Bone Marrow Cells Differentiate in Cardiac Cell Lineages After Infarction Independently of Cell Fusion

Abstract

Abstract-Recent studies in mice have challenged the ability of bone marrow cells (BMCs) to differentiate into myocytes and coronary vessels. The claim has also been made that BMCs acquire a cell phenotype different from the blood lineages only by fusing with resident cells. Technical problems exist in the induction of myocardial infarction and the successful injection of BMCs in the mouse heart. Similarly, the accurate analysis of the cell populations implicated in the regeneration of the dead tissue is complex and these factors together may account for the negative findings. In this study, we have implemented a simple protocol that can easily be reproduced and have reevaluated whether injection of BMCs restores the infarcted myocardium in mice and whether cell fusion is involved in tissue reconstitution. For this purpose, c-kit-positive BMCs were obtained from male transgenic mice expressing enhanced green fluorescence protein (EGFP). EGFP and the Y-chromosome were used as markers of the progeny of the transplanted cells in the recipient heart. By this approach, we have demonstrated that BMCs, when properly administrated in the infarcted heart, efficiently differentiate into myocytes and coronary vessels with no detectable differentiation into hemopoietic lineages. However, BMCs have no apparent paracrine effect on the growth behavior of the surviving myocardium. Within the infarct, in 10 days, nearly 4.5 million biochemically and morphologically differentiated myocytes together with coronary arterioles and capillary structures were generated independently of cell fusion. In conclusion, BMCs adopt the cardiac cell lineages and have an important therapeutic impact on ischemic heart failure. Key Words: transdifferentiation Ⅲ myocardial regeneration Ⅲ cell fusion S everal studies have suggested that adult bone marrow cells (BMCs) can differentiate into cell lineages distinct from the organ in which they reside. 1 The recognition that BMCs maintain some of the growth potential of younger cells has promoted a heated debate about stem cell plasticity and the utilization of BMCs in the treatment of ischemic heart failure. 2 The efficacy of BMCs for myocardial regeneration after infarction was documented 3 years ago, 3 and this protocol was rapidly applied clinically. 4 Nine clinical trials have been completed and several are ongoing and, with the exception of one, 5 all other show positive results. 4,6 -12 Because of the difficulty to demonstrate myocardial regeneration in humans in the absence of cardiac biopsies, three possibilities have been raised in the interpretation of the improvement of cardiac function in patients. They include the development of coronary vessels that rescue hibernating myocardium, 11,12 de novo formation of myocytes 8,10 and vascular structures 4,8,9,12 or the activation and growth of resident progenitor cells via a paracrine effect 12 mediated by BMCs. These are important biological and clinical questions that can be addressed experimentally to acquire a better understanding of the re...

Progress and prospects: Cell based regenerative therapy for cardiovascular disease

“…Initial reports suggesting transdifferentiation of cells delivered to target tissues into the organ host cells have been followed by reports of cell fusion and by claims of no meaningful cell-cell transformation, leading to a major controversy. The evidence for trans-differentiation in vivo is contradictory with some studies finding evidence for phenotypic switches following injections of cells into the heart or other organs [9][10][11] while others cannot demonstrate this phenomenon. [12][13][14][15] The reasons for these discrepancies are manifold and include both technical as well as poorly understood biological issues.…”

Adhesion Proteins, Stem Cells, and Arrhythmogenesis

“…Engraftment of unfractionated bone marrow cells as well as pure MSC do appear to have positive effects on cardiac function and these benefits were confirmed in studies by different laboratories [31][32][33]. Due to that and the fact that MSC can be obtained from the patient's own bone marrow (which significantly reduces ethical concerns and immunogenicity issue), the MSC-based therapy appears to be the most feasible clinical option, at least from today's standpoint.…”

“…First, there are studies that argue for transdifferentiation of MSC into cardiac muscle cells [31,34,35]. As an example, one can cite a recent study in which GFP-labeled MSC were isolated from a male mouse and injected into a female heart, and the progeny of the transplanted cells was identified by fluorescence, Y-chromosome markers, and microspheres [31].…”

“…As an example, one can cite a recent study in which GFP-labeled MSC were isolated from a male mouse and injected into a female heart, and the progeny of the transplanted cells was identified by fluorescence, Y-chromosome markers, and microspheres [31]. Ten days after injection the infarct size was decreased by 17% and a population of new myocytes was noted.…”

Inflammatory responses after intracoronary mononuclear BM cell therapy in swine

“…7 Known as developmental plasticity, the implanted cells could differentiate into different cells of different lineages in ischemic myocardium. [8][9][10] All of the research that has been conducted emphasizes the amelioration of the heart function several months after cell therapy, [1][2][3] whereas the variations of cytokine and heart function during the acute phase have not been delineated. Evidence indicates that cytokines are involved in the pathogenesis of various inflammatory disorders.…”