Melatonin-pretreated human umbilical cord mesenchymal stem cells improved endometrium regeneration and fertility recovery through macrophage immunomodulation in rats with intrauterine adhesions

Author:

Qin Weili1,Wang Jiawei123,Hu Qianwen1,Qin Rongyan1,Ma Nana1,Zheng Fengque1,Tian Wencai1,Jiang Jinghang1,Li Ting1,Jin Yufu1,Liao Ming1,Qin Aiping1

Affiliation:

1. Center of Reproductive Medicine, The First Affiliated Hospital of Guangxi Medical University , Nanning , China

2. Reproductive and Genetic Hospital , The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, , Hefei , China

3. University of Science and Technology of China , The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, , Hefei , China

Abstract

Abstract Intrauterine adhesions (IUA) are a common gynecological problem. Stem cell therapy has been widely used in the treatment of IUA. However, due to the complex and harsh microenvironment of the uterine cavity, the effectiveness of such therapy is greatly inhibited. This study aimed to investigate whether melatonin pretreatment enhances the efficacy of human umbilical cord mesenchymal stem cells (HucMSCs) in IUA treatment in rats. First, we explored the effect of melatonin on the biological activity of HucMSCs in vitro through a macrophage co-culture system, Cell Counting Kit 8 (CCK-8), 5-Ethynyl-2′-deoxyuridine (EdU), flow cytometry, immunofluorescence staining, and qRT-PCR. Subsequently, we established the IUA rat model and tracked the distribution of HucMSCs in this model. In addition, we observed the number of M1 and M2 macrophages through immunofluorescence staining and detected the levels of inflammatory cytokines. Four weeks after cell transplantation, HE, Masson, and immunohistochemical staining were performed. In vitro experiments showed that melatonin pretreatment of HucMSCs promoted proliferation, reduced apoptosis, up-regulated the stemness gene, and regulated macrophage polarization. In vivo, melatonin pretreatment caused more HucMSCs to remain in the uterine cavity. Melatonin-pretreated HucMSCs recruited more macrophages, regulated macrophage polarization, and reduced inflammation. Melatonin-pretreated HucMSCs relieved fibrosis, increased endometrium thickness, and up-regulated CD34, vimentin, proliferating cell nuclear antigen (PCNA), and alpha small muscle antigen (α-SMA) expression. Fertility tests showed that melatonin-pretreated HucMSCs increased the number of embryos. In summary, pretreatment with melatonin was beneficial for HucMSC treatment because it enhanced the cell’s ability to recruit macrophages and regulate macrophage polarization, which led to the regeneration of the endometrium and improved pregnancy outcomes.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Guangxi Zhuang Autonomous Region

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,General Medicine,Reproductive Medicine

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