© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Temporal patterns of bone marrow cell differentiation following transplantation in doxorubicin-induced cardiomyopathy
aInserm U572, Hôpital Lariboisière, 41, Bd de la Chapelle, 75475 Paris Cedex 10, France
bLaboratory of Hematopoietic Cell Biology, Inserm E003, Hôpital Saint-Louis, Paris, France
cUniversity Denis-Diderot, Paris, France
dDepartment of Cardiology, Hopital Européen Georges Pompidou, Paris, France
eDepartment of Cardiovascular Surgery & Inserm U572, Hopital Européen Georges Pompidou, Paris, France
onnik.agbulut{at}larib.inserm.fr
* Corresponding author. Tel.: +33-1-4463-1720; fax: +33-1-4874-2315.
Objective: Recent studies have suggested benefits of bone marrow cell transplantation for the regeneration of ischemic cardiac tissue. To extend the potential of cell transplantation, we assessed this treatment in a mouse model of acute nonischemic doxorubicin-induced cardiomyopathy. Methods: To allow detection of engrafted cells, we used transgenic mice expressing the nuclear-located LacZ under the control of either desmin or vimentin promoters, which identify muscle lineage and mesenchymal cells, respectively. All transplanted cells were also labeled with the fluorescent dye DIL. One week after the administration of doxorubicin (15 mg/kg), mice were intramyocardially injected with either allogeneic unpurified bone marrow cells (6x106 in 30 µl, n = 59) or purified sca-1pos cells (4x105 in 30 µl, n = 22). In parallel, control normal mice received only unpurified bone marrow cells (n = 28). Hearts were harvested at serial intervals until 2 weeks after transplantation and analyzed by immunohistochemistry to assess the degree of engraftment and transplanted cell differentiation. Results: In control mice, no differentiation of bone marrow cells was detected. In contrast, unpurified bone marrow cells grafted into diseased myocardium featured two successive phases of cell differentiation. The first yielded cells with a mesenchymal phenotype (44.1±10.1 cells/3x10–2 mm3 at 2 days), was transient and lasted 1 week. The second phase was characterized by cells with a muscular phenotype detected in a small number of cells (5.6±2.3 cells/3x10–2 mm3 at 7 days). Two weeks after transplantation, some of these cells appeared phenotypically close to cardiomyocytes, as evidenced by morphology and positive staining for myosin binding protein C, vinculin and myosin heavy chain. In sca-1pos hematopoietic progenitor grafted mice hearts, no transdifferentiation into cardiac cells was detected at any time point. Conclusion: These data support the hypothesis of the potential for a myogenic differentiation of bone marrow cells following engraftment in a nonischemic model of global cardiomyopathy. Bone marrow-derived cells amenable to cardiac differentiation are present in total unpurified bone marrow but not in the sca-1pos hematopoietic progenitor cell population. However, the very small number of transdifferentiated cells raises concerns over their functional efficacy.
KEYWORDS Cell therapy; Doxorubicin-induced cardiomyopathy; Hematopoietic progenitor cell; Transgenic mice
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