hUMSC transplantation restores ovarian function in POI rats by inhibiting autophagy of theca-interstitial cells via the AMPK/mTOR signaling pathway

Lu, Xin‐Yun; Bao, Hongchu; Cui, Linlu; Zhu, Wenyao; Zhang, Lianshuang; Xu, Zheng; Man, Xuejing; Chu, Yongli; Fu, Qiang; Zhang, Hongqin

doi:10.1186/s13287-020-01784-7

Cited by 40 publications

(28 citation statements)

References 49 publications

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“…According to reports in the literature, CDDP as a common anticancer drug can lead to POI [12,24]. The POI model was generated by daily intraperitoneal injections of CDDP (2 mg/kg, dissolved in saline) for 7 days [25,26]. The rats were randomly assigned to four groups: control, POI + hUMSCs, POI, and POI + PBS group.…”

Section: Group and Treatmentmentioning

confidence: 99%

hUMSCs regulate the differentiation of ovarian stromal cells via TGF-β1/Smad3 signaling pathway to inhibit ovarian fibrosis to repair ovarian function in POI rats

et al. 2020

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Objective The basic pathological changes of primary ovarian insufficiency (POI) include ovarian tissue fibrosis and follicular development disorders. The human umbilical cord mesenchymal stem cell (hUMSC) transplantation has been shown an effective method to improve the ovarian function in POI rat model; however, the exact mechanisms are still unclear. The purpose of this study is to investigate whether the recovery of ovarian function in POI rats is related to the inhibition of tissue fibrosis following hUMSC transplantation. Furthermore, the transforming growth factor-β1 (TGF-β1) signaling pathway is explored to determine the mechanisms of ovarian function recovery through its inhibition of tissue fibrosis. Methods The primary ovarian insufficiency (POI) rat model was established by intraperitoneal injection of chemotherapy drug cisplatin (CDDP) for 7 days. The levels of serum sex hormones were measured using enzyme-linked immunosorbent assay (ELISA). The tissue fibrosis in the ovary was examined using Masson staining and Sirius red staining. The collagen fibers in the ovarian tissues were detected by Western blot analysis. To investigate the mechanisms of ovarian function recovery following hUMSC transplantation, ovarian stromal cells were isolated from the ovarian cortex of immature rats. The expression of Cytochrome P450 17A1 (Cyp17a1) and fibrosis marker of alpha smooth muscle actin (α-SMA) in ovarian stromal cells was examined using immunofluorescence analysis. Also, the protein levels of Cyp17a1 and α-SMA in ovarian stromal cells were examined by Western blot analysis. The expression of TGF-β1 and Smad3 signals was measured by Western blot and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis. Results The results show that the function of the ovary in POI rats was significantly improved after hUMSC transplantation. The expression of fibrosis markers (α-SMA) and production of Collagen Type I (Collagen I) and Collagen Type III (Collagen III) in POI rats were significantly inhibited in POI rats following hUMSC transplantation. In the cultured ovarian stromal cells, the decrease of TGF-β1 and p-Smad3 protein expression was observed in hUMSC-treated POI rats. The treatment with TGF-β1 inhibitor of SB431542 further confirmed this signal pathway was involved in the process. Conclusion Our study demonstrated that the TGF-β1/Smad3 signaling pathway was involved in the inhibition of ovarian tissue fibrosis, which contributed to the restoration of ovarian function in POI rats following hUMSC transplantation.

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Section: Group and Treatmentmentioning

confidence: 99%

hUMSCs regulate the differentiation of ovarian stromal cells via TGF-β1/Smad3 signaling pathway to inhibit ovarian fibrosis to repair ovarian function in POI rats

et al. 2020

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“…Many studies have demonstrated that TSCs are recruited and differentiated into TCs, forming the follicular membranes surrounding the GCs to provide structural support and contribute to steroidogenesis for follicle maturation 21 , 47 . Lu et al reported that human umbilical cord-derived mesenchymal stem cell transplantation can restore the ovarian function by alleviating theca-interstitial cells apoptosis in POI rats 48 . We hypothesized that TSCs were more suitable for POI therapy as tissue resident stem cells.…”

Section: Discussionmentioning

confidence: 99%

Autologous transplantation of thecal stem cells restores ovarian function in nonhuman primates

et al. 2021

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Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity under the age of 40. Theca cells (TCs) play a vital role during folliculogenesis and TCs dysfunction participate in the pathogenesis of POI. Therefore, transplantation of thecal stem cells (TSCs), which are capable of self-renewal and differentiation into mature TCs, may provide a new strategy for treating POI. To investigate the feasibility, safety, and efficacy of TSCs transplantation in clinically relevant non-human primate (NHP) models, we isolate TSCs from cynomolgus monkeys, and these cells are confirmed to expand continuously and show potential to differentiate into mature TCs. In addition, engraftment of autologous TSCs into POI monkeys significantly improves hormone levels, rescues the follicle development, promotes the quality of oocytes and boosts oocyte maturation/fertilization rate. Taken together, these results for the first time suggest that autologous TSCs can ameliorate POI symptoms in primate models and shed new light on developing stem cell therapy for POI.

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“…Recently, Yin et al (2020) demonstrated that heme oxygenase-1 (HO-1) gene overexpress in hUCMSCs mediated restoration of the ovarian reserve of POI mice by regulating autophagy through the JNK/Bcl-2 signaling pathway. In addition, hUCMSCs restored ovarian function in POI rats by regulating ROS levels through the autophagy-related AMPK/mTOR pathway ( Lu et al, 2020 ). Huang et al (2019) showed that fetal liver MSCs exerted antioxidant effects by lowering ROS levels to restore ovary function in POI models.…”

Section: Mechanism Of Mscs-based Treatment For Poimentioning

confidence: 99%

Mesenchymal Stem Cells in Premature Ovarian Insufficiency: Mechanisms and Prospects

Zhang

Tian

et al. 2021

Front. Cell Dev. Biol.

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Premature ovarian insufficiency (POI) is a complex endocrine disease that severely affects the physiological and reproductive functions of females. The current conventional clinical treatment methods for POI are characterized by several side effects, and most do not effectively restore the physiological functions of the ovaries. Transplantation of mesenchymal stem cells (MSCs) is a promising regenerative medicine approach, which has received significant attention in the management of POI with high efficacy. Associated pre-clinical and clinical trials are also proceeding orderly. However, the therapeutic mechanisms underlying the MSCs-based treatment are complex and have not been fully elucidated. In brief, proliferation, apoptosis, immunization, autophagy, oxidative stress, and fibrosis of ovarian cells are modulated through paracrine effects after migration of MSCs to the injured ovary. This review summarizes therapeutic mechanisms of MSCs-based treatments in POI and explores their therapeutic potential in clinical practice. Therefore, this review will provide a theoretical basis for further research and clinical application of MSCs in POI.

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hUMSC transplantation restores ovarian function in POI rats by inhibiting autophagy of theca-interstitial cells via the AMPK/mTOR signaling pathway

Cited by 40 publications

References 49 publications

hUMSCs regulate the differentiation of ovarian stromal cells via TGF-β1/Smad3 signaling pathway to inhibit ovarian fibrosis to repair ovarian function in POI rats

hUMSCs regulate the differentiation of ovarian stromal cells via TGF-β1/Smad3 signaling pathway to inhibit ovarian fibrosis to repair ovarian function in POI rats

Autologous transplantation of thecal stem cells restores ovarian function in nonhuman primates

Mesenchymal Stem Cells in Premature Ovarian Insufficiency: Mechanisms and Prospects

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