Ca 2+ -activated mitochondrial biogenesis and functions improve stem cell fate in Rg3-treated human mesenchymal stem cel
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Ca2+-activated mitochondrial biogenesis and functions improve stem cell fate in Rg3-treated human mesenchymal stem cells Taeui Hong1,2,3†, Moon Young Kim1,3,4,5†, Dat Da Ly1,2†, Su Jung Park1,3, Young Woo Eom4,5, Kyu-Sang Park1,2* and Soon Koo Baik1,3,4,5*
Abstract Although mitochondrial functions are essential for cell survival, their critical roles in stem cell fate, including proliferation, differentiation, and senescence, remain elusive. Ginsenoside Rg3 exhibits various biological activities and reportedly increases mitochondrial biogenesis and respiration. Herein, we observed that Rg3 increased proliferation and suppressed senescence of human bone marrow-derived mesenchymal stem cells. Osteogenic, but not adipogenic, differentiation was facilitated by Rg3 treatment. Rg3 suppressed reactive oxygen species production and upregulated mitochondrial biogenesis and antioxidant enzymes, including superoxide dismutase. Consistently, Rg3 strongly augmented basal and ATP synthesis-linked respiration with high spare respiratory capacity. Rg3 treatment elevated cytosolic Ca2+ concentration contributing to mitochondrial activation. Reduction of intracellular or extracellular Ca2+ levels strongly inhibited Rg3-induced activation of mitochondrial respiration and biogenesis. Taken together, Rg3 enhances capabilities of mitochondrial and antioxidant functions mainly through a Ca2+dependent pathway, which improves the proliferation and differentiation potentials and prevents the senescence of human mesenchymal stem cells. Keywords: Mesenchymal stem cells, Ginsenoside Rg3, Cellular senescence, Oxidative stress, Mitochondria
Introduction Mitochondria are essential for energy metabolism, calcium homeostasis, cell survival, and apoptosis; however, their role in stem cell proliferation, differentiation, and senescence has not been fully elucidated. In a stem cell niche, quiescent cells have a low mitochondrial mass in a low oxygen environment [1]. These cells have less bioenergetic reliance on oxidative phosphorylation and * Correspondence: [email protected]; [email protected] † Taeui Hong, Moon Young Kim and Dat Da Ly contributed equally to this work. 1 Mitohormesis Research Center, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-Do 26426, Republic of Korea Full list of author information is available at the end of the article
more glycolytic activity. Furthermore, superoxide production from mitochondrial activities inhibits stemness, negatively affecting stem cell fate [2]. Nevertheless, counteracting evidences demonstrate mitochondrial metabolism exhibits an essential role in stem cell fate and defense against senescence [3]. Active mitochondrial respiration is required to maintain quiescence and the differentiation ability of stem cells [4]. After mitochondria transfer, recipient bone marrow-derived mesenchymal stem cells (BMSCs) displayed increased oxidative phosphorylation, which enhanced proliferation and osteogenic differentiation [5]. Conversely, mitochondrial DNA mu
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