Mobilized bone marrow cells repair the infarcted heart, improving function and survival

Abstract

Attempts to repair myocardial infarcts by transplanting cardiomyocytes or skeletal myoblasts have failed to reconstitute healthy myocardium and coronary vessels integrated structurally and functionally with the remaining viable portion of the ventricular wall. The recently discovered growth and transdifferentiation potential of primitive bone marrow cells (BMC) prompted us, in an earlier study, to inject in the border zone of acute infarcts Lin ؊ c-kit POS BMC from syngeneic animals. These BMC differentiated into myocytes and vascular structures, ameliorating the function of the infarcted heart. Two critical determinants seem to be required for the transdifferentiation of primitive BMC: tissue damage and a high level of pluripotent cells. On this basis, we hypothesized here that BMC, mobilized by stem cell factor and granulocyte-colony stimulating factor, would home to the infarcted region, replicate, differentiate, and ultimately promote myocardial repair. We report that, in the presence of an acute myocardial infarct, cytokine-mediated translocation of BMC resulted in a significant degree of tissue regeneration 27 days later. Cytokineinduced cardiac repair decreased mortality by 68%, infarct size by 40%, cavitary dilation by 26%, and diastolic stress by 70%. Ejection fraction progressively increased and hemodynamics significantly improved as a consequence of the formation of 15 ؋ 10 6 new myocytes with arterioles and capillaries connected with the circulation of the unaffected ventricle. In conclusion, mobilization of primitive BMC by cytokines might offer a noninvasive therapeutic strategy for the regeneration of the myocardium lost as a result of ischemic heart disease and, perhaps, other forms of cardiac pathology.

G-CSF Reduces Infarct Volume and Improves Functional Outcome after Transient Focal Cerebral Ischemia in Mice

“…Consequently, G-CSF is administered to patients suffering from neutropenia, most commonly as a result of chemotherapy after cancer. After administration in mice, G-CSF has been shown to increase the number of circulating bone marrow stem cells (BMC) released into the circulation (Orlic et al, 2001). After myocardial infarct, these BMC migrate to the area of damage and contribute to a significant amount of tissue regeneration (Orlic et al, 2001).…”

“…After administration in mice, G-CSF has been shown to increase the number of circulating bone marrow stem cells (BMC) released into the circulation (Orlic et al, 2001). After myocardial infarct, these BMC migrate to the area of damage and contribute to a significant amount of tissue regeneration (Orlic et al, 2001). After cerebral ischemia, it has been observed that either transplanted (Chen et al, 2001) or intravenously administered BMC (Chopp and Li, 2003) infiltrate into the lesion area.…”

Ex vivo delivered stromal cell-derived factor-1α promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium

“…This provides the required stimulus for mobilization of stem cells from BM niches to the damaged site as a part of a natural repair process [9]. The other key players involved in tissue ischemia-induced mobilization of BM progenitors to the circulation include vascular endothelial growth factor, placenta growth factor, stem cell factor, and granulocyte colony stimulating factor [10][11][12][13]. The effect of intrinsic SDF-1α up-regulated expression is, however, transient and insufficient for cardiac repair [4,6].…”

Research of cardiomyocyte precursors in adult rat heart

“…For example, bone marrow cells, including isolated populations of hematopoietic stem cells have been reported to differentiate into muscle, neurons, liver, vascular, lung, intestine and kidney tissue (Yoder, 2004). In addition, it has been shown that stem cells obtained from adult bone marrow not only were able to differentiate into cardiomyocytes but also contributed to restore cardiac function when either injected directly into the injured adult heart (Tomita et al, 1999) or exposed to myocardium via circulation (Orlic et al, 2001). Two distinct types of stem cells are currently known to reside within adult bone marrow: hematopoietic and mesenchymal stem cells.…”