Enhanced Effect of Combining Human Cardiac Stem Cells and Bone Marrow Mesenchymal Stem Cells to Reduce Infarct Size and to Restore Cardiac Function After Myocardial Infarction

• Published in: Circulation (New York, N.Y.) Vol. 127; no. 2; pp. 213 - 223
• Main Authors: WILLIAMS, Adam R, HATZISTERGOS, Konstantinos E, HARE, Joshua M, ADDICOTT, Benjamin, MCCALL, Fred, CARVALHO, Decio, SUNCION, Viky, MORALES, Azorides R, DA SILVA, Jose, SUSSMAN, Mark A, HELDMAN, Alan W
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 15.01.2013
• Subjects: Animals; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Cardiology. Vascular system; Cells, Cultured; Diastole - physiology; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fundamental and applied biological sciences. Psychology; Heart Failure - pathology; Heart Failure - physiopathology; Heart Failure - therapy; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; Medical sciences; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Myocytes, Cardiac - cytology; Proto-Oncogene Proteins c-kit - metabolism; Recovery of Function - physiology; Sus scrofa; Systole - physiology; Transplantation, Heterologous; Treatment Outcome; Ventricular Function, Left - physiology; Vertebrates: cardiovascular system; Human; Myocardial infarction; Heart failure; stem cells; Stem cell; mesenchymal stem cells; Bone marrow; Cardiovascular disease; Coronary heart disease; Myocardial disease
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.112.131110

Because mesenchymal stem cells (MSCs) induce proliferation and differentiation of c-kit(+) cardiac stem cells (CSCs) in vivo and in vitro, we hypothesized that combining human (h) MSCs with c-kit(+) hCSCs produces greater infarct size reduction compared with either cell administered alone after myocardial infarction (MI). Yorkshire swine underwent balloon occlusion of the left anterior descending coronary artery followed by reperfusion and were immunosuppressed after MI with cyclosporine and methylprednisolone. Intramyocardial combination hCSCs/hMSCs (1 million cells/200 million cells, n=5), hCSCs alone (1 million cells, n=5), hMSCs alone (200 million cells, n=5), or placebo (phosphate-buffered saline; n=5) was injected into the infarct border zones at 14 days after MI. Phenotypic response to cell therapy was assessed by cardiac magnetic resonance imaging and micromanometer conductance catheterization hemodynamics. Although each cell therapy group had reduced MI size relative to placebo (P<0.05), the MI size reduction was 2-fold greater in combination versus either cell therapy alone (P<0.05). Accompanying enhanced MI size reduction were substantial improvement in left ventricular chamber compliance (end-diastolic pressure-volume relationship; P<0.01) and contractility (preload recruitable stroke work and dP/dtmax; P<0.05) in combination-treated swine. Ejection fraction was restored to baseline in cell-treated pigs, whereas placebo pigs had persistently depressed left ventricular function (P<0.05). Immunohistochemistry showed 7-fold enhanced engraftment of stem cells in the combination therapy group versus either cell type alone (P<0.001). Combining hMSCs and hCSCs as a cell therapeutic enhances scar size reduction and restores diastolic and systolic function toward normal after MI. Taken together, these findings illustrate important biological interactions between c-kit(+) CSCs and MSCs that enhance cell-based therapeutic responses.