The Calcineurin-Drp1-Mediated Mitochondrial Fragmentation Is Aligned with the Differentiation of c-Kit Cardiac Progenitor Cells

Abstract

Background and Objectives: The heart contains a pool of c-kit ＋ progenitor cells which is believed to be able to regenerate. The differentiation of these progenitor cells is reliant on different physiological cues. Unraveling the underlying signals to direct differentiation of progenitor cells will be beneficial in controlling progenitor cell fate. In this regard, the role of the mitochondria in mediating cardiac progenitor cell fate remains unclear. Specifically, the association between changes in mitochondrial morphology with the differentiation status of c-kit ＋ CPCs remains elusive. In this study, we investigated the relationship between mitochondrial morphology and the differentiation status of c-kit ＋ progenitor cells. Methods and Results: c-kit ＋ CPCs were isolated from 2-month-old male wild-type FVB mice. To activate differentiation, CPCs were incubated in α-minimal essential medium containing 10 nM dexamethasone for up to 7 days. To inhibit Drp1-mediated mitochondrial fragmentation, either 10 μM or 50 μM mdivi-1 was administered once at Day 0 and again at Day 2 of differentiation. To inhibit calcineurin, either 1 μM or 5 μM ciclosporin-A (CsA) was administered once at Day 0 and again at Day 2 of differentiation. Dexamethasone-induced differentiation of c-kit ＋ progenitor cells is aligned with fragmentation of the mitochondria via a calcineurin-Drp1 pathway. Pharmacologically inhibiting mitochondrial fragmentation retains the undifferentiated state of the c-kit ＋ progenitor cells. Conclusions: The findings from this study provide an alternative view of the role of mitochondrial fusion-fission in the differentiation of cardiac progenitor cells and the potential of pharmacologically manipulating the mitochondria to direct progenitor cell fate.

Single-cell transcriptome reveals a novel mechanism of C-Kit+-liver sinusoidal endothelial cells in NASH

“…Damaged mitochondria release mitochondrial ROS and DNA into the cytosol, which acts as danger signals resulting in the hyperactivation of inflammatory signalling pathways [ 23 ]. Korski et al proposed that oxidative stress, mitochondrial dysfunction and cellular energy imbalance could arrest early proliferation of C-Kit + -CPCs (cardiac progenitor cells) [ 24 ]; Rahman et al also found pharmacologically inhibiting of mitochondrial fragmentation could retain the undifferentiated state of C-Kit + -CPCs [ 25 ]. Mitochondrial dysfunction is already assumed involved in the pathology of NASH with diverse mechanisms especially mitophagy (a selective autophagy eliminating damaged mitochondria to maintain mitochondrial homeostasis) [ 26 ].…”

Unravelling the Interplay between Cardiac Metabolism and Heart Regeneration

“…Studies have shown that the differentiation process of c-kit + progenitor cells involves mitochondrial fragmentation, which is controlled by the calcineurin-Drp1 pathway [ 151 ], while an environmental stressor such as high glucose milieu can alter mitochondrial dynamics and increase the expression of fission-related proteins such as Fis1 and Drp1, leading to a significant decrease in the tube-forming ability of CPCs [ 152 ]. Interestingly, pharmacological inhibition of mitochondrial fragmentation can help to maintain the undifferentiated state of c-kit + progenitor cells.…”