Journal Article

Citrate-based materials fuel human stem cells by metabonegenic regulation

Shan, Dingying, Hudock, Maria R., Tian, Xinggui, Kim, Jimin P., Bai, Xiaochun, Yang, Jian, Lin, Qiaoling, Ma, Chuying, Xie, Denghui, Ao, Xiang

2018

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Adenosine Triphosphate - metabolism / Animal models / Animals / Biocompatibility / Biocompatible Materials - chemistry / Biodegradability / Biodegradation / Biological Sciences / Biomaterials / Biomedical materials / Biomimetics / Biopolymers - chemistry / Bone growth / Bone Regeneration - physiology / Cell Adhesion / Cell Differentiation - physiology / Cell Proliferation / Citric acid / Citric Acid - metabolism / Differentiation (biology) / Disease Models, Animal / Downstream effects / Energy balance / Engineering / Femoral Fractures - pathology / Femoral Fractures - therapy / Femur / Fluorescence / Humans / Hydroxyapatite / Male / Medical Sciences / Mesenchymal Stem Cells - cytology / Mesenchymal Stem Cells - metabolism / Mesenchyme / Metabolic Networks and Pathways / Metabolic pathways / Metabolism / Microenvironments / Models, Biological / Orthopedics / Osteogenesis - physiology / Phenotype / Phosphorus / Phosphoserine / Phosphoserine - metabolism / Photoluminescence / Physical Sciences / PNAS Plus / Polymers / Rats / Rats, Sprague-Dawley / Regeneration / Regeneration (physiology) / Skull Fractures - pathology / Skull Fractures - therapy / Stem Cell Niche - physiology / Stem cell transplantation / Stem cells / Surgical implants / Symporters - metabolism / Tissue Engineering / Tissue Scaffolds - chemistry