Mesenchymal stem cells (MSCs) exist in a variety of places throughout the body. They are found in bone marrow, the lower levels of the skin, umbilical cord and umbilical cord blood, placenta, amniotic membrane, muscle, blood vessels, liver, synovial membranes that surround joints, endometrial glands, fat, tendons, and other locations as well. MSCs have the ability to differentiate into cartilage-making cells, fat-making cells, muscle-making cells or bone-making cells Other protocols exist to differentiate MSCs into heart muscle (Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease.Circ Res. 2011 Sep 30;109(8):923-40; Song YH, Pinkernell K, Alt E.Stem cell induced cardiac regeneration: fusion/mitochondrial exchange and/or transdifferentiation? Cell Cycle. 2011 Jul 15;10(14):2281-6.), neurons (Scuteri A, Miloso M, Foudah D, Orciani M, Cavaletti G, Tredici G.Mesenchymal stem cells neuronal differentiation ability: a real perspective for nervous system repair? Curr Stem Cell Res Ther. 2011 Jun;6(2):82-92), and liver cells (Al Battah F, De Kock J, Vanhaecke T, Rogiers V. Current status of human adipose-derived stem cells: differentiation into hepatocyte-like cells. ScientificWorldJournal. 2011;11:1568-81). The therapeutic possibilities of MSCs has been widely recognized by stem cell scientists and MSCs have been the subject of many past and ongoing clinical trials.
The use of MSCs to treat heart attack patients has been the subject of several clinical trials (Mazo M, Araña M, Pelacho B, Prosper F. Mesenchymal stem cells and cardiovascular disease: a bench to bedside roadmap. Stem Cells Int. 2012;2012:175979). While MSCs do provide a modicum of healing to damaged hearts, the ability of MSCs to differentiate into heart muscle is low. Many experiments have focused upon increasing the percentage of implanted MSCs that differentiate into heart muscle cells. However, a recent paper from a research group at the Keio University School of Medicine and the National Institute for Child Health and Development in Tokyo, Japan has taken a different approach to this problem.
Drugs that treat blood pressure include the “angiotensin II receptor blockers” or ARBs. ARBs prevent a small polypeptide called angiotensin II from binding its receptor. WHen it binds to its receptor, angiotensin II causes rather substantial constriction of blood vessels throughout the body, and this raises blood pressure. By preventing blood vessel constriction, ARBs can lower blood pressure. Also, many heart attack patients are on blood pressure medicines, and ARBs are one of the those normally given to heart attack patients.
One particular ARB is called candesartan, and the commercial names are Atacand, Amias, Blopress, and Ratacand. In this paper by Yohei Namasawa and colleagues in the laboratories of Kaoru Segawa, Satoshi Ogawa, and Akihiro Umezawa, determined if treating human MSCs from bone marrow could increase the ability of these cells to form heart muscle cells. To induce heart muscle cells, they used a popular technique from the literature that grows MSCs in culture with mouse heart muscle cells. The interaction between the MSCs and the heart muscle cells in culture drives the MSCs to form heart muscle-like cells at a somewhat low-frequency. This group determined if MSCs became heart muscle cells by testing for the presence of heart muscle-specific proteins (cardiac-specific troponin-I). To prevent them from confusing MSCs with the mouse heart muscle cells, the MSCs were pre-labeled with a fluorescent protein.
Candesartan treatment of MSCs more than doubled the ability of MSCs to form heart muscle cells in culture. When these same cells were transplanted into the hearts of rats that had suffered heart attacks, the results were even more interesting. MSC transplantation into the hearts of rats that had recently suffered a heart attack. Those animals that had undergone surgery but were not given any heart attacks, showed an average reduction of about 3% in their ejection fraction (percentage of blood that pumped from the heart during each heart beat). Given that the standard deviation was close to this number, this change is not significant. The control animals that were not given MSC treatments showed an average decrease of just over 10% in their ejection fraction. Animals treated with MSCs that had suffered heart attacks showed a decrease of about 6-7%. This is significantly less of a decrease than in the control, but it is still a decrease. When the rat hearts were treated with MSCs that had been pretreated with candesartan, they showed an average 3-4% increase in ejection fraction. If the rats were given candesartan after the heart attack, it raised the ejection fraction 1-2%. If the rats were given candesartan, and treated with bone marrow cells after the heart attack, their ejection fractions decreased by the same as the sham group. However, if the rats were given candesartan and MSCs that had been pretreated with candesartan after the heart attack, their ejection fractions increased by 10-12%. Other heart function indicators improved too, since transplantation of the candesartan-treated bone marrow cells improved the “end systolic dimension,” which is an indication of how well the heart contracts.
When hearts were examined after the animals died, those animals that had received transplantations of the candesartan-pretreated bone marrow cells had 2-3 times more heart muscle cells derived from the implanted MSCs than did the controls transplanted with non-treated bone marrow. Also, post-mortem examination of hearts from the treated rats showed that the rats treated with candesartan-pretreated bone marrow cells had much small heart scars than the other groups (5%-7% smaller).
These experiments, though pre-clinical, suggest that pre-treatment of MSCs with compounds like candesartan can increase their ability to differentiate into heart muscle cells. This would certainly augment their ability of heal the hearts of patients after a heart attack. While further work is certainly warranted, a clinical study should be proposed to test if this efficacy applies to human hearts as well.