International immunopharmacology · 2026
Recombinant humanized type III collagen attenuates recurrent spontaneous abortion by regulating stromal cell decidualization and reinforcing protective immune microenvironment at the maternal-fetal interface.
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Dong Zhiyong, Wang Li, Dai Jingcong, You Shuang, Liu Jiashuo, Zeng Hui, Wei Quan, Chen Jiaming, Xing Jie, Wang Xinyi, Liu Shuaibin, Dong Xiaojing, Yang Xia, He Fan, Hu Lina
Аннотация
BACKGROUND: Recurrent spontaneous abortion (RSA), the common early pregnancy complication, remains elusive in its pathogenesis and treatment. Recombinant humanized type III collagen (rhCOLIII), a novel biomaterial, has demonstrated efficacy in treating various diseases. However, the role of rhCOLIII in RSA is unclear. This study aimed to explore the therapeutic potential and underlying mechanisms of rhCOLIII in RSA at single-cell resolution.
METHODS: Human endometrium/decidua samples derived from healthy donors/normal pregnant and RSA patients were obtained to detect type III collagen (COLIII) expression via immunohistochemistry (IHC) and Western blot. A murine RSA model (CBA/J ♀ × DBA/2 ♂) was established, followed by intrauterine perfusion of rhCOLIII to evaluate its therapeutic efficacy. Uterine tissues from RSA and rhCOLIII-treated mice were collected on gestation day 8 for single-cell RNA sequencing, with findings validated by IHC, multiplex IHC (mIHC), and flow cytometry (FCM).
RESULTS: COLIII expression was significantly reduced in RSA endometrial/decidual tissues. Intrauterine rhCOLIII treatment in a murine RSA model significantly decreased the embryo resorption rate from 31.62% to 3.82% (P < 0.001). Single-cell analysis identified 19 cell clusters, with stromal cells as the predominant population, further classified into seven functional subtypes and their differential composition between the RSA and rhCOLIII groups was confirmed by mIHC. Furthermore, rhCOLIII reprogrammed stromal cell function by activating oxidative-stress response pathways and regulating decidualization. Concurrently, our results showed that rhCOLIII could enhance anti-inflammatory macrophage activity and increase CD16+ NK cell abundance. Cell-cell communication analysis uncovered that APOE-TREM2 signaling between decidual stromal cells and macrophages, as well as BSG-PPIA signaling in decidual stromal cell-NK cell interactions, was augmented following rhCOLIII treatment. FCM analysis demonstrated that rhCOLIII increased TREM2+ macrophages associated with M2 polarization.
CONCLUSIONS: Our study demonstrates that rhCOLIII exerts therapeutic effects in RSA mice potentially by modulating stromal cell decidualization and promoting a protective immune microenvironment, highlighting a promising therapeutic strategy for RSA.
METHODS: Human endometrium/decidua samples derived from healthy donors/normal pregnant and RSA patients were obtained to detect type III collagen (COLIII) expression via immunohistochemistry (IHC) and Western blot. A murine RSA model (CBA/J ♀ × DBA/2 ♂) was established, followed by intrauterine perfusion of rhCOLIII to evaluate its therapeutic efficacy. Uterine tissues from RSA and rhCOLIII-treated mice were collected on gestation day 8 for single-cell RNA sequencing, with findings validated by IHC, multiplex IHC (mIHC), and flow cytometry (FCM).
RESULTS: COLIII expression was significantly reduced in RSA endometrial/decidual tissues. Intrauterine rhCOLIII treatment in a murine RSA model significantly decreased the embryo resorption rate from 31.62% to 3.82% (P < 0.001). Single-cell analysis identified 19 cell clusters, with stromal cells as the predominant population, further classified into seven functional subtypes and their differential composition between the RSA and rhCOLIII groups was confirmed by mIHC. Furthermore, rhCOLIII reprogrammed stromal cell function by activating oxidative-stress response pathways and regulating decidualization. Concurrently, our results showed that rhCOLIII could enhance anti-inflammatory macrophage activity and increase CD16+ NK cell abundance. Cell-cell communication analysis uncovered that APOE-TREM2 signaling between decidual stromal cells and macrophages, as well as BSG-PPIA signaling in decidual stromal cell-NK cell interactions, was augmented following rhCOLIII treatment. FCM analysis demonstrated that rhCOLIII increased TREM2+ macrophages associated with M2 polarization.
CONCLUSIONS: Our study demonstrates that rhCOLIII exerts therapeutic effects in RSA mice potentially by modulating stromal cell decidualization and promoting a protective immune microenvironment, highlighting a promising therapeutic strategy for RSA.