Adipose tissue–derived stem cells protect the primordial follicle pool from both direct follicle death and abnormal activation after ovarian tissue transplantation

Cacciottola, Luciana; Courtoy, Guillaume E.; Nguyen, Thu Yen Thi; Hossay, Camille; Donnez, Jacques; Dolmans, Marie-Madeleine

doi:10.1007/s10815-020-02005-z

Cited by 21 publications

(10 citation statements)

References 49 publications

(76 reference statements)

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“…However, improving follicle outcomes after OTT would be a huge step forward in increasing the fertility potential and extending the graft lifespan, especially in patients with a diminished ovarian reserve from the start. The preparation of the transplantation site using ASCs has been proven to decrease hypoxia in grafted tissues (22) by boosting revascularization through ASC differentiation into endothelial-like lineages and growth factor secretion (24). This ensures both the protection of preexisting vessels in the host component and the earlier migration of endothelial progenitors from the graft component, as shown in our findings, resulting in enhanced primordial follicle survival after short-term (22,23) and long-term (38) grafting.…”

Section: Discussionsupporting

confidence: 64%

“…Boosting neoangiogenesis has proven to be effective in enhancing follicle outcomes in other experimental models that administered VEGF and fibroblast growth factor after OTT (43,44). ASCs exert a protective effect on the follicle pool in grafted ovarian tissues, as widely demonstrated (22,24,38,45), because of their ability to shorten the hypoxic period responsible for follicle loss that occurs soon after transplantation.…”

Section: Figurementioning

confidence: 98%

“…Among them, adipose tissue-derived stem cells (ASCs) were used in a 2-step ovarian tissue xenotransplantation strategy as they are known for their angiogenic potential and capacity to enhance angiogenesis by secreting growth factors and differentiating into vessels (20,21). This approach proved to effectively boost reoxygenation and revascularization in human xenografts (22,23), mitigate follicle loss (22), and also maintain quiescence in primordial follicles soon after OTT (24).…”

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confidence: 99%

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Modulating hypoxia and oxidative stress in human xenografts using adipose tissue-derived stem cells

et al. 2021

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Objective: To investigate whether adipose tissue-derived stem cells (ASCs) modulate hypoxia and oxidative stress in human ovarian tissue transplants. Design: Prospective experimental study Setting: Gynecological research unit in a university hospital Patient(s): Cryopreserved ovarian cortex from 5 adult women. Intervention(s): Thirty mice were grafted with frozen-thawed human ovarian tissue, with or without ASCs (2-step/ASCsþovarian tissue [OT] group and OT group). The ovarian grafts were retrieved on days 3 (n ¼ 5), 10 (n ¼ 5), and 21 (n ¼ 5). The 10 animals grafted for 21 days underwent in vivo evaluations using microdialysis. One piece of ovarian tissue per patient was fixed for analysis after thawing (non-grafted controls). Main Outcome Measure(s): Direct reactive oxygen species were collected every second day after grafting by means of microdialysis. Analyses of ovarian fragments included immunolabeling for double CD34 (revascularization by host and graft components); immunofluorescence for hypoxia-inducible factor 1a (hypoxia-related response), nuclear factor erythroid 2-related factor 2 (oxidative stressrelated response), and 8-hydroxy-deoxyguanosine (oxidative stress-related DNA damage); and gene expression (quantitative reverse transcription polymerase chain reaction) for vascular endothelial growth factor-A (neoangiogenesis), superoxide dismutase 2 (antioxidant activity), and nuclear respiratory factor 1 (mitochondrial biogenesis). Result(s): Reactive oxygen species peaked earlier in the ASC group (day 2) compared with that in the OT group (day 10) after grafting. Total vascularization was stable in the ASC group at all time points, while it was lower in the OT group 3 days after grafting. Hypoxiainducible factor 1a expression, also detected in non-grafted controls, was significantly lower in the ASC group than in the OT group on days 3 and 10. The increase in VEGF gene expression lasted significantly longer in the ASC group than in the OT group. There was no significant upturn in the oxidative stress-related response (nuclear factor erythroid 2-related factor 2 pathway) or oocyte DNA damage (8-hydroxy-deoxyguanosine) in any of the grafted groups. Conclusion(s): Use of ASCs allows faster ovarian graft reperfusion and mitigates the hypoxia-related response through rapid revascularization, sustained by prolonged increase in vascular endothelial growth factor after grafting. No evidence of oxidative stress-related damage was detected irrespective of the transplantation strategy.

