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However, inclusion of free Ca2+<\/jats:sup> intracellularly revealed a prominent inwardly rectifying current identified as the intermediate conductance Ca2+<\/jats:sup>\u2010activated K+<\/jats:sup> current (KCa3.1)<\/jats:p><\/jats:list-item>\nElectrical function of both c\u2010Kit+<\/jats:sup> eCPCs and bone marrow\u2010derived mesenchymal stem cells is critically governed by KCa3.1 calcium\u2010dependent potassium channels.<\/jats:p><\/jats:list-item>\nCa2+<\/jats:sup>\u2010induced increases in KCa3.1 conductance are necessary to optimize membrane potential during Ca2+<\/jats:sup> entry. Membrane hyperpolarization due to KCa3.1 activation maintains the driving force for Ca2+<\/jats:sup> entry that activates stem cell proliferation.<\/jats:p><\/jats:list-item>\nCardiac disease downregulates KCa3.1 channels in resident cardiac progenitor cells. Alterations in KCa3.1 may have pathophysiological and therapeutic significance in regenerative medicine.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>Abstract<\/jats:title>Endogenous c\u2010Kit+<\/jats:sup> cardiac progenitor cells (eCPCs) and bone marrow (BM)\u2010derived mesenchymal stem cells (MSCs) are being developed for cardiac regenerative therapy, but a better understanding of their physiology is needed. Here, we addressed the unknown functional role of ion channels in freshly isolated eCPCs and expanded BM\u2010MSCs using patch\u2010clamp, microfluorometry and confocal microscopy. Isolated c\u2010Kit+<\/jats:sup> eCPCs were purified from dog hearts by immunomagnetic selection. Ion currents were barely detectable in freshly isolated c\u2010Kit+<\/jats:sup> eCPCs with buffering of intracellular calcium (Ca2+<\/jats:sup>i<\/jats:sub>). Under conditions allowing free intracellular Ca2+<\/jats:sup>, freshly isolated c\u2010Kit+<\/jats:sup> eCPCs and ex vivo<\/jats:italic> proliferated BM\u2010MSCs showed prominent voltage\u2010independent conductances that were sensitive to intermediate\u2010conductance K+<\/jats:sup>\u2010channel (KCa3.1 current, I<\/jats:italic>KCa3.1<\/jats:sub>) blockers and corresponding gene (KCNN4<\/jats:italic>)\u2010expression knockdown. Depletion of Ca2+<\/jats:sup>i<\/jats:sub> induced membrane\u2010potential (V<\/jats:italic>mem<\/jats:sub>) depolarization, while store\u2010operated Ca2+<\/jats:sup> entry (SOCE) hyperpolarized V<\/jats:italic>mem<\/jats:sub> in both cell types. The hyperpolarizing SOCE effect was substantially reduced by I<\/jats:italic>KCa3.1<\/jats:sub> or SOCE blockade (TRAM\u201034, 2\u2010APB), and I<\/jats:italic>KCa3.1<\/jats:sub> blockade (TRAM\u201034) or KCNN4<\/jats:italic>\u2010knockdown decreased the Ca2+<\/jats:sup> entry resulting from SOCE. I<\/jats:italic>KCa3.1<\/jats:sub> suppression reduced c\u2010Kit+<\/jats:sup> eCPC and BM\u2010MSC proliferation, while significantly altering the profile of cyclin expression. I<\/jats:italic>KCa3.1<\/jats:sub> was reduced in c\u2010Kit+<\/jats:sup> eCPCs isolated from dogs with congestive heart failure (CHF), along with corresponding KCNN4<\/jats:italic> mRNA. Under perforated\u2010patch conditions to maintain physiological [Ca2+<\/jats:sup>]i<\/jats:sub>, c\u2010Kit+<\/jats:sup> eCPCs from CHF dogs had less negative resting membrane potentials (\u221258\u00a0\u00b1\u00a07\u00a0mV) versus<\/jats:italic> c\u2010Kit+<\/jats:sup> eCPCs from control dogs (\u221273\u00a0\u00b1\u00a03\u00a0mV, P<\/jats:italic>\u00a0<\u00a00.05), along with slower proliferation. Our study suggests that Ca2+<\/jats:sup>\u2010induced increases in I<\/jats:italic>KCa3.1<\/jats:sub> are necessary to optimize membrane potential during the Ca2+<\/jats:sup> entry that activates progenitor cell proliferation, and that alterations in KCa3.1 may have pathophysiological and therapeutic significance in regenerative medicine.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp275388","type":"journal-article","created":{"date-parts":[[2018,3,25]],"date-time":"2018-03-25T18:02:54Z","timestamp":1522000974000},"page":"2359-2379","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Calcium\u2010dependent potassium channels control proliferation of cardiac progenitor cells and bone marrow\u2010derived mesenchymal stem cells"],"prefix":"10.1113","volume":"596","author":[{"given":"Patrick","family":"Vigneault","sequence":"first","affiliation":[{"name":"Research Center and Department of Medicine, Montreal Heart Institute 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