Endometrial regenerative cells for treatment of heart failure: a new stem cell enters the clinic

Leo Bockeria, Vladimir Bogin, Olga Bockeria, Tatyana Le, Bagrat Alekyan, Erik J Woods, Amalia A Brown, Thomas E Ichim and Amit N Patel

Journal of Translational Medicine 2013, 11:56 doi:10.1186/1479-5876-11-56
Published: 5 March 2013

Heart failure is one of the key causes of morbidity and mortality world-wide. The recent findings that regeneration is possible in the heart have made stem cell therapeutics the Holy Grail of modern cardiovascular medicine. The success of cardiac regenerative therapies hinges on the combination of an effective allogeneic “off the shelf” cell product with a practical delivery system. In 2007 Medistem discovered the Endometrial Regenerative Cell (ERC), a new mesenchymal-like stem cell. Medistem and subsequently independent groups have demonstrated that ERC are superior to bone marrow mesenchymal stem cells (MSC), the most widely used stem cell source in development. ERC possess robust expansion capability (one donor can generate 20,000 patients doses), key growth factor production and high levels of angiogenic activity. ERC have been published in the peer reviewed literature to be significantly more effect at treating animal models of heart failure (Hida et al. Stem Cells 2008).Current methods of delivering stem cells into the heart suffer several limitations in addition to poor delivery efficiency. Surgical methods are highly invasive, and the classical catheter based techniques are limited by need for sophisticated cardiac mapping systems and risk of myocardial perforation. Medistem together with Dr. Amit Patel Director of Clinical Regenerative Medicine at University of Utah have developed a novel minimally invasive delivery method that has been demonstrated safe and effective for delivery of stem cells (Tuma et al. J Transl Med 2012). Medistem is evaluating the combination of ERC, together with our retrograde delivery procedure in a 60 heart failure patient, double blind, placebo controlled phase II trial. To date 17 patients have been dosed and preliminary analysis by the Data Safety Monitoring Board has allowed for trial continuation.The combined use of a novel “off the shelf” cell together with a minimally invasive 30 minute delivery method provides a potentially paradigm-shifting approach to cardiac regenerative therapy.


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.

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.