Abstract
BackgroundControlling the adipo-osteogenic lineage commitment of bone marrow mesenchymal stem cell (BMSC) in favor of osteogenesis is considered a promising approach for bone regeneration and repair. Accumulating evidence indicates that oxidative phosphorylation (OXPHOS) is involved in regulating cell fate decisions. As an essential cofactor for OXPHOS, nicotinamide adenine dinucleotide (NAD) has been shown to correlate with the differentiation of stem cells. However, whether NAD manipulates BMSC lineage commitment through OXPHOS remains elusive. Therefore, it is critical to investigate the potential role of NAD on energy metabolism in mediating BMSC lineage commitment.MethodsIn this study, the mitochondrial respiration and intracellular NAD+ level were firstly compared between osteogenic and adipogenic cells. For validating the role of NAD in mitochondrial OXPHOS, the inhibitor of NAD+ salvage pathway FK866 and activator P7C3 were used to manipulate the NAD+ level during osteogenesis. Furthermore, a murine femur fracture model was established to evaluate the effect of FK866 on bone fracture repair.ResultsWe elucidated that osteogenic committed BMSCs exhibited increased OXPHOS activity and a decreased glycolysis accompanied by an elevated intracellular NAD+ level. In contrast, adipogenic committed BMSCs showed little change in OXPHOS but an upregulated activity in glycolysis and a decline in intracellular NAD+ level in vitro. Moreover, attenuates of NAD+ via salvage pathway in BMSCs diminished osteogenic commitment due to mitochondria dysfunction and reduced activity of OXPHOS. The cells were rescued by supplementing with nicotinamide mononucleotide. In addition, treatment with NAD+ inhibitor FK866 impaired bone fracture healing in vivo.ConclusionOur data reveals NAD+-mediated mitochondrial OXPHOS is indispensable for osteogenic commitment in BMSCs and bone repair, which might provide a potential therapeutic target for bone repair and regeneration.
Highlights
Bone marrow mesenchymal stem cells (BMSCs) are being exploited as seed cells for tissue regeneration andA variety of factors contribute to the lineage commitment of bone marrow mesenchymal stem cell (BMSC) toward adipocyte or osteoblast formation, including extracellular environment, transcriptional factors, and cell metabolism [1]
The Human bone marrow-derived mesenchymal stem cells (hBMSCs) were seeded at 2 × 104 cells/cm2 and the ST2 cells were seeded at 1 × 104 cells/ cm2 for osteogenic and adipogenic induction
Osteogenic committed hBMSCs exhibited a notable increase in the basal oxygen consumption rate (OCR) but little change in basal extracellular acidification rate (ECAR) (Fig. 1A, B)
Summary
Bone marrow mesenchymal stem cells (BMSCs) are being exploited as seed cells for tissue regeneration andA variety of factors contribute to the lineage commitment of BMSCs toward adipocyte or osteoblast formation, including extracellular environment, transcriptional factors, and cell metabolism [1]. Studies found that OXPHOS coupled energy homeostasis could regulate cell fate decisions via the mTOR signaling pathway [4]. OXPHOS plays a critical role in energy homeostasis and is considered a potential target for multiple diseases [5, 7]. The role of OXPHOS in regulating BMSCs cell fate decision and differentiation was just begun to explore. Controlling the adipo-osteogenic lineage commitment of bone marrow mesenchymal stem cell (BMSC) in favor of osteogenesis is considered a promising approach for bone regeneration and repair. Accumulating evidence indicates that oxidative phosphorylation (OXPHOS) is involved in regulating cell fate decisions. As an essential cofactor for OXPHOS, nicotinamide adenine dinucleotide (NAD) has been shown to correlate with the differentiation of stem cells. It is critical to investigate the potential role of NAD on energy metabolism in mediating BMSC lineage commitment
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