February 13, 2012 by

Rare Heart Defect Reproduced in Petri Dish, Hope for Cure

Dr. Ananya Mandal, MD

A team of researchers has created beating heart cells in the lab using skin cells of children with a rare heart defect. The team, led by Ricardo Dolmetsch of Stanford University took skin cells from children with Timothy syndrome, a rare heart condition commonly associated with autism, as well as syndactyly (webbing of fingers and toes).

The process the team underwent included reprogramming the stem cells and then developing them into cardiac cells in order to have a human model to test on, instead of mice models. “Because every cell in our body has the same genetic programming, that means we can take skin cells and reprogram them to generate stem cells, and we can take those cells to make heart cells,” said Dolmetsch.

Once the heart cells were developed, the team then used them to test several heart rhythm drugs. Unfortunately, none of the drugs initially tested corrected the heart problems associated with Timothy syndrome. However, further research and testing resulted in the discovery of the success of a cancer compound roscovitine, which is now in phase 2 clinical trials. Dolmetsch added that “The potential is really large”, Stanford has applied for patents on this technology and several drug companies have expressed interest in this research.

Filed Under: Heart Disease, News, Stem Cell Research Tagged With: , , , , , ,
December 3, 2010 by

How Inflammation Suppresses Stem Cell Function

Wang et al. PLoS One;5(12):e14206.

Low grade inflammation is well known to correlate with development of numerous disease conditions such as heart failure, kidney failure, and diabetes. It is generally accepted that oxidative stress caused by inflammation is one of the means by which disease evolution occurs. Inflammatory conditions usually generate oxygen free radicals that damage cells and cause the cells of the body to lose function. Importance of reducing inflammation in terms of preventing diseases, such as heart disease, is seen by the beneficial effects of antiinflammatories such as aspirin.

A recent paper (Wang et al. TLR4 Inhibits Mesenchymal Stem Cell (MSC) STAT3 Activation and Thereby Exerts Deleterious Effects on MSC-Mediated Cardioprotection. PLoS One. 2010 Dec 3;5(12):e14206.) suggests that inflammation may actually inhibit the activity of stem cells, and through suppressing the body’s repair processes, causes various diseases to appear.

The mesenchymal stem cell is a type of stem cell found in the bone marrow, fat, heart, and other tissues, that is activated in response to injury and acts to heal damaged tissues. Particularly in the case of heart attacks, it has been demonstrated that administration of bone marrow mesenchymal stem cells causes accelerated healing both in humans and animals. The therapeutic effects of mesenchymal stem cells seem to be mediated by production of growth factors, as well as proteins that support creation of new blood vessels, a process called angiogenesis. Currently several companies are currently developing mesenchymal stem cell based drug candidates including Osiris Therapeutics, Athersys Inc, Mesoblast, and Medistem.

Given the fact that these cells are not a “laboratory experiment” but have actually been used in more than a 1000 patients, understanding conditions that affect their activity, as well as means of making them more effective is important. Inflammatory mediators are believed to influence activity of mesenchymal stem cells, since the protein toll like receptor 4 (TLR4), which recognizes tissue inflammation is found in high concentrations on mesenchymal stem cells. TLR-4 was originally found on cells of the “innate” immune system as a molecule that recognizes “danger signals”.

In order to determine the function of TLR4 on bone marrow mesenchymal stem cells, scientists at Indiana University used mice that have been genetically engineered not to have expression of this protein. Bone marrow mesenchymal stem cells from the mice lacking TLR-4 were demonstrated to function in a similar manner to normal mesenchymal stem cells in the test tube. However when these mesenchymal stem cells were administered to mice after a heart attack, the cells were capable of generating a highly significant improvement in heart function as compared to normal mesenchymal stem cells. The scientists concluded that inflammatory signals “instruct” mesenchymal stem cells to produce less therapeutic factors than they normally would.

These data are very interesting since other reports have suggested that inflammatory mediators actually stimulate mesenchymal stem cells to produce higher amounts of anti-inflammatory factors such as interleukin-10. One of the reasons for the discrepancy may be that inflammation in the context of a heart attack may be different than the inflammatory signals used by other studies.

Filed Under: Adult Stem Cells, News, Stem Cell Research Tagged With: , , , , ,
August 31, 2010 by

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.”

Filed Under: Adult Stem Cells, Heart Disease, News, Stem Cell Research Tagged With: , , , ,
April 30, 2010 by

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.

Filed Under: Heart Disease, News, Stem Cell Research Tagged With: , , ,
April 18, 2010 by

Saginaw stem-cell therapy study breaking new ground

Use of stem cells for treatment of degenerative diseases offers great hope. Unfortunately, this hope is tempered by practical
considerations. For example, in patients with heart attacks it is known that readministration of their own stem cells into the infarct related area results in profound improvement
http://www.youtube.com/watch?v=flv0RmzPyLU. The problem with this is that stem cells need to be extracted from the bone marrow of the heart attack patient, which is a difficult and invasive procedure, and additionally the patient’s stem cells need to be processed extensively before they can be re-infused. To compound the problem, the stem cells from patients with heart attacks usually have suboptimal function. Therefore novel ways of performing stem cell therapy are needed that would make this approach practical.

