Transplantation of the LRP1high subpopulation of human umbilical cord-derived mesenchymal stem cells improves ovarian function in mice with premature ovarian failure and aged mice

Jiacheng Shen; Li Wu; Xiaoying Shi; Gang Chen; Tingwei Liu; Fangfang Xu; Xiaocui Xu; Xiaochen Kou; Yanhong Zhao; Hong Wang; Chenfei Wang; Shaorong Gao; Shaohua Xu

doi:10.1186/s13287-024-03660-0

Transplantation of the LRP1^high subpopulation of human umbilical cord-derived mesenchymal stem cells improves ovarian function in mice with premature ovarian failure and aged mice

Stem Cell Res Ther. 2024 Mar 5;15(1):64. doi: 10.1186/s13287-024-03660-0.

Authors

Jiacheng Shen^#¹, Li Wu^#², Xiaoying Shi^{3

4}, Gang Chen¹, Tingwei Liu¹, Fangfang Xu¹, Xiaocui Xu¹, Xiaochen Kou^{1

4}, Yanhong Zhao^{1

4}, Hong Wang^{1

4}, Chenfei Wang^{3

4}, Shaorong Gao^{5

6}, Shaohua Xu⁷

Affiliations

¹ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
² Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. 14_wuli@tongji.edu.cn.
³ Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedics, Tongji Hospital, School of Life Science and Technology, Tongji University, Tongji, 200092, China.
⁴ Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
⁵ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. gaoshaorong@tongji.edu.cn.
⁶ Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. gaoshaorong@tongji.edu.cn.
⁷ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. xushaohua@tongji.edu.cn.

^# Contributed equally.

Abstract

Background: Premature ovarian failure (POF) has a profound impact on female reproductive and psychological health. In recent years, the transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) has demonstrated unprecedented potential in the treatment of POF. However, the heterogeneity of human UC-MSCs remains a challenge for their large-scale clinical application. Therefore, it is imperative to identify specific subpopulations within UC-MSCs that possess the capability to improve ovarian function, with the aim of reducing the uncertainty arising from the heterogeneity while achieving more effective treatment of POF.

Methods: 10 × Genomics was performed to investigate the heterogeneity of human UC-MSCs. We used LRP1 as a marker and distinguished the potential therapeutic subpopulation by flow cytometry, and determined its secretory functions. Unsorted UC-MSCs, LRP1^high and LRP1^low subpopulation was transplanted under the ovarian capsules of aged mice and CTX-induced POF mice, and therapeutic effects was evaluated by assessing hormone levels, estrous cycles, follicle counts, and embryo numbers. RNA sequencing on mouse oocytes and granulosa cells after transplantation was performed to explore the mechanism of LRP1^high subpopulation on mouse oocytes and granulosa cells.

Results: We identified three distinct functional subtypes, including mesenchymal stem cells, multilymphoid progenitor cells and trophoblasts. Additionally, we identified the LRP1^high subpopulation, which improved ovarian function in aged and POF mice. We elucidated the unique secretory functions of the LRP1^high subpopulation, capable of secreting various chemokines, cytokines, and growth factors. Furthermore, LRP1 plays a crucial role in regulating the ovarian microenvironment, including tissue repair and extracellular matrix remodeling. Consistent with its functions, the transcriptomes of oocytes and granulosa cells after transplantation revealed that the LRP1^high subpopulation improves ovarian function by modulating the extracellular matrix of oocytes, NAD metabolism, and mitochondrial function in granulosa cells.

Conclusion: Through exploration of the heterogeneity of UC-MSCs, we identified the LRP1^high subpopulation capable of improving ovarian function in aged and POF mice by secreting various factors and remodeling the extracellular matrix. This study provides new insights into the targeted exploration of human UC-MSCs in the precise treatment of POF.

Keywords: Aging; Human umbilical cord-derived mesenchymal stem cells; LRP1; Ovarian function; Premature ovarian failure; Transplantation.

MeSH terms

Aged
Animals
Female
Humans
Low Density Lipoprotein Receptor-Related Protein-1 / genetics
Mesenchymal Stem Cells*
Mice
Oocytes
Primary Ovarian Insufficiency* / therapy
Stem Cells

Substances

LRP1 protein, human
Low Density Lipoprotein Receptor-Related Protein-1

Abstract

MeSH terms

Substances

Grants and funding