Explore chapters and articles related to this topic
Artificial gametes The oocyte
Published in David K. Gardner, Ariel Weissman, Colin M. Howles, Zeev Shoham, Textbook of Assisted Reproductive Techniques, 2017
Evelyn E. Telfer, Kelsey M. Grieve
The identification of early germ cells within culture demonstrates recapitulation of the earliest stages of the complex pathway for germ cell development; however, prior to germ cell migration, germ cell fate is induced in the epiblast cells in mice by bone morphogenetic protein 4 (BMP4) signaling from the surrounding soma (6). Epiblast-like cells (EpiLCs) have been induced from mESCs with gene expression consistent with pre-gastrulating epiblasts. BMP4 induced expression of Blimp1 in EpiLCs and further gene expression analysis also showed up-regulation of Nanos3, Dppa3 and Prdm14 associated with primordial germ cell specification and down-regulation of somatic markers Hoxa1, Hoxb1, and Snai1—these observations were seen in conjunction with epigenetic changes (7), replicating in vivo differentiation of epiblast cells into primordial germ cells. These results suggest successful differentiation of EpiLCs to primordial germ cell-like cells (PGCLCs) in vitro in a similar fashion to the in vivo situation. BMP4-dependent differentiation of PGCLCs could be inhibited by Noggin (a BMP4 antagonist), whereas Wnt3a—another mesoderm-promoting factor—also induced PGCLCs in culture (8), illustrating the importance of somatic factors in in vitro differentiation of germ cells. PGCLCs derived from embryoid bodies (EBs) differentiated into oocyte-like cells with expression of oocyte-specific genes (Figa, GDF9, ZP1, ZP2, and ZP3) and an early meiotic marker (SCP3) when co-cultured with granulosa cells (9); similar results were observed when PGCLCs were co-cultured with Chinese hamster ovary cells (10). However, these results could not be replicated with granulosa cell-conditioned medium (9), suggesting an important role for cell-cell interactions with ovarian somatic cells. Using a reconstituted ovary model, PGCLCs combined with embryonic ovarian somatic cells and xeno-transplanted to the ovarian bursa of immune-deficient recipient mice generated oocyte-like cells within developing follicles (Figure 30.2).
TGF-β signaling in testicular development, spermatogenesis, and infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Poonam Mehta, Meghali Joshi, Rajender Singh
Bone morphogenetic proteins were first identified in the mid-1960s as ectopic bone formation–inducing proteins (70). Since then, many studies have reported the ability of BMPs to induce mesenchymal stem cell differentiation into bone, suggesting their role in cartilage and bone formation. BMP signaling is involved in many processes, such as cell growth, apoptosis and differentiation (71–73). The role of BMP signaling in the development of male accessory sex organs was reported (21). In a study, the deletion of GDF7, a member of the BMP family, resulted in abnormal growth, branching and differentiation of seminal vesicle epithelium. It has been reported that ablation of BMP ligands, such as BMP4 (74) and their receptors, such as BMPR1A (75), leads to the lack of formation of PGCs, confirming their role in gonadal development. In testes, BMP4 signaling is involved in spermatogonial differentiation (40). Dorsomorphin (an inhibitor of BMP type I receptors) treatment to the spermatogonial culture system resulted in the inhibition of spermatogonial differentiation and promotion of proliferation (76). In another study, a mutation in the Zebrafish BMP type I receptor resulted in impairment of spermatogonial differentiation in vivo (77), while the addition of BMP4 to mouse SSCs promoted differentiation and production of spermatids (40,78). It has been reported that BMP4 signaling along with retinoic acid signaling promote spermatogonial differentiation, suggesting a coordinated role of both of these pathways in spermatogonial differentiation (79). Similarly, other BMP ligands, BMP7 and BMP8a/b, are known to play important roles in male germ cell development (80,81). Their transcripts have been found in different stages of differentiation in male germ cells. Mutations in BMP8b in adult mice resulted in progressive germ cell apoptosis and degeneration, leading to small testes size (81). Mouse lacking BMP8a along with mutation in a single allele of BMP7 resulted in a similar phenotype as generated by BMP8b KO (80). BMP2 and BMP7 have been reported to be important for the proliferation of Sertoli and germ cells during early postnatal development in mice (82). In addition to BMP4, BMP7, BMP8a/b, growth-differentiation factor 9 (GDF9) expressed strongly in testes, specifically in the pachytene spermatocytes and early round spermatids (83). However, GDF9-deficient male mice were fertile (84), suggesting that the testicular GDF9 is not essential for normal spermatogenesis. Another member of the BMP family, GDF7, was seen in the seminal vesicle, and it was found that it is important for the development of seminal vesicle (21). Male mice deficient in GDF7 were found to be sterile and displayed defects in seminal vesicle development.
