Locally existing endothelial cells and pericytes in ovarian stroma, but not bone marrow-derived vascular progenitor cells, play a central role in neovascularization during follicular development in mice

Kizuka-Shibuya, Fumie; Tokuda, Nobuko; Takagi, Kiyoshi; Adachi, Yasuhiro; Lee, Lifa; Tamura, Isao; Tamura, Hiroshi; Suzuki, Takashi; Owada, Yuji

doi:10.1186/1757-2215-7-10

Cited by 15 publications

(14 citation statements)

References 34 publications

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“…In addition, VE-Cadherin, FGF-1, VWF and Dll-1 were even up regulated in the AOEC group. Since ovarian endothelial cells play a central role in neovascularization during follicular development, as demonstrated in mice [ 31 ], the comparable expression of angiocrines between AOEC and fresh EC is essential.…”

Section: Discussionmentioning

confidence: 99%

Activated ovarian endothelial cells promote early follicular development and survival

et al. 2017

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BackgroundNew data suggests that endothelial cells (ECs) elaborate essential “angiocrine factors”. The aim of this study is to investigate the role of activated ovarian endothelial cells in early in-vitro follicular development.MethodsMouse ovarian ECs were isolated using magnetic cell sorting or by FACS and cultured in serum free media. After a constitutive activation of the Akt pathway was initiated, early follicles (50–150 um) were mechanically isolated from 8-day-old mice and co-cultured with these activated ovarian endothelial cells (AOEC) (n = 32), gel (n = 24) or within matrigel (n = 27) in serum free media for 14 days. Follicular growth, survival and function were assessed.ResultsAfter 6 passages, flow cytometry showed 93% of cells grown in serum-free culture were VE-cadherin positive, CD-31 positive and CD 45 negative, matching the known EC profile. Beginning on day 4 of culture, we observed significantly higher follicular and oocyte growth rates in follicles co-cultured with AOECs compared with follicles on gel or matrigel. After 14 days of culture, 73% of primary follicles and 83% of secondary follicles co-cultured with AOEC survived, whereas the majority of follicles cultured on gel or matrigel underwent atresia.ConclusionsThis is the first report of successful isolation and culture of ovarian ECs. We suggest that co-culture with activated ovarian ECs promotes early follicular development and survival. This model is a novel platform for the in vitro maturation of early follicles and for the future exploration of endothelial-follicular communication.CapsuleIn vitro development of early follicles necessitates a complex interplay of growth factors and signals required for development. Endothelial cells (ECs) may elaborate essential “angiocrine factors” involved in organ regeneration. We demonstrate that co-culture with ovarian ECs enables culture of primary and early secondary mouse ovarian follicles.

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Section: Discussionmentioning

confidence: 99%

Activated ovarian endothelial cells promote early follicular development and survival

et al. 2017

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“…The methodology we used is based on current models employed in animal research, and it is thus simple and easy to implement. The mouse parabiotic model is being progressively applied in recent years (9), particularly in research addressing ageing/rejuvenation (20,25,31) and repair/regeneration (1,2,17,18,28). After parabiosis surgery, we waited for 2 wk to ensure that cross-circulation was well established.…”

Section: Discussionmentioning

confidence: 99%

“…The parabiotic model has been used in recent years to investigate the molecular and cell communication between same-age animals under different pathological conditions [homochronic parabiosis (8,15,17,18)] and to investigate how systemic soluble factors from a young animal modify the response of an old animal subjected to different challenges [heterochronic parabiosis (20,25,31)]. In the field of respiratory diseases, parabiosis has been employed to assess repair mechanisms in lung injury (1) and pulmonary fibrosis (28), but not to study hypoxia.…”

Section: Discussionmentioning

confidence: 99%

“…See text in DISCUSSION for explanation. nary disease, pulmonary hypertension, lung fibrosis, sleep apnea), diabetes (23), liver alterations (19), fat metabolism (22,26), cardiac fibrosis (2), neovascularization (17), or cancer (8). Another potential new application of the parabiotic hypoxic/ normoxic model is to investigate the interaction between oxygenation and aging: demyelinating diseases (25), cognitive function impairments and synaptic plasticity (31), muscle loss (29), or cardiac hypertrophy (20).…”

