BMSCs and Osteoblast-Engineered ECM Synergetically Promotes Osteogenesis and Angiogenesis in an Ectopic Bone Formation Model

Chi Zhang; Dongdong Xia; Jiajing Li; Yanan Zheng; Bowen Weng; Haijiao Mao; Jing Mei; Tao Wu; Mei Li; Jiyuan Zhao

doi:10.3389/fbioe.2022.818191

BMSCs and Osteoblast-Engineered ECM Synergetically Promotes Osteogenesis and Angiogenesis in an Ectopic Bone Formation Model

Front Bioeng Biotechnol. 2022 Jan 21:10:818191. doi: 10.3389/fbioe.2022.818191. eCollection 2022.

Authors

Chi Zhang^{1

2}, Dongdong Xia³, Jiajing Li¹, Yanan Zheng¹, Bowen Weng¹, Haijiao Mao⁴, Jing Mei², Tao Wu⁵, Mei Li^{1

6}, Jiyuan Zhao¹

Affiliations

¹ Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China.
² Medical Research Center, Ningbo City First Hospital, Ningbo, China.
³ Orthopedic Department, Ningbo City First Hospital, Ningbo, China.
⁴ Department of Orthopaedic Surgery, the Affiliated Hospital of Medical School, Ningbo University, Ningbo, China.
⁵ Cardiovascular Center, the Affiliated Hospital of Medical School, Ningbo University, Ningbo, China.
⁶ Ningbo Institute of Medical Sciences, Ningbo, China.

Abstract

Bone mesenchymal stem cells (BMSCs) have been extensively used in bone tissue engineering because of their potential to differentiate into multiple cells, secrete paracrine factors, and attenuate immune responses. Biomaterials are essential for the residence and activities of BMSCs after implantation in vivo. Recently, extracellular matrix (ECM) modification with a favorable regenerative microenvironment has been demonstrated to be a promising approach for cellular activities and bone regeneration. The aim of the present study was to evaluate the effects of BMSCs combined with cell-engineered ECM scaffolds on osteogenesis and angiogenesis in vivo. The ECM scaffolds were generated by osteoblasts on the small intestinal submucosa (SIS) under treatment with calcium (Ca)-enriched medium and icariin (Ic) after decellularization. In a mouse ectopic bone formation model, the SIS scaffolds were demonstrated to reduce the immune response, and lower the levels of immune cells compared with those in the sham group. Ca/Ic-ECM modification inhibited the degradation of the SIS scaffolds in vivo. The generated Ca/Ic-SIS scaffolds ectopically promoted osteogenesis according to the results of micro-CT and histological staining. Moreover, BMSCs on Ca/Ic-SIS further increased the bone volume percentage (BV/TV) and bone density. Moreover, angiogenesis was also enhanced by the Ca/Ic-SIS scaffolds, resulting in the highest levels of neovascularization according to the data ofCD31 staining. In conclusion, osteoblast-engineered ECM under directional induction is a promising strategy to modify biomaterials for osteogenesis and angiogenesis. BMSCs synergetically improve the properties of ECM constructs, which may contribute to the repair of large bone defects.

Keywords: angiogenesis; bone mesenchymal stem cells; ectopic bone formation model; extracellular matrix modification; osteogenesis.