Prolonged elevated levels of c‐kit+ progenitor cells after a myocardial infarction by beta 2 adrenergic receptor priming

Abstract

Endogenous progenitor cells may participate in cardiac repair after a myocardial infarction (MI). The beta 2 adrenergic receptor (ß2‐AR) pathway induces proliferation of c‐kit+ cardiac progenitor cells (CPC) in vitro. We investigated if ß2‐AR pharmacological stimulation could ameliorate endogenous CPC‐mediated regeneration after a MI. C‐kit+ CPC ß1‐AR and ß2‐AR expression was evaluated in vivo and in vitro. A significant increase in the percentage of CPCs expressing ß1‐AR and ß2‐AR was measured 7 days post‐MI. Accordingly, 24 hrs of low serum and hypoxia in vitro significantly increased CPC ß2‐AR expression. Cell viability and differentiation assays validated a functional role of CPC ß2‐AR. The effect of pharmacological activation of ß2‐AR was studied in C57 mice using fenoterol administered in the drinking water 1 week before MI or sham surgery or at the time of the surgery. MI induced a significant increase in the percentage of c‐kit+ progenitor cells at 7 days, whereas pretreatment with fenoterol prolonged this response resulting in a significant elevated number of CPC up to 21 days post‐MI. This increased number of CPC correlated with a decrease in infarct size. The immunofluorescence analysis of the heart tissue for proliferation, apoptosis, macrophage infiltration, cardiomyocytes surface area, and vessel density showed significant changes on the basis of surgery but no benefit due to fenoterol treatment. Cardiac function was not ameliorated by fenoterol administration when evaluated by echocardiography. Our results suggest that ß2‐AR stimulation may improve the cardiac repair process by supporting an endogenous progenitor cell response but is not sufficient to improve the cardiac function.

Dystrophin Deficiency Causes Progressive Depletion of Cardiovascular Progenitor Cells in the Heart

“…With ageing, we observed a depletion of CVPC population, consistent with the decrease of the progenitor cells in dystrophin-deficient skeletal muscle [ 20 ]. Therefore, although CVPCs and satellite cells have different functions, our findings likely reveal a common phenomenon involving an early-stage recruitment triggered by cardiac injury as also previously shown [ 34 , 52 ], but followed by rapid depletion of the CVPC pool. We summarize our findings and a proposed mechanism of the CVPC in the dystrophin-deficient heart in the diagram of Figure 7 .…”

“…Other stromal cells possibly involved in cardiac homeostasis, survival, and disease dynamics are cardiovascular progenitor cells (CVPCs) [ 30 ], among which the CD117 + (also named c-kit)/CD45 − fraction is the main focus of recent studies [ 31 , 32 , 33 ]. We recently showed that CVPCs are activated and recruited to the site of cardiac injury [ 34 ], supporting the hypothesis of their paracrine regulation of cardiac function in pathophysiological conditions [ 31 , 35 , 36 ]. We found a CVPC depletion associated with late-stage pathological remodeling of cardiac muscle in BMD patients [ 37 ].…”

Cardiovascular progenitor cells and tissue plasticity are reduced in a myocardium affected by Becker muscular dystrophy

“…Heart failure due to DCM is a common clinical manifestation in patients with BMD [5]. It has been shown that CVPCs, including c-kit + /CD45 − cells, are involved in cardiac injury and degeneration [17,23], resulting, for example, in capillary rarefaction, fibrosis, and other pathogeneses of an affected heart [24,25]. The pathogenesis of dystrophinopathy was previously linked to increased DNA damage and to increased mutagenesis in pluripotent stem cells reprogrammed from DMD patients and lacking dystrophin, as we showed previously [26].…”

“…Other stromal cells possibly involved in cardiac homeostasis, survival, and disease dynamics are cardiovascular progenitor cells (CVPC) [14], which include the CD117 + (or c-kit)/ CD45 − fraction, and has been the main focus of several recent studies [15,16]. Currently, the evidence shows that c-kit + /CD45 − are activated by cardiac injury [17] supporting the hypothesis of paracrine regulation of cardiac function under pathophysiological conditions [16,18,19]; however, their role and fate in the human heart remains to be elucidated.…”