Section: Discussionmentioning

confidence: 99%

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Parabiotic model for differentiating local and systemic effects of continuous and intermittent hypoxia

Torres

Rojas

Campillo

et al. 2015

Journal of Applied Physiology

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Hypoxia can be damaging either because cells are directly sensitive to low oxygen pressure in their local microenvironment and/or because they are exposed to circulating factors systemically secreted in response to hypoxia. The conventional hypoxia model, breathing hypoxic air, does not allow one to distinguish between these local and systemic effects. Here we propose and validate a model for differentially applying local and systemic hypoxic challenges in an animal. We used parabiosis, two mice sharing circulation by surgical union through the skin, and tested the hypothesis that when one of the parabionts breathes room air and the other one is subjected to hypoxic air, both mice share systemic circulation but remain normoxic and hypoxic, respectively. We tested two common hypoxic paradigms in 10 parabiotic pairs: continuous hypoxia (10% O2) mimicking chronic lung diseases, and intermittent hypoxia (40 s, 21% O2; 20 s, 5% O2) simulating sleep apnea. Arterial oxygen saturation and oxygen partial pressure at muscle tissue were measured in both parabionts. Effective cross-circulation was assessed by intraperitoneally injecting a dye in one of the parabionts and measuring blood dye concentration in both animals after 2 h. The results confirmed the hypothesis that tissues of the parabiont under room air were perfused with normally oxygenated blood and, at the same time, were exposed to all of the systemic mediators secreted by the other parabiont actually subjected to hypoxia. In conclusion, combination of parabiosis and hypoxic/normoxic air breathing is a novel approach to investigate the effects of local and systemic hypoxia in respiratory diseases.

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“…The fresh ovarian medulla was found to be the best cell source to provide an environment for paracrine secretion. In addition, local endothelial cells in ovarian tissues, rather than bone marrow-derived vascular progenitor cells, contributed to neovascularisation during follicular development (Kizuka-Shibuya et al, 2014). Therefore, combined use of stromal and endothelial cells from fresh ovarian medullary tissues should be considered for cotransplantation with follicles to increase the efficiency of the artificial ovary.…”

Section: Designing Scaffolds For Isolated Follicle Deliverymentioning

confidence: 99%

A new possibility in fertility preservation: The artificial ovary

Cho

Kim

Noh

et al. 2019

J Tissue Eng Regen Med

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Conventional fertility preservation methods such as oocyte or embryo cryopreservation are currently insufficient to treat including those patients with prepubertal cancer and premature ovarian failure. Ovarian tissue cryopreservation presents as an alternative but has limitations with a potential risk of reintroducing malignant cells in patients who recover from cancer, those of chemotherapy prior to tissue cryopreservation. The so called “artificial ovary” aims to resolve this issue by transplanting isolated follicles with or without a biological scaffold. The artificial ovary may also offer an effective alternative option for those who cannot benefit from traditional assisted reproductive techniques such as in vitro fertilisation. To date, in animal studies and human trial, the artificial ovary restored endocrine function, achieved in vivo follicular development, and resulted in successful pregnancies. However, development of a technique for higher follicular recovery rate and a more optimised design of delivery scaffold, better transplantation techniques to prevent postsurgical ischemia, and consideration for genetic safety are required for safer and consistent human clinical applications. Ideas from different transplantation surgeries (e.g., entire ovary, ovarian cortex, and transplantation with tissue‐engineered products) can be applied to enhance the efficacy of artificial ovarian transplantation. For the better application of artificial ovary, a deeper understanding of mechanical and biochemical properties of the ovary and folliculogenesis after cryopreservation, transplantation with or without scaffold, and development of sophisticated in vivo imaging techniques of transplanted artificial ovary need to precede its efficient clinical application.

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Locally existing endothelial cells and pericytes in ovarian stroma, but not bone marrow-derived vascular progenitor cells, play a central role in neovascularization during follicular development in mice

Cited by 15 publications

References 34 publications

Activated ovarian endothelial cells promote early follicular development and survival

Activated ovarian endothelial cells promote early follicular development and survival

Parabiotic model for differentiating local and systemic effects of continuous and intermittent hypoxia

A new possibility in fertility preservation: The artificial ovary

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