Mechanism of Improved Cardiac Function After Bone Marrow Mononuclear Cell Therapy

Abstract

Background-Cell therapy is a promising option to improve functional recovery after ischemia. Several subsets of bone marrow-derived cells were shown to reduce infarct size and increase ejection fraction in experimental models of ischemia. The mechanisms underlying the functional improvement are diverse and have been shown to include paracrine effects of the injected cells, as well as a variable degree of differentiation to endothelial cells, pericytes, smooth muscle, and cardiac muscle. Methods and Results-To elucidate the true nature of such plasticity and contribution to recovery, we engineered vectors that encoded inducible suicide genes under the control of endothelium (endothelial nitric oxide synthase)-, smooth muscle (SM22␣)-, and cardiomyocyte (␣-MHC)-specific promoters, thereby allowing selective depletion of the individual cell lineage acquired by the transplanted undifferentiated bone marrow-derived cells. Lentivirally delivered thymidine kinase, which converts the prodrug ganciclovir into a cytotoxic agent, was used to selectively eliminate cells 2 weeks after transplantation of bone marrow mononuclear cells in an acute myocardial infarction model. We demonstrate that elimination of transplanted endothelium-committed or SM22␣-expressing cells, but not cardiaccommitted cells, induced a significant deterioration of ejection fraction. Moreover, elimination of endothelial nitric oxide synthase-expressing cells 2 weeks after injection reduced capillary and arteriole density. Key Words: cell therapy Ⅲ endothelial nitric oxide synthase Ⅲ vasculature Ⅲ angiogenesis-inducing agents C ell therapy is a promising option to restore cardiac function after ischemia or during heart failure. Various subsets of adult bone marrow-derived or tissue-resident progenitor cells were shown to augment the recovery of cardiac function after ischemia in experimental models. Most clinical studies to date have been performed with total bone marrow mononuclear cells (BMCs), which comprise hematopoietic progenitor cells, mesenchymal stem cells, and monocytes. Treatment of patients with acute myocardial infarction with BMCs induced a modest increase in ejection fraction and beneficially interfered with left ventricular remodeling processes in most but not all studies. 1 However, the mechanisms underlying the functional improvement are discussed controversially, and the long-term engraftment and differentiation were variable between the studies. Because cardiac function was improved in some studies even in the absence of significant long-term engraftment and differentiation of the injected cells, it has been speculated that paracrine mechanisms might be responsible for the therapeutic benefit achieved by bone marrow-derived cells (for review, see Gnecchi et al 2 ). Meanwhile, various studies confirmed that progenitor cells release paracrine factors that modulate angiogenesis, cardiomyocyte apoptosis, fibrosis, and inflammation, and various cytokines and growth factors have been identified in progenitor cells that mechanistically cont...

Pluripotent Stem Cell-Engineered Cell Sheets Reassembled with Defined Cardiovascular Populations Ameliorate Reduction in Infarct Heart Function Through Cardiomyocyte-Mediated Neovascularization

“…How can we achieve a more profound elucidation of the mechanism, which is hampered due to the heterogeneity of the transplanted cells? Recently, Yoon et al tackled this issue through the injection of genetically modified lines of BM mononuclear cells for acute MI model, followed by selective cell depletions of CMs (aMHC þ ), ECs (endothelial nitric oxide synthase positive), or MCs (SM22a þ ) 2 weeks after injection [49]. The results that elimination of ECs or MCs induced a significant deterioration of cardiac function suggested the importance of angiogenesis in functional restoration after BM cell therapy.…”

Bone marrow mononuclear cells induce beneficial remodeling and reduce diastolic dysfunction in the left ventricle of hypertensive SS/MCWi rats

“…Numerous studies have investigated possible underlying mechanisms of action for BMMNCs when administered to rats after myocardial infarction (14,17,30). Evidence for both direct integration of cells, to revascularize and regenerate damaged muscle tissue, as well as indirect paracrine actions, such as the secretion of proangiogenic and/or antifibrotic growth factors and cytokines, has been found.…”

Loss of AngiomiR-126 and 130a in Angiogenic Early Outgrowth Cells From Patients With Chronic Heart Failure

“…More recently, 2 studies have supported the concept that proangiogenic effects of bone marrow-derived mononuclear cells or CD34 ϩ cells are crucial for their capacity to improve cardiac function, using either selective elimination of endothelial nitric oxide synthase or anti-vascular endothelial growth factor treatment. 23,24 Of note, in the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) study, a beneficial effect of administration of angiogenic EOCs on cardiac function was observed in patients with acute MI, 25 whereas no such effect was detected in patients with an ischemic cardiomyopathy (ICM). 26 The present study was therefore designed to characterize regulation of angiomiRs in angiogenic EOCs and circulating CD34 ϩ cells from patients with chronic heart failure (CHF) caused by ICM and to determine their role for in vivo cardiac neovascularization and functional cardiac repair capacity as examined after transplantation of angiogenic EOCs into nude mice with MI.…”