concentration are still not known for creation of new blood vessels.

2010-04-30T17:55:51+00:00 April 30th, 2010|Heart Disease, News, Stem Cell Research|