[HTML][HTML] Angiogenesis, cardiomyocyte proliferation and anti-fibrotic effects underlie structural preservation post-infarction by intramyocardially-injected cardiospheres

E Tseliou, G De Couto, J Terrovitis, B Sun, L Weixin… - PloS one, 2014 - journals.plos.org
E Tseliou, G De Couto, J Terrovitis, B Sun, L Weixin, L Marbán, E Marbán
PloS one, 2014journals.plos.org
Objective We sought to understand the cellular and tissue-level changes underlying the
attenuation of adverse remodeling by cardiosphere transplantation in acute myocardial
infarction (MI). Background Cardiospheres (CSps) are heart-derived multicellular clusters
rich in stemness and capable of multilineage differentiation. Post-MI CSp transplantation
improves left ventricular (LV) function and attenuates remodeling in both small and large
animal studies. However, the mechanisms of benefit have not yet been fully elucidated …
Objective
We sought to understand the cellular and tissue-level changes underlying the attenuation of adverse remodeling by cardiosphere transplantation in acute myocardial infarction (MI).
Background
Cardiospheres (CSps) are heart-derived multicellular clusters rich in stemness and capable of multilineage differentiation. Post-MI CSp transplantation improves left ventricular (LV) function and attenuates remodeling in both small and large animal studies. However, the mechanisms of benefit have not yet been fully elucidated.
Methods
Four groups were studied: 1) “Sham” (Wistar Kyoto rats with thoracotomy and ligature without infarction); 2) “MI” (proximal LAD ligation with peri-infarct injection of vehicle); 3) “MI+CSp” (MI with cardiospheres injected in the peri-infarct area); 4) “Small MI” (mid-LAD ligation only).
Results
In vivo 1 week after CSp transplantation, LV functional improvement was associated with an increase in cardiomyocyte proliferation. By 3 weeks, microvessel formation was enhanced, while cardiomyocyte hypertrophy and regional fibrosis were attenuated. Collagen deposition was reduced, collagen degradation was enhanced, and MMPs were upregulated. The beneficial effects of CSp transplantation were not observed in the Small MI group, indicating that the effects are not solely due to CSp-induced cardioprotection. In vitro, CSp-conditioned media reduced collagen production in coculture with fibroblasts and triggered neoangiogenesis in an ex vivo aortic ring assay.
Conclusion
Cardiospheres enhance cardiomyocyte proliferation and angiogenesis, and attenuate hypertrophy and fibrosis, in the ischemic myocardium. These synergistic effects underlie the attenuation of adverse remodeling by cardiospheres.
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