M2 macrophage-derived exosomes promote diabetic fracture healing by acting as an immunomodulator

Yili Wang; Qiushui Lin; Hao Zhang; Sicheng Wang; Jin Cui; Yan Hu; Jinlong Liu; Mengmeng Li; Kun Zhang; Fengjin Zhou; Yingying Jing; Zhen Geng; Jiacan Su

doi:10.1016/j.bioactmat.2023.05.018

M2 macrophage-derived exosomes promote diabetic fracture healing by acting as an immunomodulator

Bioact Mater. 2023 Jun 1:28:273-283. doi: 10.1016/j.bioactmat.2023.05.018. eCollection 2023 Oct.

Authors

Yili Wang^{1

2

3

4

5}, Qiushui Lin⁶, Hao Zhang^{1

4

5}, Sicheng Wang^{1

7}, Jin Cui^{1

4

5

8}, Yan Hu^{1

4

5}, Jinlong Liu^{1

4

5}, Mengmeng Li^{1

4

5}, Kun Zhang⁹, Fengjin Zhou⁹, Yingying Jing^{1

4

5

10

11}, Zhen Geng^{1

4

5}, Jiacan Su^{1

4

5

12}

Affiliations

¹ Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China.
² School of Medicine, Shanghai University, Shanghai, 200444, China.
³ School of Life Sciences, Shanghai University, Shanghai, 200444, China.
⁴ Organoid Research Center, Shanghai University, Shanghai, 200444, China.
⁵ National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, 200444, China.
⁶ Department of Spine Surgery, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
⁷ Department of Orthopedics, Shanghai Zhongye Hospital, Shanghai, 200941, China.
⁸ Department of Orthopedics Trauma, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
⁹ Department of Orthopedics, Honghui Hospital, Xi'an Jiao Tong University, Xi'an, 710000, China.
¹⁰ Suzhou Innovation Center of Shanghai University, Suzhou, 215000, Jiangsu, China.
¹¹ Shaoxing Institute of Technology at Shanghai University, Shaoxing, 312000, Zhejiang, China.
¹² Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.

Abstract

Diabetes mellitus is a chronically inflamed disease that predisposes to delayed fracture healing. Macrophages play a key role in the process of fracture healing by undergoing polarization into either M1 or M2 subtypes, which respectively exhibit pro-inflammatory or anti-inflammatory functions. Therefore, modulation of macrophage polarization to the M2 subtype is beneficial for fracture healing. Exosomes perform an important role in improving the osteoimmune microenvironment due to their extremely low immunogenicity and high bioactivity. In this study, we extracted the M2-exosomes and used them to intervene the bone repair in diabetic fractures. The results showed that M2-exosomes significantly modulate the osteoimmune microenvironment by decreasing the proportion of M1 macrophages, thereby accelerating diabetic fracture healing. We further confirmed that M2-exosomes induced the conversion of M1 macrophages into M2 macrophages by stimulating the PI3K/AKT pathway. Our study offers a fresh perspective and a potential therapeutic approach for M2-exosomes to improve diabetic fracture healing.

Keywords: Diabetic fracture healing; M2-exosomes; Macrophage polarization; Osteoimmune microenvironment; PI3K/AKT signaling pathway.