Osiris Therapeutics has developed a clinical product called Prochymal, that consists of expanded bone marrow mesenchymal stem cells. This product has been demonstrated safe by intravenous infusion and perhaps more importantly, does not require matching with the recipient. Currently Osiris has completed Phase III trials and is in discussions with the FDA regarding its commercialization path for this product.

Recently Osiris completed a Phase I trial using Prochymal for treatment of post infarct pathological cardiac remodeling. These results were positive and prompted the company to initiate a Phase II study. Part of this study is being conducted at Michigan Stem & Regenerative Medicine Program of the Michigan CardioVascular Institute and Covenant Health Care under the leadership of Dr. Safwan Kassas, an interventional cardiologist .

"Stem cells represent a promising cardiac research avenue, given their potential to preserve heart function in at-risk patients," Kassas said. "Cardiologists today are unable to reverse cardiac deterioration following a severe heart attack."

To date 2 patients, William C. Smith, 60, of Bay City, in December, and Brenda Sigmund, 62, of Caro, in January where infused with the Prochymal product.

Kathleen Mostek, director of research and regenerative medicine for MCVI, 1015 S. Washington in Saginaw, said the stem cells were taken from five volunteers, grown in a lab and stored in a bank in a freezer. He stated "This protocol is adult stem cells, they are the same for everyone in the world, with no rejection,".

The study is a double-blind, placedo-controlled stem cell investigation being conducted in the U.S. and Canada and will enroll about 220 patients. To be eligible for the trial, patients must have experienced their first heart attack within seven days.

Filed Under: Adult Stem Cells, News, Stem Cell Research Tagged With: , , ,
April 12, 2010 by

Magnetic Attraction of Stem Cells to Injured Heart Creates Potent Treatment

The intracoronary administration of bone marrow stem cells in patients who have suffered a heart attack has been demonstrated to cause beneficial effects in double blind studies, as discussed in this video http://www.youtube.com/watch?v=flv0RmzPyLU. Intracoronary administration has potential side effects since a balloon needs to be expanded in the area where the heart attack occurred, which may cause exacerbation of the existing damage. A more attractive method of stem cell delivery would be via the intravenous route. Unfortunately, intravenous administration has the drawback that some of the cells become lodged in organs such as the lung and liver.
Despite this, intravenous administration has demonstrated positive results, for example in a clinical trial conducted by Osiris (Hare et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009 Dec 8;54(24):2277-86) an improvement in heart pumping
ability was observed.

One way of improving stem cell homing to the area of need is through direct administration of proteins, or genes encoding the proteins, that specifically attract stem cells. This approach has been performed with SDF-1 in animal models, and now the company BioHeart is doing Phase I clinical trials. Other ways include the use of laser therapy to induce expression of stem cell homing molecules as being developed by the San Diego company Entest Biomedical.

Today a new approach was reported in the journal Circulation Research, which is published by the American Heart Association.
Scientists at Cedars-Sinai Heart Institute have loaded stem cells with iron-nanoparticles and administered them intravenously in animals that were induced to undergo a heart attack by ligation of the coronary artery. The scientists found that by
applying magnetic fields to the heart, they could increase the number of injected stem cells that lodged into the heart by 3-times. This was accompanied by functional improvement.

"Stem cell therapies show great promise as a treatment for heart injuries, but 24 hours after infusion, we found that less than 10 percent of the stem cells remain in the injured area. Once injected into a patient’s artery, many stem cells are lost due to the combination of tissue blood flow, which can wash out stem cells, and cardiac contraction, which can squeeze out
stem cells. We needed to find a way to guide more of the cells directly to the area of the heart that we want to heal." Said Eduardo Marban, M.D., director of the Cedars-Sinai Heart Institute.

Commenting on the success of the present study, he stated "This remarkably simple method could easily be coupled with current stem cell treatments to enhance their effectiveness."

Filed Under: Adult Stem Cells, Heart Disease, News, Stem Cell Research Tagged With: , ,
March 5, 2010 by

Stem Cell Treatment for Heart Attacks: Timing is Everything

Skeletal myoblasts are a type of muscle-specific stem cell
that have been used previously in several clinical trials, particularly for
heart failure and post-heart attack patients.  Advantages of this type of stem
cell include the fact that they are from adult sources (no risk of cancer), they
are already committed to becoming muscle cells, and they can easily be grown in
the laboratory.  Disadvantages include the possibility of arrhythmias, as well
as lack of efficacy in several systems. Additionally, unlike mesenchymal stem
cells, which can be used as "universal donors" because of their
anti-inflammatory effects, skeletal myoblasts have to either be used from the
same patient (autologous), or co-administered with immune suppression to prevent
their rejection.

