Biomineralized materials as bone ECM mimetics: From understanding molecular mechanisms to new therapeutic interventions
June 5-9, 2018
Bone extracellular matrix is a heterogeneous composite material consisting, of an inorganic (or mineral) phase, an organic phase and water. In an effort to mimic the mineral environment of bone tissue, we recently employed biomineralization and created mineralized biomaterials (1). Our studies showed that these biomineralized materials induced osteogenic differentiation of stem cells, including human pluripotent stem cells (which includes both embryonic stem cells and induced pluripotent stem cells), even in growth medium devoid of any osteogenic inducing molecules (2,3). By employing these mineralized materials, we have studied the molecular mechanism through which calcium phosphate minerals support osteogenesis with an emphasis on phosphate metabolism (4). Our studies show that extracellular phosphate (resulting from the dissolution of calcium phosphate minerals) 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 intra-mitochondrial phosphate and ATP synthesis. Our studies further show that the phosphate-ATP-adenosine signaling axis not only promotes osteogenic differentiation of multipotent progenitor cells but also inhibits their adipogenic differentiation (5). When implanted in vivo, these acellular mineralized biomaterials recruited endogenous cells and induced their differentiation to form vascularized bone tissues (6) and also supported donor bone marrow transplantation (7). Leveraging these understandings, we are currently studying the pivotal role of Adenosine A2b receptor, a G-protein coupled receptor on the cell membrane, in regulating bone-specific cells and treating bone metabolic disorders. In this talk, I will discuss these results and the identification of possible drug targets for osteoporosis.
 Phadke A, Zhang C, Hwang YS, Vecchio K, Varghese S. “Templated mineralization of synthetic hydrogels for bone like composite material: Role of matrix hydrophobicity”, Biomacromolecules. 2010; 11, 2060
 Phadke A, Shig Y-R, Varghese, S. “Mineralized synthetic matrices as an instructive microenvironment for osteogenic differentiation of human mesenchymal stem cells” Macromol Biosci. 2012, 12, 1022
 Kang H, Shih Y-RV, Hwang YS, Wen C, Rao V, Seo T, and Varghese S. “Mineralized gelatin methacrylate-based matrices induce osteogenic differentiation of human induced pluripotent stem cells” Acta Biomater. 2014, 10, 4961
 Shih Y-RV, Hwang YS, Phadke A, Kang H, Hwang NS, Caro EJ, Nguyen S, Siu M, Theodorakis EA, Gianneschi NC, Vecchio KS, Chien S, Lee OK and Varghese S. “Calcium phosphate-bearing matrices induce osteogenic differentiation of stem cells through adenosine signaling” Proc. Natl. Acad. Sci. 2014, 111, 990.
 Kang H, Shih Y-RV, Varghese S. “Biomineralized matrices dominate soluble cues to direct osteogenic differentiation of human mesenchymal stem cells through adenosine signaling” Biomacromolecules 2015, 16, 1050
 Shih Y-RV, Phadke A, Yamaguchi T, Kang H, Inoue N, Masuda K and Varghese S. “Synthetic bone mimetic matrix-mediated in situ bone tissue formation through host cell recruitment” Acta Biomater. 2015, 19, 1.
 Shih Y-RV, Kang H, Rao V, Chu Y-J, Kown SK, and Varghese S. “In vivo engineering of bone organoids with hematopoietic functions” Proc. Natl. Acad. Sci, 2017, 114, 5419.
Shyni Varghese, "Biomineralized materials as bone ECM mimetics: From understanding molecular mechanisms to new therapeutic interventions" in "Nanotechnology in Medicine II: Bridging Translational in vitro and in vivo Interfaces", Millicent Sullivan, PhD, University of Delaware, USA Josué Sznitman, Dr. Sc., Technion-Israel Institute of Technology, Israel Lola Eniola-Adefeso, PhD, University of Michigan, USA Srivatsan Kidambi, PhD, University of Nebraska - Lincoln, USA Eds, ECI Symposium Series, (2018). http://dc.engconfintl.org/nanotech_med_ii/26