Abstract
Abstract only
Background:
Most clinical studies used autologous bone marrow stem cells (BMSCs) for myocardial repair in elderly patients. Accounting for the limited success in clinical studies, we hypothesized that aging impairs the reparability of BMSCs which limits their therapeutic efficacy.
Methods and Results
: We compared MSCs from young (
Yng
MSCs; 8–12 weeks) and old (
Old
MSCs; 24–26 weeks) rats for their responsiveness to anoxia and therapeutic potential. A significantly higher expression of angiogenic growth factors was observed by
Yng
MSCs under anoxia as compared with
Old
MSCs, cultured either alone or in co-culture (
Co-old
MSCs) with
Yng
MSCs. Likewise,
Yng
MSCs showed significantly higher ability to form tubular structures during Matrigel assay. LDH release assay showed that
Yng
MSCs were more tolerant to apoptotic stimuli (glucose and serum starvation under anoxia) as compared with
Old
MSCs and
Co-old
MSCs, with a possible role for pro-survival proteins
p21
and
p27
which showed increased gene expression (>8-fold and 13-fold respectively) in
Yng
MSCs under anoxia as compared with
Old
MSCs. For
in vivo
studies, acute myocardial infarction model was developed in Fisher-344 rats (n=38). The animals were grouped to receive 70μl DMEM without cells (group-1) or containing 3×10
6 Yng
MSCs (PKH67 labeled; group-2), or
Old
MSCs (PKH26 labeled; group-3) and mixture of
Yng
MSCs+
Old
MSCs (1.5×10
6
cells each, group-4). Histological studies revealed that by day-7,
Yng
MSCs were already showing elongated morphology with orientation similar to the host muscle architecture. Transmission electron microscopy and confocal imaging after immuno-staining for vonWillebrand Factor-VIII, myosin heavy chain, cardiac actinin and connexin-43, showed superior angiomyogenic potential of
Yng
MSCs. Echocardiography showed significantly improved indices of left ventricle contractile function in group-4.
Conclusions:
Aging significantly weakened the responsiveness of
Old
MSCs to anoxia and their differentiation potential. Their reparability of infarcted heart was also impaired with aging which was not improved by the presence of
Yng
MSCs. Hence, transplantation of stem cells from young donors should be considered for heart cell therapy in elderly patients for better prognosis.