In a recent publication (O’Blenes et al. Engraftment is
optimal when myoblasts are transplanted early: the role of hepatocyte growth
factor. Ann Thorac Surg. 2010 Mar;89(3):829-35) Canadian researchers at
Dalhousie University sought to determine whether an optimum time exists for
myoblast administration after cardiac injury. 

Using rats, the scientists cut off circulation to the
coronary artery to mimic a heart attack by ligation using microsurgery. 
Myoblasts where implanted at the time of ligation or 5 weeks after the infarct. 
Much higher engraftment of the cells was observed in animals that received the
cells immediately after the infarct.  Additionally, the hearts that received
myoblasts earlier seemed to have less damage.  This prompted the scientists to
ask the question; "why would delayed administration result in less homing and
retention?"

Previously we at Cellmedicine discussed the biological
observation that after a heart attack the injured heart muscle generates
chemicals that attract the body’s own stem cells.  One of these chemicals is
VEGF, which was discussed in this video

http://www.youtube.com/watch?v=NqEggEYilh0. Another chemical made by injured
heart tissue is hepatocyte growth factor (HGF).  Both of these proteins are made
when cells "sense" reduced oxygen, as well as various alterations in their
environment.  In the current study it was found that levels of HGF are
substantially elevated after the infarct and subsequently diminish by the 5th
week.  The investigators found that HGF stimulated proliferation and activity of
the myoblasts, and therefore believed that the decline in HGF may be one of the
reasons for the decreased efficacy with time. 

This could be a possible explanation for their results,
however, numerous factors may also be important to consider.  For example, it is
known in various situations of injury that as scar tissue forms, components of
the scar tissue inhibit regeneration.  Stem cells such as bone marrow
mesenchymal cells contain matrix metalloproteases that actively can "dig
through" scar tissue and support regeneration.  Myoblasts do not express such
enzymes, and additionally do not have the same homing ability to injured tissue.

The study would have substantially made more of a strong
case for the importance of HGF in stem cell activity if they used blocking
antibodies or knock-out mice specific for this gene.  Such a study would have
conclusively demonstrated the importance of HGF in this situation by
demonstrating less stem cell homing in its absence. 

One interesting point that is made is the possibility of
administering HGF into the myocardium of patients so as to enhance stem cell
homing.  Indeed, some companies such as Bioheart are already using such an
approach, see link

http://www.bioheartinc.com/prod-myocellsdf1.html.

Filed Under: Adult Stem Cells, Heart Disease, News, Stem Cell Research Tagged With: , , , ,
February 26, 2010 by

Adult Stem Cells Healing Hearts

Adult stem cells are being more and more used in patients
to achieve effects.  In the treatment of patients with heart failure, Dr. David
Prentice, discussed two studies in which adult stem cells appear to have some
benefit. 

The first study was the result of a Brazil-Florida joint
effort in which it was discovered that adult stem cells injected directly into
the heart could relieve angina. These data are not all that surprising given
that the first use of stem cells for heart failure involved a similar injection
procedure in Japan more than a decade ago.   Stem cell administration for
cardiac conditions has been performed in numerous clinical trials, here is a
link to a video on a previously published Phase III study in patients who
previously had a heart attack

http://www.youtube.com/watch?v=flv0RmzPyLU

In the current study eight patients were received the stem
cell treatment and according to the principle investigator Dr. Nelson Americo
Hossne, Jr, all of the patients treated exhibited some degree of improvement. 
The study suggested that the patients improved through stimulation of production
of new blood vessels.  Furthermore, the authors believed that the cells and the
procedure used to administer them are safe and effective. 

Dr. Hossne stated "For our patients, angina symptom
relief began as early as three months post-procedure with continuing improvement
through the twelfth month and sustained improvement past 18 months. Symptom
relief improved in all patients, suggesting that the effect is sustained, not
transitory."

The second study that Dr. Prentice discussed is from a
Chinese group in which the protein apelin was demonstrated to have an effect on
the ability of cardiac regenerative mechanisms.  In the study, 20 heart failure
patients were treated with their own bone marrow, 20 received placebo, and 20
healthy patients were compared for control.  All twenty of the heart failure
patients treated with adult stem cells showed significant improvement in cardiac
function within 21 days of treatment, while the standard medication patients
showed no improvement. The patients who received stem cells demonstrated a
significant increase in levels of apelin, which correlated with the recovery of
cardiac function.

Dr. Amit Patel, a world-recognized stem cell pioneer,
professor at University of Utah School of Medicine and an Editor of the journal
in which the papers were published stated: "Both studies demonstrate a
possible mechanistic approach in a clinical trial. These important findings
further enhance the understanding of the use of bone marrow derived cell therapy
for the treatment of cardiovascular disease."

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