| dc.description.abstract | 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. | en_US |
