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UBC Theses and Dissertations

The role of cardiac-resident mesenchymal progenitors in the development of fibrosis in the heart Paylor, Ben Arthur


Fibrosis is a response to injury that involves cell proliferation and deposition of extracellular matrix; pathological fibrosis can be considered to be imperfect wound healing that impairs organ function. Our understanding of the role and source of cardiac fibroblasts (CFs) in the development of pathological fibrosis is severely hampered by a lack of robust in vivo markers and understanding of the heterogeneity within this vaguely defined population. Here we demonstrate the existence of cardiac-resident mesenchymal progenitor cells (cMSCs, identified as CD31-:CD45-:PDGFRα+:Sca-1+) and show that their in vivo pharmacological modulation with the receptor tyrosine kinase inhibitors nilotinib or imatinib reduces fibrosis and improves cardiac function following acute or chronic cardiac injury. We observed in vivo the initial expansion of Sca-1+ cMSCs following acute cardiac injury contributes to mature collagen-producing PDGFRα+:Sca-1- CFs. In two models of acute injury, isoproterenol treatment and ligation of the left anterior descending artery (LAD), treatment with nilotinib led to reduced proliferation of both cMSCs and CFs but an increased relative prevalence of cMSCs, suggesting a blockade in the fibrogenic differentiation of these cells. Extending these observations into mdx mice, a model of chronic myocardial dystrophy displaying cardiac fibrosis after one year of age, we investigated the effects of long-term treatment with imatinib as a potential pharmacologic therapy. mdx mice treated with imatinib for 15 months displayed improved cardiac function and reduced cardiac fibrosis. These improvements were matched by a reduced quantity of cMSCs within treated myocardial tissue. Finally, given the well-known role of PDGFRα+ Sca-1+ mesenchymal progenitors in the development of fibrofatty infiltration in skeletal muscle, we postulated a role for phenotypically similar cMSCs in the fibrofatty infiltrate observed inarrhythmogenic cardiomyopathy. Using a genetic model that dysregulates quiescence in mesenchymal populations, we observed hyperproliferation of cMSCs and spontaneous generation of adipose deposits within the myocardium, supporting our hypothesis that cMSCs are the cellular source of the fibrofatty infiltrate. In their entirety, our findings demonstrate the importance of differing subsets of mesenchymal cell populations within the heart and potential therapeutic benefit of targeting them pharmacologically following acute ischemic damage or during chronic dystrophic injury.

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