Rôle fonctionnel des canaux potassiques activés par le calcium au sein de progéniteurs cardiaques : implication en médecine régénérative

Heart failure (HF) is a progressive disease characterized by extensive pathological remodelling of the heart and myocardial damage. Regardless of the etiology, a decrease of about 30% in the number of ventricular cardiomyocytes is observed at the terminal stage of HF. Based on converging preclinical data in HF models, the innovative concept of cell therapy has generated a great deal of enthusiasm in cardiology. Although the role of cardiac stem cells in cardiac homeostasis is highly controversial, the multipotent progenitors that persist within the adult myocardium possess the ideal characteristics for cardiac regeneration, especially because of their cardiogenic committment. Plasma membrane ion channels are involved in the fundamental processes of virtually all cells that make up the human body, including stem cells. A wide range of functional ion channels was identified in ex vivo proliferated endogenous cardiac progenitor cells (eCPCs), but their function remains poorly understood. We have completed the very first characterization of the ionic profile of freshly-isolated c-Kit+ eCPCs. We found that the intermediate conductance Ca2+-activated potassium current (IKCa3.1) is the predominant conductance and contributes to the determination of membrane potential (Vmem). The hyperpolarization generated by the activation of the KCa3.1 channel (SK4; KCNN4) maintains the electrical gradient and promotes store-operated Ca2+-entry (SOCE) that activates progenitor cell proliferation. Experimental congestive heart failure (CHF) significantly decreased the expression of KCa3.1 as well as cell cycle regulatory proteins. Taken together, these findings suggest that alterations in KCa3.1 may have pathophysiological and therapeutic significance in regenerative medicine  In addition to c-Kit+ eCPCs, cardiac explants-derived cells (EDCs) represent another promising cell product for myocardial repair. EDCs are obtained as a heterogeneous mixture composed of complementary subpopulations. Interestingly, it was found that a high proportion of CD90+ cells reduce the functional benefits of EDCs therapy. Consistent with this observation, it has recently been shown that the CD90- population constitutes the active fraction in terms of therapeutic efficacy. In order to gain insight into the ionic determinants of EDCs function, the electrophysiological properties of the CD90+ and CD90- populations were studied. Considering the importance of KCa3.1 in c-Kit+ CPCs, we evaluated the presence of KCa channels in human EDCs. We have identified 2 types of KCa channels in ex vivo expanded EDCs. While KCa1.1 (BKCa; KCNMA1) channel was homogeneously expressed in both subpopulations, KCa3.1 was found exclusively in the CD90- cell fraction. Similar to our previous observations in freshly isolated c-Kit+ eCPCs, KCa3.1 was responsible for the determination of Vmem under resting conditions and during SOCE. Importantly, we demonstrated that transplantation of genetically-modified EDCs to over-express KCNN4 potentiates cardiac regeneration in a murine model of ischemic cardiomyopathy. This study provides the first evidence in the literature that modulating the activity of a single plasma membrane ion channel can truly improves the therapeutic efficacy of progenitor cells.

Keyphrases: Calcium-dependent potassium channels, Membrane potential, Stem cells, Heart failure, Cell therapy