Citrate-based materials fuel human stem cells by metabonegenic regulation
- 26 November 2018
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 115 (50), 201813000-E11750
- https://doi.org/10.1073/pnas.1813000115
Abstract
A comprehensive understanding of the key microenvironmental signals regulating bone regeneration is pivotal for the effective design of bioinspired orthopedic materials. Here, we identified citrate as an osteopromotive factor and revealed its metabonegenic role in mediating citrate metabolism and its downstream effects on the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Our studies show that extracellular citrate uptake through solute carrier family 13, member 5 (SLC13a5) supports osteogenic differentiation via regulation of energy-producing metabolic pathways, leading to elevated cell energy status that fuels the high metabolic demands of hMSC osteodifferentiation. We next identified citrate and phosphoserine (PSer) as a synergistic pair in polymeric design, exhibiting concerted action not only in metabonegenic potential for orthopedic regeneration but also in facile reactivity in a fluorescent system for materials tracking and imaging. We designed a citrate/phosphoserine-based photoluminescent biodegradable polymer (BPLP-PSer), which was fabricated into BPLP-PSer/hydroxyapatite composite microparticulate scaffolds that demonstrated significant improvements in bone regeneration and tissue response in rat femoral-condyle and cranial-defect models. We believe that the present study may inspire the development of new generations of biomimetic biomaterials that better recapitulate the metabolic microenvironments of stem cells to meet the dynamic needs of cellular growth, differentiation, and maturation for use in tissue engineering.Keywords
Funding Information
- HHS | National Institutes of Health (AR072731)
- Cystic Fibrosis Foundation (Yang17G0)
- HHS | National Institutes of Health (CA182670)
- HHS | National Institutes of Health (EB024829)
This publication has 45 references indexed in Scilit:
- Synthesis and characterization of biomimetic citrate‐based biodegradable compositesJournal of Biomedical Materials Research Part A, 2013
- Comparative molecular assessment of early osseointegration in implant-adherent cellsBone, 2013
- Evaluation of bone regeneration using the rat critical size calvarial defectNature Protocols, 2012
- Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viabilityProceedings of the National Academy of Sciences of the United States of America, 2011
- MC3T3-E1 cell differentiation and in vivo bone formation induced by phosphoserineBiotechnology Letters, 2011
- Gene expression patterns in bone following mechanical loadingJournal of Bone and Mineral Research, 2010
- Development of aliphatic biodegradable photoluminescent polymersProceedings of the National Academy of Sciences of the United States of America, 2009
- Enzyme Directed Templating of Artificial Bone MineralAdvanced Materials, 2009
- Effect of modification of hydroxyapatite/collagen composites with sodium citrate, phosphoserine, phosphoserine/RGD-peptide and calcium carbonate on bone remodellingBone, 2007
- Comparative study of three different membranes for guided bone regeneration of rat cranial defectsInternational Journal of Oral & Maxillofacial Surgery, 2001