Temporal patterns of bone marrow cell differentiation following transplantation in doxorubicin-induced cardiomyopathy.
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 (6 x 10(6) in 30 microl, n=59) or purified sca-1(pos) cells (4 x 10(5) in 30 microl, 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/3 x 10(-2) mm(3) 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/3 x 10(-2) mm(3) 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-1(pos) hematopoietic progenitor grafted mice hearts, no transdifferentiation into cardiac cells was detected at any time point.


CONCLUSIONS
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-1(pos) hematopoietic progenitor cell population. However, the very small number of transdifferentiated cells raises concerns over their functional efficacy.
Agbulut
Onnik
O
Inserm U572, Hôpital Lariboisière, 41, Bd de la Chapelle, 75475 Cedex 10, Paris, France. onnik.agbulut@larib.inserm.fr
Menot
Marie-Laurence
ML
Li
Zhenlin
Z
Marotte
Françoise
F
Paulin
Denise
D
Hagège
Albert A
AA
Chomienne
Christine
C
Samuel
Jane-Lyse
JL
Menasché
Philippe
P
D000818:Animals; D000903:Antibiotics, Antineoplastic; D000067696:Ataxin-1; D000067528:Ataxins; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D003893:Desmin / Q000235:genetics; D004317:Doxorubicin; D005455:Fluorescent Antibody Technique; D006333:Heart Failure / Q000601:surgery / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007763:Lac Operon; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D003893:Desmin; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D004317:Doxorubicin