title: Calcium phosphate-bearing matrices induce osteogenic differentiation of stem cells through adenosine signaling.
abstract: Synthetic matrices emulating the physicochemical properties of tissue-specific ECMs are being developed at a rapid pace to regulate stem cell fate. Biomaterials containing calcium phosphate (CaP) moieties have been shown to support osteogenic differentiation of stem and progenitor cells and bone tissue formation. By using a mineralized synthetic matrix mimicking a CaP-rich bone microenvironment, we examine a molecular mechanism through which CaP minerals induce osteogenesis of human mesenchymal stem cells with an emphasis on phosphate metabolism. Our studies show that extracellular phosphate uptake through solute carrier family 20 (phosphate transporter), member 1 (SLC20a1) supports osteogenic differentiation of human mesenchymal stem cells via adenosine, an ATP metabolite, which acts as an autocrine/paracrine signaling molecule through A2b adenosine receptor. Perturbation of SLC20a1 abrogates osteogenic differentiation by decreasing intramitochondrial phosphate and ATP synthesis. Collectively, this study offers the demonstration of a previously unknown mechanism for the beneficial role of CaP biomaterials in bone repair and the role of phosphate ions in bone physiology and regeneration. These findings also begin to shed light on the role of ATP metabolism in bone homeostasis, which may be exploited to treat bone metabolic diseases.
authors.affiliation: Departments of Bioengineering, Chemistry and Biochemistry, and Nanoengineering, Institute of Engineering in Medicine, and Materials Science and Engineering, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Yu-Ru V
authors.initials: YR
authors.lastname: Shih
authors.forename: YongSung
authors.initials: Y
authors.lastname: Hwang
authors.forename: Ameya
authors.initials: A
authors.lastname: Phadke
authors.forename: Heemin
authors.initials: H
authors.lastname: Kang
authors.forename: Nathaniel S
authors.initials: NS
authors.lastname: Hwang
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Caro
authors.forename: Steven
authors.initials: S
authors.lastname: Nguyen
authors.forename: Michael
authors.initials: M
authors.lastname: Siu
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Theodorakis
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Gianneschi
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Vecchio
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.forename: Oscar K
authors.initials: OK
authors.lastname: Lee
authors.forename: Shyni
authors.initials: S
authors.lastname: Varghese
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D001672:Biocompatible Materials / Q000737:chemistry; D001842:Bone and Bones / Q000378:metabolism; D002130:Calcium Phosphates / Q000737:chemistry* / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured / Q000166:cytology; D002851:Chromatography, High Pressure Liquid; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology; D010012:Osteogenesis / Q000502:physiology; D010641:Phenotype; D010710:Phosphates / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*
chemical_list: D001672:Biocompatible Materials; D002130:Calcium Phosphates; D010710:Phosphates; D034741:RNA, Small Interfering; D043704:Receptor, Adenosine A2B; C493586:SLC20A1 protein, human; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D000255:Adenosine Triphosphate; C020243:calcium phosphate; D000241:Adenosine
keywords: biomimetic material; bone metabolism; mineralized matrix; phosphate signaling