HIF-1α Regulates Osteogenesis of Periosteum-Derived Stem Cells Under Hypoxia Conditions via Modulating POSTN Expression

Yu Zhuang; Zhiyang Zhao; Mengjia Cheng; Meng Li; Jiawen Si; Kaili Lin; Hongbo Yu

doi:10.3389/fcell.2022.836285

HIF-1α Regulates Osteogenesis of Periosteum-Derived Stem Cells Under Hypoxia Conditions via Modulating POSTN Expression

Front Cell Dev Biol. 2022 Feb 17:10:836285. doi: 10.3389/fcell.2022.836285. eCollection 2022.

Authors

Yu Zhuang^{1

2

3}, Zhiyang Zhao^{1

2

3}, Mengjia Cheng^{1

2

3}, Meng Li^{1

2

3}, Jiawen Si^{1

2

3}, Kaili Lin^{1

2

3}, Hongbo Yu^{1

2

3}

Affiliations

¹ Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² National Clinical Research Center for Oral Diseases, Shanghai, China.
³ Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, China.

Abstract

Periosteum is indispensable in bone repair and is an important source of skeletal stem cells (SSCs) for endogenous bone regeneration. However, there are only a few studies about SSCs in periosteum. The craniomaxillofacial bone regeneration is done under the hypoxia microenvironment, in which HIF-1α plays an important role. The effect of HIF-1α on periosteum-derived stem cells (PDSCs) and the mechanisms of PDSCs activation under hypoxia conditions are unknown. In this study, the calvarial bone defect was established, with the periosteum removed or retained. Results show that the bone regeneration was severely impaired in the periosteum removed group. Moreover, pluripotent PDSCs isolated from the periosteum were positive for mesenchymal stem cell (MSC) markers. To determine the role of HIF-1α, the expression of HIF-1α was knocked down in vivo and in vitro, impairing the bone regeneration or osteogenesis of PDSCs. Furthermore, the knockdown of HIF-1α expression also reduced periostin (POSTN) expression, and recombinant POSTN addition partly rescued the osteogenic inhibition. Finally, to explore the mechanism under POSTN activation, the phosphorylation level of the PI3K/AKT pathway was assessed in transfected PDSCs. The phosphorylation level of PI3K and AKT was enhanced with HIF-1α overexpression and inhibited with HIF-1α knockdown, and the addition of PI3K activator or AKT activator could partly rescue POSTN expression. In conclusion, as a potential target to promote bone repair under the hypoxia microenvironment, HIF-1α can regulate the osteogenic differentiation of PDSCs via the PI3K/AKT/POSTN pathway, which lay a solid foundation for periosteum-based craniomaxillofacial bone regeneration.

Keywords: HIF-1α; POSTN; bone regeneration; hypoxia; periosteum-derived stem cells.