Effect of Mesenchymal Stem Cells Overexpressing BMP-9 Primed with Hypoxia on BMP Targets, Osteoblast Differentiation and Bone Repair

• Published in: Biology (Basel, Switzerland) Vol. 12; no. 8; p. 1147
• Main Authors: Paz, Jessica Emanuella Rocha Moura, Adolpho, Leticia Faustino, Ramos, Jaqueline Isadora Reis, Bighetti-Trevisan, Rayana Longo, Calixto, Robson Diego, Oliveira, Fabiola Singaretti, Almeida, Adriana Luisa Gonçalves, Beloti, Marcio Mateus, Rosa, Adalberto Luiz
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.08.2023; MDPI
• Subjects: Antibodies; BMP-9; bone; bone formation; Bone growth; Bone healing; Bone marrow; Bone morphogenetic protein 9; Bone morphogenetic proteins; Cell differentiation; Cell migration; cell movement; Cell therapy; Cell viability; chlorides; Cobalt; Cobalt chloride; CRISPR; Electrical wire and cable industry; Fractures; Gene expression; Genetically modified organisms; Growth factors; HIF-1α; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-inducible factor 1a; Instrument industry; Kinases; Laboratories; Mesenchymal stem cells; Osteoblastogenesis; Osteoblasts; Osteogenesis; Oxygen tension; Paracrine signalling; Protein expression; Proteins; rats; Regeneration; Skull; Stem cells; therapeutics; Transplantation; United States; United States > US
• ISSN: 2079-7737; 2079-7737
• DOI: 10.3390/biology12081147

Bone formation is driven by many signaling molecules including bone morphogenetic protein 9 (BMP-9) and hypoxia-inducible factor 1-alpha (HIF-1α). We demonstrated that cell therapy using mesenchymal stem cells (MSCs) overexpressing BMP-9 (MSCs+BMP-9) enhances bone formation in calvarial defects. Here, the effect of hypoxia on BMP components and targets of MSCs+BMP-9 and of these hypoxia-primed cells on osteoblast differentiation and bone repair was evaluated. Hypoxia was induced with cobalt chloride (CoCl2) in MSCs+BMP-9, and the expression of BMP components and targets was evaluated. The paracrine effects of hypoxia-primed MSCs+BMP-9 on cell viability and migration and osteoblast differentiation were evaluated using conditioned medium. The bone formation induced by hypoxia-primed MSCs+BMP-9 directly injected into rat calvarial defects was also evaluated. The results demonstrated that hypoxia regulated BMP components and targets without affecting BMP-9 amount and that the conditioned medium generated under hypoxia favored cell migration and osteoblast differentiation. Hypoxia-primed MSCs+BMP-9 did not increase bone repair compared with control MSCs+BMP-9. Thus, despite the lack of effect of hypoxia on bone formation, the enhancement of cell migration and osteoblast differentiation opens windows for further investigations on approaches to modulate the BMP-9-HIF-1α circuit in the context of cell-based therapies to induce bone regeneration.