The role of bone marrow derived cells in cardiac repair
Current pharmacological therapies fail to address the final end-point of cardiac ischaemia — the death and dysfunction of cardiomyocytes. Advances in stem cell biology have provided hope, for the first time, of addressing this underlying pathology. The work performed here was designed to further understanding of the mechanisms by which bone marrow derived cells improve damaged myocardium. In situ hybridisation was used to detect sex chromosomes within ex-planted, human, sex-mismatch hearts. Host derived cells were found at low frequency in donor hearts, suggesting ongoing post-natal cardiac tissue repair. Human mesenchymal stem cells were examined in vitro and in a rat model of ischaemia-reperfusion injury. Cardiomyocytes were not formed when cultured with either 5-azacytidine or ascorbic acid, and the cells failed to home to the ischaemic heart or improve cardiac function. In the same model, rat mononuclear cells significantly reduced infarct size when administered immediately upon reperfusion. Cells were rarely identified within the myocardium. No functional improvement was seen acutely, but at seven days cardiac function had improved. The low frequency of cells retained in the heart suggested that a process other than transdifferentiation accounted for the observations. Hence, evidence for paracrine actions was sought. In the same model, apoptosis and necrosis in cardiomyocytes were found to be significantly reduced. Western blots demonstrated activation of the reperfusion salvage kinase pathway, analogous to that seen in ischaemic pre- and post-conditioning. Blocking this pathway abolished the infarct size reduction. Global proteomic analysis confirmed alterations in protein expression consistent with known cardioprotective pathways. In conclusion, endogenous myocardial repair processes are inadequate to compensate for pathological insults. Supplementation with mononuclear cells in an ischaemia-reperfusion model produced significant benefit to infarct size and cardiac function. The mechanism of benefit appears to be induced by paracrine effects activating pro-survival pathways.
AuthorsLovell, Matthew J.
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