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Adipose-derived stem cells promote the repair of chemotherapy-induced premature ovarian failure by inhibiting granulosa cells apoptosis and senescence

BACKGROUND: Chemotherapeutic drugs, particularly alkylating cytotoxics such as cyclophosphamide (CTX), play an important role to induce premature ovarian failure (POF). Hormone replacement therapy (HRT) is a widely used treatment to improve hormone secretion. However, the long-term HRT increases the...

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Detalles Bibliográficos
Autores principales: Ai, Guihai, Meng, Meng, Guo, Jing, Li, Caixia, Zhu, Jihui, Liu, Li, Liu, Biting, Yang, Wenhan, Shao, Xiaowen, Cheng, Zhongping, Wang, Lian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10088140/
https://www.ncbi.nlm.nih.gov/pubmed/37038203
http://dx.doi.org/10.1186/s13287-023-03297-5
Descripción
Sumario:BACKGROUND: Chemotherapeutic drugs, particularly alkylating cytotoxics such as cyclophosphamide (CTX), play an important role to induce premature ovarian failure (POF). Hormone replacement therapy (HRT) is a widely used treatment to improve hormone secretion. However, the long-term HRT increases the risk of breast cancer and cardiovascular disease are attracting concerns. Therefore, there is an urgent need to develop a safe and effective treatment for POF. METHOD: Adipose-derived stem cells (ADSCs) were isolated and identified from human adipose tissue. For POF modeling, CTX were intraperitoneal injected into CTX-acute group, CTX-chronic group, CTX-acute + ADSCs group and CTX-chronic + ADSCs group rats; For transplantation, ADSCs were transplanted into POF rats through tail-vein. The control group rats were injected with PBS. The effects of POF modeling and transplantation were determined by estrous cycle analysis, histopathological analysis, immunohistochemical staining and apoptosis-related marker. To evaluate the effects of ADSC on granulosa cells in vitro, CTX-induced senescent KGN cells were co-cultured with ADSCs, and senescent-related marker expression was investigated by immunofluorescent staining. RESULTS: In vivo studies revealed that ADSCs transplantation reduced the apoptosis of ovarian granulosa cells and secretion of follicle-stimulating hormone. The number of total follicles, primordial follicles, primary follicles, and mature follicles and secretion of anti-Müllerian hormone and estradiol (E2) were also increased by ADSCs. The estrous cycle was also improved by ADSC transplantation. Histopathological analysis showed that CTX-damaged ovarian microenvironment was improved by ADSCs. Furthermore, TUNEL staining indicated that apoptosis of granulosa cells was decreased by ADSCs. In vitro assay also demonstrated that ADSC markedly attenuated CTX-induced senescence and apoptosis of granulosa cell. Mechanistically, both in vivo and in vitro experiments proved that ADSC transplantation suppressed activation of the PI3K/Akt/mTOR axis. CONCLUSION: Our experiment demonstrated that a single injection of high-dose CTX was a less damaging chemotherapeutic strategy than continuous injection of low-dose CTX, and tail-vein injection of ADSCs was a potential approach to promote the restoration of CTX-induced POF.