title: Hyaluronan Upregulates Mitochondrial Biogenesis and Reduces Adenoside Triphosphate Production for Efficient Mitochondrial Function in Slow-Proliferating Human Mesenchymal Stem Cells.
abstract: Hyaluronan-coated surfaces preserve the proliferation and differentiation potential of mesenchymal stem cells by prolonging their G1-phase transit, which maintains cells in a slow-proliferative mode. Mitochondria are known to play a crucial role in stem cell self-renewal and differentiation. In this study, for the first time, the metabolic mechanism underlying the hyaluronan-regulated slow-proliferative maintenance of stem cells was investigated by evaluating mitochondrial functions. Human placenta-derived mesenchymal stem cells (PDMSCs) cultured on hyaluronan-coated surfaces at 0.5, 3.0, 5.0, and 30 µg/cm2were found to have an average 58% higher mitochondrial mass and an increase in mitochondrial DNA copy number compared to noncoated tissue culture surfaces (control), as well as a threefold increase in the gene expression of the mitochondrial biogenesis-related gene PGC-1α. Increase in mitochondrial biogenesis led to a hyaluronan dose-dependent increase in mitochondrial membrane potential, ATP content, and oxygen consumption rate, with reactive oxygen species levels shown to be at least three times lower compared to the control. Although hyaluronan seemed to favor mitochondrial function, cell entry into a hyaluronan-regulated slow-proliferative mode led to a fivefold reduction in ATP production and coupling efficiency levels. Together, these results suggest that hyaluronan-coated surfaces influence the metabolic proliferative state of stem cells by upregulating mitochondrial biogenesis and function with controlled ATP production. This more efficiently meets the energy requirements of slow-proliferating PDMSCs. A clear understanding of the metabolic mechanism induced by hyaluronan in stem cells will allow future applications that may overcome the current limitations faced in stem cell culture. Stem Cells 2016;34:2512-2524.
authors.affiliation: Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Mairim Alexandra
authors.initials: MA
authors.lastname: Solis
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.|Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yau-Huei
authors.initials: YH
authors.lastname: Wei
authors.affiliation: Department of Obstetrics and Gynecology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chiung-Hsin
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Obstetrics and Gynecology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chen-Hsiang
authors.initials: CH
authors.lastname: Yu
authors.affiliation: Department of Obstetrics and Gynecology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Pao-Lin
authors.initials: PL
authors.lastname: Kuo
authors.affiliation: Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan. lynn@mail.ncku.edu.tw.|Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan. lynn@mail.ncku.edu.tw.|Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. lynn@mail.ncku.edu.tw.|Research Center of Excellence in Regenerative Medicine, National Cheng Kung University, Tainan, Taiwan. lynn@mail.ncku.edu.tw.|Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan, Taiwan. lynn@mail.ncku.edu.tw.
authors.forename: Lynn L H
authors.initials: LL
authors.lastname: Huang
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D020099:Coated Materials, Biocompatible / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology*; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D001678:Organelle Biogenesis; D010920:Placenta / Q000166:cytology; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D020099:Coated Materials, Biocompatible; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D006820:Hyaluronic Acid; D054409:Nicotinamide Phosphoribosyltransferase; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human
keywords: Cellular proliferation; Hyaluronan; Mesenchymal stem cells; Mitochondria; Mitochondrial biogenesis