An update on platelet-rich plasma (PRP) therapy in endometrium and ovary related infertilities: clinical and molecular aspects
Published in Systems Biology in Reproductive Medicine, 2021
Hamed Hajipour, Laya Farzadi, Zeinab Latifi, Neda Keyhanvar, Nazli Navali, Amir Fattahi, Mohammad Nouri, Ralf Dittrich
The ovary is an extremely angiogenic organ, therefore it can be expected that PRP-derived angiogenic factors provoke neoangiogenesis in ovarian tissue and pave the way for tissue regeneration and reactivation (Farimani et al. 2019). This potential of PRP has also been used to induce angiogenesis in the autologous transplantation of human ovary (Callejo et al. 2013). Besides, it has been revealed that growth and survival rates of follicles from PRP supplemented culture media were significantly higher than those without PRP; this proves that PRP can support the early stage of follicle development (Hosseini et al. 2017). Growth differentiation factor 9 (GDF-9), a TGF-β superfamily member is one of the factors that can be found in PRP, and its role in oocyte maturation has previously been demonstrated (Krüger et al. 2013). More interestingly, mutation of the GDF-9 gene can result in premature ovarian failure (Otsuka et al. 2011). Furthermore, the establishment of a balance between cell apoptosis and survival can be another possible mechanism by which PRP affects follicular growth and development. This feature of PRP is related to the presence of both apoptotic (Fas-L, CD40L, TRAIL, and TWEAK) and anti-apoptotic (HGF, SDF-1, serotonin, adenosine diphosphate, and sphingosine-1 phosphate) molecules in this fraction (Hu et al. 2012).
Growth differentiation factor 9 inhibits vascular endothelial growth factor expression in human granulosa cells
Published in Gynecological Endocrinology, 2020
Congcong Guo, Minghui Chen, Wenmin Ma, Bing Cai, Yanwen Xu, Yiping Zhong, Canquan Zhou
Growth differentiation factor 9 (GDF9) is an oocyte-derived factor and a member of the TGFβ family that also includes TGFβ, activin, and bone morphogenetic proteins (BMPs). This ligand is required for the growth of follicles, and female GDF9-knockout mice are infertile, exhibiting a complete block in folliculogenesis at the primary stage [8]. GDF9 signaling is mediated by ALK5 and BMP type II receptor in rat granulosa cells [9,10]. However, the effect of GDF9 on VEGF expression in human granulosa cells is still unknown. In the present study, we determined the effect of GDF9 on VEGF expression and explored the role of ALK5 in the regulation of this process in human granulosa cells.
Differential expression of BMP/SMAD signaling and ovarian-associated genes in the granulosa cells of FecB introgressed GMM sheep
Published in Systems Biology in Reproductive Medicine, 2020
Satish Kumar, Pradeep Kumar Rajput, Sangharatna V. Bahire, Basanti Jyotsana, Vijay Kumar, Davendra Kumar
It is well known that the type 1 receptor (TGFβRI) and the type 2 receptor (BMPRII) are the downstream of the GDF9 ligand on the cell surface (Vitt et al. 2002; Mazerbourg et al. 2004). GDF9 ligand binds to BMPRII and interacts with downstream TGFβRI (Gilchrist et al. 2008). After binding of GDF9 to BMPRII and TGFβRI, this ligand-receptor activation allows the downstream phosphorylation and activation of the SMAD proteins (Castro et al. 2015). Thus, GDF9 specifically activates the SMAD2 and SMAD3 signaling which in turn forms a complex with common SMAD4. This complex translocates into the nucleus and regulates the expression of the target gene (Gilchrist et al. 2008). Thus, GDF9 is essential for early follicular development and ovulation through its direct action on the granulosa cells allowing their proliferation and differentiation (Otsuka et al. 2011). In comparison, the TGFβ ligand binds to the extracellular domain of the TGFβRI, which in turn activates the receptor and allows it to bind with other receptors (TGFβRII) on the cell surface. Hence, these three proteins form a complex and trigger signal transduction by activating the signaling molecules (SMAD2 and SMAD3) through the TGFβ signaling pathway (Source: Genetic Home Reference: https://ghr.nlm.nih.gov/gene/TGFβR1; https://omim.org/entry/190181; Franzen et al. 1993). The role of TGFβ1 has been implicated in ovarian folliculogenesis, steroidogenesis, and proliferation of the granulosa cells (Rosairo et al. 2008). In summary, the molecules of BMP/SMAD pathway, GDF9, and TGFβ1 interact with each other and play an important role in the regulation of ovulation rate and folliculogenesis in prolific ewes.