title: Transcriptional profiling of young and old mesenchymal stem cells in response to oxygen deprivation and reparability of the infarcted myocardium.
abstract: Most clinical studies have used autologous bone marrow (BM) stem cells for myocardial regeneration in elderly patients. We hypothesize that aging impairs the survival and differentiation potential of BM stem cells thus limiting their therapeutic efficacy. BM-derived MSCs from young ((Yng)MSCs; 8-12 weeks) and old ((Old)MSCs; 24-26 months) rats were purified and assessed for their responsiveness to anoxia and reparability of infarcted heart. Higher expression of angiogenic growth factors was observed by (Yng)MSCs under anoxia as compared to (Old)MSCs, cultured either alone or in co-culture ((Co-old)MSCs) with (Yng)MSCs. Likewise, (Yng)MSCs were more tolerant to apoptotic stimuli and showed higher ability to form tubular structures during in vitro Matrigel assay as compared to (Old)MSCs and (Co-old)MSCs with a possible role of p21 and p27 as contributory survival factors. For in vivo studies, acute myocardial infarction model was developed in Fischer-344 rats (n=38). The animals were grouped to receive 70 microl basal DMEM without cells (group 1) or containing 2 x 10(6)(Yng)MSCs (PKH67 labeled; group 2) or (Old)MSCs (PKH26 labeled; group 3) and mixture of (Yng)MSCs + (Old)MSCs (1 x 10(6) cells each; group 4). Histological studies revealed that by day 7, (Yng)MSCs showed elongated morphology with orientation similar to the host muscle architecture. Electron microscopy and confocal imaging after fluorescent immunostaining showed superior angiomyogenic potential of (Yng)MSCs. Echocardiography showed significantly preserved heart function indices in the animals transplanted with (Yng)MSCs. Aging impairs the responsiveness of (Old)MSCs to anoxia and their differentiation potential. (Yng)MSCs fail to alter the survival of (Old)MSCs under in vitro as well as in vivo conditions. It is therefore concluded that transplantation of stem cells from young donors would be a better option for heart cell therapy in future clinical studies.
authors.affiliation: Department of Pathology and Laboratory Medicine, 231-Albert Sabin Way, University of Cincinnati, OH 45267-0529, USA.
authors.forename: Shujia
authors.initials: S
authors.lastname: Jiang
authors.forename: Husnain
authors.initials: H
authors.lastname: Kh Haider
authors.forename: Rafeeq P H
authors.initials: RP
authors.lastname: Ahmed
authors.forename: Niagara M
authors.initials: NM
authors.lastname: Idris
authors.forename: Asmat
authors.initials: A
authors.lastname: Salim
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashraf
mesh_terms: D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008854:Microscopy, Electron; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D010100:Oxygen