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Free keywords:
RANDOMIZED PHASE-1 TRIAL; STEM-CELLS; HEART; SURVIVAL; CARDIOMYOPATHY;
MATRIX; ADULT; DIFFERENTIATION; PROLIFERATION; REGENERATIONadult stem cells; cell adhesion molecules fibronectins; myocardial
infarction;
Abstract:
Rationale: Adoptive transfer of cardiac progenitor cells (CPCs) has entered clinical application, despite limited mechanistic understanding of the endogenous response after myocardial infarction (MI). Extracellular matrix undergoes dramatic changes after MI and therefore might be linked to CPC-mediated repair.
Objective: To demonstrate the significance of fibronectin (Fn), a component of the extracellular matrix, for induction of the endogenous CPC response to MI.
Methods and Results: This report shows that presence of CPCs correlates with the expression of Fn during cardiac development and after MI. In vivo, genetic conditional ablation of Fn blunts CPC response measured 7 days after MI through reduced proliferation and diminished survival. Attenuated vasculogenesis and cardiogenesis during recovery were evident at the end of a 12-week follow-up period. Impaired CPC-dependent reparative remodeling ultimately leads to continuous decline of cardiac function in Fn knockout animals. In vitro, Fn protects and induces proliferation of CPCs via (1)-integrin-focal adhesion kinase-signal transducer and activator of transcription 3-Pim1 independent of Akt.
Conclusions: Fn is essential for endogenous CPC expansion and repair required for stabilization of cardiac function after MI.
