Recombinant humanized collagen remodels endometrial immune microenvironment of chronic endometritis through macrophage immunomodulation

Shuang You; Yun Zhu; Hu Li; Fan He; Shuaibin Liu; Xia Yang; Li Wang; Hui Zeng; Jingcong Dai; Lina Hu

doi:10.1093/rb/rbad033

Recombinant humanized collagen remodels endometrial immune microenvironment of chronic endometritis through macrophage immunomodulation

Regen Biomater. 2023 Apr 3:10:rbad033. doi: 10.1093/rb/rbad033. eCollection 2023.

Authors

Shuang You¹, Yun Zhu², Hu Li¹, Fan He^{1

3}, Shuaibin Liu¹, Xia Yang⁴, Li Wang¹, Hui Zeng¹, Jingcong Dai¹, Lina Hu^{1

3

5

6}

Affiliations

¹ Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
² National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
³ Joint International Research Lab for Reproduction and Development, Ministry of Education, Chongqing 400010, China.
⁴ Shanxi Jinbo Pharmaceutical Co., Ltd, Taiyuan, Shanxi 030031, China.
⁵ Reproduction and Stem Cell Therapy Research Center of Chongqing, Chongqing 400010, China.
⁶ Center for Collagen Transformation of Chongqing Medical University, Chongqing 400010, China.

Abstract

Recently, evidence has suggested that chronic endometritis (CE) is a crucial factor associated with infertility and failure of assisted reproductive techniques, prompting concern in the reproductive field. Studies have shown that persistent infiltered immune cells stimulation result in the disturbance of endometrial immune microenvironment could lead to the infertility of CE patients finally. Conventional treatments are limited because they lack immune regulation, so it is urgent to develop a novel approach to treat CE and promote embryo implantation in patients with CE. Herein, we prepared recombinant humanized type III collagen (rhCol III) with high cell adhesion activity to regulate macrophages and repair the endometrium. In this study, M1 macrophages and M1 macrophages cultured medium and lipopolysaccharide (LPS) co-stimulated inflammatory endometrium stromal cells (ESCs) were established in vitro to mimic CE condition. rhCol III promoted M1 macrophages toward M2 phenotype, improved cell migration, viability and collagen components of inflammatory ESCs. Also, the inflammatory response of inflammatory ESCs was downregulated after rhCol III treatment. Subsequently, LPS was used for CE rat model and a 28-day observation was performed; inflammatory cells' infiltration, endometrium repair, extracellular matrix (ECM) remodeling and pregnancy outcomes were promoted after rhCol III endometrial infusion. In conclusion, rhCol III promoted (i) macrophage polarization toward M2 macrophages, (ii) pro-inflammatory cytokine production and anti-inflammatory cytokine reduction, (iii) ECM remodeling and (iv) fertility restoration. Meanwhile, rhCol III enhanced cell biological functions by interacting with discoidin domain receptors, regulated cell metabolism and reduced the inflammatory response through the inhibition of the NF-κB/YAP signaling pathway. Overall, the results illustrated the potential therapeutic prospects of rhCol III for CE treatment.

Keywords: chronic endometritis; macrophages; recombinant humanized collagen; type III collagen.