Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries

Kristensen, Stine Gry; Kumar, Ajay; Mamsen, Linn Salto; Kalra, Bhanu; Pors, Susanne Elisabeth; Bøtkjær, Jane Alrø; Macklon, Kirsten Tryde; Fedder, Jens; Ernst, Erik; Hardy, Kate; Andersen, Claus Yding

doi:10.1210/clinem/dgac272

Cited by 21 publications

(5 citation statements)

References 65 publications

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“…The concentration of GDF9 in spent media was approximately 10-times higher than BMP15, which corroborates recent measurements by our group in follicular fluid from human small antral follicles [39]. This 10-times excess GDF9 in relation to BMP15 indicates that the vast majority of GDF9 are not bound in a heterodimer complex and may have a role on its own during folliculogenesis.…”

Section: Discussionsupporting

confidence: 90%

Concentrations of oocyte secreted GDF9 and BMP15 decrease with MII transition during human IVM

Pors¹,

Kumar²,

Kalra³

et al. 2022

Reprod Biol Endocrinol

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Background The suggested effects of the oocyte secreted GDF9 and BMP15 growth factors on oocyte maturation are currently based on recombinant proteins, and little is known about native GDF9 and BMP15 in humans. Methods Human immature cumulus-oocyte complexes (COCs) obtained in connection with ovarian tissue cryopreservation (OTC) underwent in vitro maturation (IVM). Oocyte-produced GDF9 and BMP15 were detected in COCs using immunofluorescence, and in fresh GV oocytes and in GV and MII oocytes after IVM by western blot. Concentrations of GDF9, BMP15 homodimers, and GDF9/BMP15 heterodimer in spent media after IVM were measured by ELISA. The relative expression of seven genes from the GDF9 and BMP15 signaling pathways (BMPR2, ALK5, ALK6, SMAD1, SMAD2, SMAD3, and SMAD5) was evaluated in fresh cumulus cells (before IVM) and in cumulus cells from GV and MII oocytes after IVM by RT-qPCR. Results We detected native pro-mature GDF9 and BMP15 in human oocytes with molecular weights (Mw) of 47 kDa and 43 kDa, respectively. Concentrations of GDF9 and BMP15 in spent media after IVM were detected in 99% and 64% of the samples, respectively. The GDF9/BMP15 heterodimer was detected in 76% of the samples. Overall, the concentration of GDF9 was approximately 10-times higher than BMP15. The concentrations of both GDF9 and BMP15 were significantly lower in spent medium from MII oocytes than in media from oocytes that remained at the GV stage. Concentrations of the GDF9/BMP15 heterodimer did not differ between GV and MII oocytes. Furthermore, BMPR2, SMAD3, and SMAD5 were significantly upregulated in cumulus cells from MII oocytes, indicating that both GDF9 and BMP15 signaling were active during oocyte meiotic resumption in vitro. Conclusion These data suggest that the driving mechanisms for oocyte nuclear maturation may involve both GDF9 and BMP15 homodimers, while the role of the GDF9/BMP15 heterodimer is questionable.

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Section: Discussionsupporting

confidence: 90%

Concentrations of oocyte secreted GDF9 and BMP15 decrease with MII transition during human IVM

Pors¹,

Kumar²,

Kalra³

et al. 2022

Reprod Biol Endocrinol

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“…Plasma AMH kinetics were similar over time in grafted groups. The tendency of AMH was the same as GDF9 expression, which is a marker of oocyte development quality [ 67 ]. The H-MSCs + OT group showed higher Prog and lower FSH than the OT group on day 3 and 7.…”

Section: Discussionmentioning

confidence: 99%

Effects of hypoxia-preconditioned HucMSCs on neovascularization and follicle survival in frozen/thawed human ovarian cortex transplanted to immunodeficient mice