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Section: Discussionsupporting

confidence: 64%

Section: Figurementioning

confidence: 98%

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confidence: 99%

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Modulating hypoxia and oxidative stress in human xenografts using adipose tissue-derived stem cells

et al. 2021

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“…Numerous cytokines and molecules that favor ectopic lesion hyperproliferation, such as VEGF, IL-6, and TNF-α, may support accelerated follicle activation in the surrounding healthy ovarian cortex, as well as triggering the PI3K/Akt/mTOR signaling pathway involved in primordial follicle recruitment [118]. Moreover, ROS can directly modulate the ovarian reserve, not only by enhancing the proinflammatory environment and PI3K/Akt/mTOR pathway activation [119,120] but also by precipitating cell death due to cumulative DNA damage [121,122]. Intraovarian oxidative stress is further compounded around endometriomas by the presence of increased uncoupled iron levels resulting from the imbalance between iron storage mechanisms and its reactivity [123].…”

Section: Targeting Oxidative Stress To Treat Endometriosis-related Infertilitymentioning

confidence: 99%

Can Endometriosis-Related Oxidative Stress Pave the Way for New Treatment Targets?

Cacciottola

Donnez

Dolmans

2021

IJMS

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Endometriosis is a disease of reproductive age characterized by chronic pelvic pain and infertility. Its pathogenesis is complex and still partially unexplained. However, there is increasing evidence of the role of chronic inflammation, immune system dysregulation, and oxidative stress in its development and progression. The latter appears to be involved in multiple aspects of the disease. Indeed, disease progression sustained by a hyperproliferative phenotype can be related to reactive oxygen species (ROS) imbalance, as numerous experiments using drugs to counteract hyperproliferation have shown in recent years. Chronic pelvic pain is also associated with cell function dysregulation favoring chronic inflammation and oxidative stress, specifically involving macrophages and mast cell activation. Moreover, there is increasing evidence of a role for ROS and impaired mitochondrial function not only as deleterious effectors of the ovarian reserve in patients with endometriomas but also in terms of oocyte quality and, hence, embryo development impairment. Targeting oxidative stress looks to be a promising strategy to both curb endometriotic lesion progression and alleviate endometriosis-associated symptoms of chronic pain and infertility. More investigations are nevertheless needed to develop effective therapeutic strategies for clinical application.

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“…This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (F.R.S.-FNRS/FRIA FC29657 awarded to Luciana Cacciottola, FNRS-PDR Convention T.0077. 14…”

Section: Fundingmentioning

confidence: 99%

Ovarian tissue damage after grafting: systematic review of strategies to improve follicle outcomes

Cacciottola

Donnez

Dolmans

2021

Reproductive BioMedicine Online

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Frozen-thawed human ovarian tissue endures large-scale follicle loss in the early post-grafting period, characterized by hypoxia lasting around 7 days. Tissue revascularization occurs progressively through new vessel invasion from the host and neoangiogenesis from the graft. Such reoxygenation kinetics lead to further potential damage caused by oxidative stress. The aim of the present manuscript is to provide a systematic review of proangiogenic growth factors, hormones and various antioxidants administered in the event of ovarian tissue transplantation to protect the follicle pool from depletion by boosting revascularization or decreasing oxidative stress. While almost all investigated studies revealed an advantage in terms of revascularization and reduction in oxidative stress, far fewer demonstrated a positive impact on follicle survival.Since the cascade of events driven by ischemia after transplantation is a complex process involving numerous players, it appears that acting on specific molecular mechanisms, such as levels of proangiogenic growth factors, is not enough to significantly mitigate tissue damage. Strategies exploiting the activated tissue response to ischemia for tissue healing and remodeling purposes, like use of antiapoptotic drugs and adult stem cells, are also discussed in the present review, since they yielded promising results in terms of follicle pool protection.

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Adipose tissue–derived stem cells protect the primordial follicle pool from both direct follicle death and abnormal activation after ovarian tissue transplantation

Cited by 21 publications

References 49 publications

Modulating hypoxia and oxidative stress in human xenografts using adipose tissue-derived stem cells

Modulating hypoxia and oxidative stress in human xenografts using adipose tissue-derived stem cells

Can Endometriosis-Related Oxidative Stress Pave the Way for New Treatment Targets?

Ovarian tissue damage after grafting: systematic review of strategies to improve follicle outcomes

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