Blood Vessel-Making Stem Cells Reprogrammed into Heart Muscle Cells That Improve Heart Function After a Heart Attack

Douglas Losardo at Northwestern University, Chicago, IL has done some extremely innovative work with transplanting bone marrow stem cells into the heart of human heart attack patients. His clinical trials have shown that human heart attack patients that receive infusions of their own bone marrow stem cells, on the average, show improved heart function, abatement of symptoms and improved prognosis.

In particular, Losardo has used CD34+ stem cells from bone marrow. CD34 is a cell surface protein that marks blood cell-making stem cells. CD34+ stem cells have been intensely studied and can form blood vessels in addition to red and white blood cells. The formation of new blood vessels in a sick heart improves the delivery of oxygen and blood to the heart, which improves heart function and recovery after a heart attack. Additionally, the CD34+ stem cells release a host of molecules that help the heart recover and function better.

The downside of CD34+ stem cells, is that they show limited ability to differentiate into heart muscle cells, and also do not survive terribly well in the heart after a heart attack. Therefore, Losardo has been on the hunt for a better technique for healing sick hearts, and a recent paper from his laboratory with mice provides a proof-of-concept of using reprogramming to form cells that can be used for regenerative therapies for the heart.

In this paper, Losardo and his team used a bone marrow stem cell called and “EPC,” which is short for “endothelial progenitor cell.” Endothelial cells compose blood vessels and EPCs make blood vessels. EPC infusions into a heart after a heart attack can improve heart function, but only modestly.

The first author of this paper, Melissa A. Thal, and her colleagues from Losordo’s laboratory treated EPCs isolated from mouse bone marrow with a cocktail of chemicals to move their gene expression patterns away from an EPC-specific pattern to that of a heart muscle cell. Their chemical cocktail contained either 5-Azacytidine, which changes the epigenetic profile of cells, and valproic acid, another epigenetic modifier, or a G9a histone dimethyltransferase called BIX-01294, which is also an epigenetic modifier. After soaking their EPCs in these chemicals for 48 hours, Genomic expression studies showed that pluripotency genes were expressed in these cells, as were genes for heart muscle and blood vessels. When cultured under the right conditions, these reprogrammed EPCs also formed good heart muscle cells.

These results were so remarkable that Losardo and his team decided to test these reprogrammed cells in the hearts of mice that have just experienced a heart attack. Transplantations of EPCs, or reprogrammed (REPCs) definitively showed that mice that had experienced heart attacks and did not have any interventions continued to deteriorate. However, EPC transplantations slightly improved the functional characteristics of the heart and tended to arrest the degradation of the heart. However, mice that had received REPCs had almost twice the % of blood ejected from the heart, significant reduction in the size of the damaged area, much less blood left in the heart after each pumping cycle, and better heart muscle function. Tissue examinations of the hearts showed that the REPC-transplanted hearts had grown new heart muscle whereas the EPC-transplanted hearts did not.

Thus this paper shows that it is feasible to reprogram EPCs from bone marrow into heart muscle cells and that it is also feasible to use these cells to repair the heart after a heart attack.

There were no significant side effects seen in the laboratory animals with the REPC transplantations. There were no tumors, no funky heart rhythms, and no sign of immunological rejection. Further work in animals will hopefully lead to human clinical trials and maybe even a commercially available treatment for heart attacks that use your own bone marrow stem cells. While that is a long way off, it is a hope that we all share.

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

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