Cheng

Ruan

et al. 2022

Stem Cell Res Ther

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Background The massive loss of follicles in the early stage of ovarian tissue transplantation is considered a significant restriction to the efficacy of ovarian tissue cryopreservation (OTC) and transplantation (OT). The use of mesenchymal stem cells (MSCs) before transplantation of ovarian fragments shortened the hypoxic period and boosted neovascularization. Hypoxia-preconditioned MSCs can enhance the potential of angiogenesis. Can hypoxia-preconditioned human umbilical cord mesenchymal stem cell (HucMSCs) and ovarian tissue co-xenotransplantation improve more neovascularization and subsequently more follicle survival in human ovarian tissue? Methods Frozen-thawed cortical pieces from 4 patients were transplanted into the bilateral renal capsule of immune-deficient nude mice without HucMSCs or normoxia/hypoxia-preconditioned HucMSCs. Sixty-four mice were randomly distributed into 4 groups. In each group, the mice were euthanized for blood and/or graft retrieval on post-transplantation days 3 (n = 8) and 7 (n = 8), respectively. Non-grafted frozen-thawed ovarian fragment was taken for non-grafted control. Grafts were histologically processed and analysed for follicle density and atretic follicles by HE, neovascularization by CD34 and CD31 immunohistochemical staining, primordial follicle growth by Ki67 staining, and apoptosis of stromal cell and follicles by immunofluorescence using TUNEL. The ROS and TAC levels of grafted and non-grafted tissue were assessed. We evaluated the protein expression of HIF1α, VEGFA, pAkt, Akt, and GDF9 in grafted and non-grafted ovarian tissue. E2, Prog, AMH, and FSH levels in the plasma of mice were measured after 3 and 7 days of OT. Results Hypoxia-preconditioned HucMSCs positively protect the grafted ovarian tissue by significantly decreasing the apoptosis and increasing higher expression of CD31, CD34, and VEGFA for earlier angiogenesis. They are crucial to preserving the resting primordial follicle pool by modulation of follicle death. Conclusion This is the first study to demonstrate that co-transplantation of hypoxia-preconditioned HucMSC with ovarian tissue improved earlier vascularization of ovarian grafts in the early post-grafting period, which correlates with increased follicle survival and reduced apoptosis. The HIF1α/VEGFA signal pathways may play an important role in elucidating the mechanisms of action of hypoxia-preconditioned HucMSCs with regard to OT and clinical implementation.

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“…BMP15 is a well-known paracrine factor secreted by oocytes [ 36 ] and primarily responsible for regulating the secretion of steroid hormones, cell mitosis, and follicle development [ 37 ]. Previous research has demonstrated a negative correlation between intrafollicular concentrations of BMP15 and follicle size [ 38 ]. Studies have revealed that the expression of BMP15 in human ovarian granulosa cells stimulates the production of estrogen [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of the Ovary Transcriptome among Wanyue Black and Yorkshire Gilts Using RNA-Seq

Zhang,

Chen,

Liu

et al. 2024

Veterinary Sciences

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Pubertal genetic variations between the indigenous Chinese Wanyue Black pig breed and the imported Yorkshire breed significantly impact their reproductive capacity. In order to identify the differentially expressed genes, gene networks, and metabolic pathways in ovary transcriptome of gilts, the serum hormone levels were analyzed by ELISA, and RNA-seq was performed to analyze ovarian genes. Our results reveal higher estradiol (E2) levels in Wanyue black gilts compared to Yorkshire gilts, while Yorkshire gilts exhibit elevated progesterone (P4) and GnRH levels. We identified a total of 154 differentially expressed genes (DEGs), with 87 up-regulated and 67 down-regulated genes in the Wanyue black gilts ovaries compared to the Yorkshire gilts. GO enrichment analysis unveiled the participation of DEGs in processes such as “Reproduction”, “Reproductive system development”, and “Ovarian follicle development”. Moreover, KEGG enrichment analysis revealed the involvement of DEGs in multiple signaling pathways associated with hormone biosynthesis and puberty, encompassing “Steroid hormone biosynthesis”, “Estrogen signaling pathway”, and “Prolactin signaling pathway”. The subsequent bioinformatics analysis identified nine functional genes that potentially contribute to the disparity in ovaries between Wanyue black gilts and Yorkshire gilts. This study offers significant insights into the endocrine and genetic aspects of pubertal development in gilts.

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Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries

Cited by 21 publications

References 65 publications

Concentrations of oocyte secreted GDF9 and BMP15 decrease with MII transition during human IVM

Concentrations of oocyte secreted GDF9 and BMP15 decrease with MII transition during human IVM

Effects of hypoxia-preconditioned HucMSCs on neovascularization and follicle survival in frozen/thawed human ovarian cortex transplanted to immunodeficient mice

Comparative Analysis of the Ovary Transcriptome among Wanyue Black and Yorkshire Gilts Using RNA-Seq

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