In situ delivery of apoptotic bodies derived from mesenchymal stem cells via a hyaluronic acid hydrogel: A therapy for intrauterine adhesions

Liaobing Xin; Cheng Wei; Xiaomei Tong; Yangyang Dai; Dong Huang; Jianmin Chen; Lie Ma; Songying Zhang

doi:10.1016/j.bioactmat.2021.10.025

In situ delivery of apoptotic bodies derived from mesenchymal stem cells via a hyaluronic acid hydrogel: A therapy for intrauterine adhesions

Bioact Mater. 2021 Oct 22:12:107-119. doi: 10.1016/j.bioactmat.2021.10.025. eCollection 2022 Jun.

Authors

Liaobing Xin^{1

2}, Cheng Wei^{1

2}, Xiaomei Tong^{1

2}, Yangyang Dai^{1

3

2}, Dong Huang^{1

2}, Jianmin Chen^{1

2}, Lie Ma^{3

2}, Songying Zhang^{1

2}

Affiliations

¹ Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
² Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province. No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China.
³ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China.

Abstract

Stem cell-based and stem cell-derived exosome-based therapies have shown promising potential for endometrial regeneration and the clinical treatment of intrauterine adhesions (IUAs). Evidence shows that apoptosis occurs in a majority of grafted stem cells, and apoptotic bodies (ABs) play a critical role in compensatory tissue regeneration. However, the therapeutic potential of AB-based therapy and its mechanism have not been explored in detail. Here, a cell-free therapeutic strategy was developed by incorporating mesenchymal stem cell-derived ABs into a hyaluronic acid (HA) hydrogel to achieve endometrial regeneration and fertility restoration. Specifically, we found that the ABs could induce macrophage immunomodulation, cell proliferation, and angiogenesis in vitro. The HA hydrogel promoted the retention of ABs and facilitated their continuous release. In a murine model of acute endometrial damage and a rat model of IUAs, in situ injection of the AB-laden HA hydrogel could efficiently reduce fibrosis and promote endometrial regeneration, resulting in the fertility restoration. Consequently, ABs show good potential as therapeutic vesicles, and the AB-laden HA hydrogel appears to be a clinically feasible and cell-free alternative for endometrial regeneration and IUA treatment.

Keywords: Apoptotic bodies; Endometrial regeneration; Intrauterine adhesions; Mesenchymal stem cells; Tissue engineering.