Abstract
Mesenchymal stem cells (MSCs) of fetal origin, such as umbilical cord blood MSCs (UCB MSCs), have emerged as a promising cell source for musculoskeletal tissue regeneration because of their higher proliferation potential, lack of donor site morbidity, and their off-the-shelf potential. MSCs differentiated toward the osteogenic lineage exhibit a specific metabolic phenotype characterized by reliance to oxidative phosphorylation for energy production and reduced glycolytic rates. Currently, limited information exists on the metabolic transitions at different stages of the osteogenic process after osteoinduction with different agents. Herein, the osteoinduction efficiency of BMP-2 and dexamethasone on UCB MSCs was assessed using gas chromatography–mass spectrometry (GC-MS) metabolomics analysis, revealing metabolic discrepancies at 7, 14, and 21 days of induction. Whereas both agents when administered individually were able to induce collagen I, osteocalcin, and osteonectin expression, BMP-2 was less effective than dexamethasone in promoting alkaline phosphatase expression. The metabolomics analysis revealed that each agent induced distinct metabolic alterations, including changes in amino acid pools, glutaminolysis, one-carbon metabolism, glycolysis, and tricarboxylic acid cycle. Importantly, we showed that in vitro-differentiated UCB MSCs acquire a metabolic physiology similar to primary osteoblasts when induced with dexamethasone but not with BMP-2, highlighting the fact that metabolomics analysis is sensitive enough to reveal potential differences in the osteogenic efficiency and can be used as a quality control assay for evaluating the osteogenic process.
Highlights
Mesenchymal stem cells (MSCs) are multipotent cells that are widely used in musculoskeletal tissue regeneration, which currently accounts for the largest share of the global tissue engineering market [1,2]
We show by performing time-course metabolomics analysis of the osteogenic differentiation process over 21 days that umbilical cord blood (UCB) MSCs go through various metabolic states before acquiring their final metabolic phenotype, which is treatment dependent
BMP-2 is less efficient than dexamethasone in inducing osteogenesis of UCB MSCs
Summary
Mesenchymal stem cells (MSCs) are multipotent cells that are widely used in musculoskeletal tissue regeneration, which currently accounts for the largest share of the global tissue engineering market [1,2]. MSCs derived from fetal tissues, such as umbilical cord matrix, amniotic fluid, and umbilical cord blood (UCB) have emerged as an attractive alternative to adult MSCs, because of their higher proliferation potential, lack of donor site morbidity, and the possibility of their off-the-shelf use for the production of personalized autologous bone grafts [3,4]. Bone marrow MSCs exhibit a glycolytic phenotype with increased reactive oxygen species (ROS) production [5] while at the same time retaining oxidative phosphorylation (OXPHOS) for partial energy production [6]. When differentiated to osteoblasts in vitro, their energy production is based on OXPHOS associated with increased biogenesis of mitochondria and a reduction of ROS production [5,7]
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