Key Takeaways & Executive Findings
- •• Identified a novel LRP1high subpopulation within human UC-MSCs that significantly improves ovarian function in both aged and chemotherapy-induced POF mouse models. • The LRP1high subpopulation exerts therapeutic effects via unique secretory functions, including chemokines, cytokines, and growth factors, and by remodeling the extracellular matrix. • Single-cell RNA sequencing revealed three distinct functional subtypes in UC-MSCs, highlighting the importance of subpopulation selection for effective stem cell therapy. • Mechanistically, the LRP1high subpopulation modulates oocyte extracellular matrix, NAD metabolism, and mitochondrial function in granulosa cells, offering new targets for POF treatment.
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, LRP1high and LRP1low 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 LRP1high 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 LRP1high subpopulation, which improved ovarian function in aged and POF mice. We elucidated the unique secretory functions of the LRP1high 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 LRP1high 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 LRP1high 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.
1. Introduction
Premature ovarian failure (POF) is a debilitating condition that substantially affects female reproductive function and psychological well-being [1, 2]. According to epidemiological data, the global incidence of POF ranges from 1 to 3% and has been increasing in recent years, with a trend towards younger age groups [3]. Currently, hormone replacement therapy (HRT) is the primary clinical approach for treating POF. However, HRT only provides temporary relief of menopausal symptoms and cannot effectively reverse ovarian failure [4].
With the advancement of regenerative medicine, stem cells, as a population of undifferentiated cells, have emerged as a promising avenue for POF treatment [5–8]. Increasing clinical evidence suggests that mesenchymal stem cells, particularly umbilical cord-derived mesenchymal stem cells (UC-MSCs), are an ideal cell source for clinical POF therapy due to their low tumorigenicity, low immunogenicity, high proliferation rate, and easy accessibility [9–12]. Despite the major advantages of UC-MSCs in POF research, their heterogeneity limits the study and application of UC-MSCs [13, 14]. Some studies suggest that regardless of donor and passage, human UC-MSCs exhibit limited heterogeneity [15].
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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 (2026). 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. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-024-03660-0
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Frequently Asked Questions
What is the main finding of this study?
The study identifies a specific subpopulation of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) characterized by high expression of LRP1 (LRP1high) that significantly improves ovarian function in both aged and chemotherapy-induced premature ovarian failure (POF) mouse models.
How does the LRP1high subpopulation improve ovarian function?
The LRP1high subpopulation secretes various chemokines, cytokines, and growth factors, and modulates the extracellular matrix, NAD metabolism, and mitochondrial function in granulosa cells, thereby enhancing ovarian function.
Why is the heterogeneity of UC-MSCs a challenge?
Heterogeneity among UC-MSCs can lead to inconsistent therapeutic outcomes, making it difficult to standardize treatments. Identifying specific subpopulations like LRP1high helps reduce uncertainty and improve efficacy.
What methods were used in this study?
The study used single-cell RNA sequencing (10× Genomics) to investigate heterogeneity, flow cytometry to isolate LRP1high and LRP1low subpopulations, and transplantation into mouse models to assess therapeutic effects. RNA sequencing on oocytes and granulosa cells was performed to explore mechanisms.
What are the potential clinical implications of this research?
This research provides a basis for targeted stem cell therapy for POF, potentially leading to more effective and personalized treatments by selecting the LRP1high subpopulation for transplantation.
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