Enhanced bone regeneration via endochondral ossification using Exendin-4-modified mesenchymal stem cells

Zihao He; Hui Li; Yuanyuan Zhang; Shuang Gao; Kaini Liang; Yiqi Su; Yanan Du; Du Wang; Dan Xing; Zhen Yang; Jianhao Lin

doi:10.1016/j.bioactmat.2023.12.007

Enhanced bone regeneration via endochondral ossification using Exendin-4-modified mesenchymal stem cells

Bioact Mater. 2023 Dec 19:34:98-111. doi: 10.1016/j.bioactmat.2023.12.007. eCollection 2024 Apr.

Authors

Zihao He^{1

2}, Hui Li^{1

2}, Yuanyuan Zhang³, Shuang Gao³, Kaini Liang³, Yiqi Su^{1

2}, Yanan Du³, Du Wang^{1

2}, Dan Xing^{1

2}, Zhen Yang^{1

2}, Jianhao Lin^{1

2}

Affiliations

¹ Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, 100044, China.
² Arthritis Institute, Peking University, Beijing, 100044, China.
³ Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, 100084, China.

Abstract

Nonunions and delayed unions pose significant challenges in orthopedic treatment, with current therapies often proving inadequate. Bone tissue engineering (BTE), particularly through endochondral ossification (ECO), emerges as a promising strategy for addressing critical bone defects. This study introduces mesenchymal stem cells overexpressing Exendin-4 (MSC-E4), designed to modulate bone remodeling via their autocrine and paracrine functions. We established a type I collagen (Col-I) sponge-based in vitro model that effectively recapitulates the ECO pathway. MSC-E4 demonstrated superior chondrogenic and hypertrophic differentiation and enhanced the ECO cell fate in single-cell sequencing analysis. Furthermore, MSC-E4 encapsulated in microscaffold, effectively facilitated bone regeneration in a rat calvarial defect model, underscoring its potential as a therapeutic agent for bone regeneration. Our findings advocate for MSC-E4 within a BTE framework as a novel and potent approach for treating significant bone defects, leveraging the intrinsic ECO process.

Keywords: Bone tissue engenieering; Endochondral ossification; Exendin-4; Genetic engineering; Mesenchymal stem cells; Nonunion; Regenerative medicine.