Researchers report that they were able to guide bone marrow-derived human mesenchymal stem cells (hMSCs) into a cardiac progenitor phenotype that could heal, repair, and regenerate damaged heart tissue. Stem cells isolated from patients normally have a limited capacity to repair the heart, according to the team of Mayo Clinic investigators and Belgian collaborators.
The team thus primed the cells with a cocktail of recombinant cardiogenic growth factors. Using a mouse model of heart failure, they found a superior functional and structural benefit without adverse side effects over a one-year follow-up period.
The findings are published in the Journal of the American College of Cardiology in a paper titled "Guided Cardiopoiesis Enhances Therapeutic Benefit of Bone Marrow Human Mesenchymal Stem Cells in Chronic Myocardial Infarction."
hMSCs were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of transforming growth factor-beta1, bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-6 was formulated to engage hMSCs into cardiopoiesis. Derived hMSCs were injected into the myocardium of a nude infarcted murine model and followed over one year for functional and structural end points.
Although the majority of patient-derived hMSCs in their native state demonstrated limited effect on ejection fraction, two of 11 individuals showed an unusual capacity to improve contractile performance. These rare cells were characterized by high expression of homeobox transcription factor Nkx-2.5, T-box transcription factor TBX5, helix-loop-helix transcription factor MESP1, and myocyte enhancer factor MEF2C.
The cardiogenic cocktail was then used to induce this signature in nonreparative patient stem cells to program their capacity to repair the heart. "The successful use of guided lineage specified human stem cells is based on natural cardiogenic cues," notes Atta Behfar, M.D., Ph.D., first author of the study.
Mouse models with heart failure, injected with these cells, demonstrated significant heart function recovery along with improved survival rate after a year, compared to those treated with unguided stem cells or saline.
Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric, and gap junction content along with induction of myocardial cell cycle activity. Specifically, researchers found that the heart tissue healed more effectively, human cardiac and vascular cells participated in the regeneration, there was repair and strengthening of heart structures within the area of injury, and scars and vestiges of heart damage appeared to fade away.
Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived hMSCs in chronic ischemic cardiomyopathy, the scientists conclude. In an editorial also published in the Journal of the American College of Cardiology, Eduardo Marban, M.D., Ph.D., and Konstantinos Malliaras, M.D., of Cedars-Sinai Heart Institute in Los Angeles, write that the study "provides the first convincing evidence that MSCs, at least in vitro, can in fact become functional cardiomyocytes."