Abstract:Ectopic xenografting of testis is a feasible option for preservation of male fertility and angiogenesis plays a pivotal role in xenograft survival and functionality. When compared to immature testis, the adult testis is unable to establish functional xenografts due to potentially lower efficiency to induce angiogenesis. The precise molecular mechanism, however, remains elusive. In the present study, we compared adult and immature testis xenografts for survival, maturation and germ cell differentiation. Further… Show more
“…However, the absence of elongated spermatids in the xenografted testis indicated that the spermatogenesis remained incomplete. These results are consistent with previous reports in which incomplete spermatogenesis was reported in xenografted rat testis at 8-wk post-grafting with a spermatogenic arrest at pachytene-stage spermatocytes 8 , 9 . Spermatogenesis was observed to remain incomplete even after an extended grafting period (12 wk; data not shown).…”
Section: Discussionsupporting
confidence: 93%
“…Following xenografting, immature rat testis showed a progressive increase in weight over 8 wk, suggestive of consistent growth of seminiferous tubules and supporting cellular structures 19 and establishment of an effective vascular connection between the xenograft and the recipient, resulting in its survival 8 . Similarly, a progressive increase and subsequent restoration of the recipient’s seminal vesicle weight, an indicator of circulating bioactive testosterone 8,16,19–23 , suggests that not only the spermatogenic but also the steroidogenic function of the immature rat testis was recovered in the xenografts. This also indicates that the donor tissue responded to gonadotrophin stimulation of the recipient mice.Figure 7A model for spermatogenic arrest in xenografted testis.…”
Testis tissue xenografting complemented with cryopreservation is a feasible technique for fertility preservation in children with malignancy receiving gonadotoxic therapy and for endangered species with high neonatal mortality rate. However, xenografted testis of human and most endangered species are known to undergo spermatogenic arrest. In this study, we xenografted immature rat testis onto immunodeficient male mice to investigate the plausible underlying causes of spermatogenic arrest. Histological analysis of xenografted testes collected 8-wk post-grafting showed incomplete spermatogenesis with pachytene-stage spermatocytes as the most advanced germ cells. Although the levels of serum luteinizing hormone and testosterone were normal in recipient mice, those of follicle stimulating hormone (FSH) were significantly high, and specific receptors of FSH were absent in the xenografts. The xenografts demonstrated dysregulated expression of Sertoli cell-transcriptional regulators (WT1 and SOX9) and secretory proteins (SCF and GDNF). In conclusion, results from our study suggested that an altered hormonal milieu in recipients and dysregulated protein expression in xenografts could be a potential cause of spermatogenic arrest in xenografted immature rat testis. Further stereological analysis of xenografts can demonstrate precise cellular composition of xenografts to decipher interactions between germ and somatic cells to better understand spermatogenic arrest in xenografted testis.
“…However, the absence of elongated spermatids in the xenografted testis indicated that the spermatogenesis remained incomplete. These results are consistent with previous reports in which incomplete spermatogenesis was reported in xenografted rat testis at 8-wk post-grafting with a spermatogenic arrest at pachytene-stage spermatocytes 8 , 9 . Spermatogenesis was observed to remain incomplete even after an extended grafting period (12 wk; data not shown).…”
Section: Discussionsupporting
confidence: 93%
“…Following xenografting, immature rat testis showed a progressive increase in weight over 8 wk, suggestive of consistent growth of seminiferous tubules and supporting cellular structures 19 and establishment of an effective vascular connection between the xenograft and the recipient, resulting in its survival 8 . Similarly, a progressive increase and subsequent restoration of the recipient’s seminal vesicle weight, an indicator of circulating bioactive testosterone 8,16,19–23 , suggests that not only the spermatogenic but also the steroidogenic function of the immature rat testis was recovered in the xenografts. This also indicates that the donor tissue responded to gonadotrophin stimulation of the recipient mice.Figure 7A model for spermatogenic arrest in xenografted testis.…”
Testis tissue xenografting complemented with cryopreservation is a feasible technique for fertility preservation in children with malignancy receiving gonadotoxic therapy and for endangered species with high neonatal mortality rate. However, xenografted testis of human and most endangered species are known to undergo spermatogenic arrest. In this study, we xenografted immature rat testis onto immunodeficient male mice to investigate the plausible underlying causes of spermatogenic arrest. Histological analysis of xenografted testes collected 8-wk post-grafting showed incomplete spermatogenesis with pachytene-stage spermatocytes as the most advanced germ cells. Although the levels of serum luteinizing hormone and testosterone were normal in recipient mice, those of follicle stimulating hormone (FSH) were significantly high, and specific receptors of FSH were absent in the xenografts. The xenografts demonstrated dysregulated expression of Sertoli cell-transcriptional regulators (WT1 and SOX9) and secretory proteins (SCF and GDNF). In conclusion, results from our study suggested that an altered hormonal milieu in recipients and dysregulated protein expression in xenografts could be a potential cause of spermatogenic arrest in xenografted immature rat testis. Further stereological analysis of xenografts can demonstrate precise cellular composition of xenografts to decipher interactions between germ and somatic cells to better understand spermatogenic arrest in xenografted testis.
“…In patients with testicular tumor or infertility, abnormal activity of signaling pathways was observed, including the Wnt signaling pathway, the PI3k/Akt signaling pathway, etc 56,[132][133][134][135][136][137] . We had discussed of the TGF-β/Smad, AMPK, and MAPK signaling pathways in SCs to regulate normal spermatogenesis.…”
Section: Pathways and Potential Clinical Applications Of Abnormal Spementioning
The functions of Sertoli cells in spermatogenesis have attracted much more attention recently. Normal spermatogenesis depends on Sertoli cells, mainly due to their influence on nutrient supply, maintenance of cell junctions, and support for germ cells’ mitosis and meiosis. Accumulating evidence in the past decade has highlighted the dominant functions of the MAPK, AMPK, and TGF-β/Smad signaling pathways during spermatogenesis. Among these pathways, the MAPK signaling pathway regulates dynamics of tight junctions and adherens junctions, proliferation and meiosis of germ cells, proliferation and lactate production of Sertoli cells; the AMPK and the TGF-β/Smad signaling pathways both affect dynamics of tight junctions and adherens junctions, as well as the proliferation of Sertoli cells. The AMPK signaling pathway also regulates lactate supply. These signaling pathways combine to form a complex regulatory network for spermatogenesis. In testicular tumors or infertile patients, the activities of these signaling pathways in Sertoli cells are abnormal. Clarifying the mechanisms of signaling pathways in Sertoli cells on spermatogenesis provides new insights into the physiological functions of Sertoli cells in male reproduction, and also serves as a pre-requisite to identify potential therapeutic targets in abnormal spermatogenesis including testicular tumor and male infertility.
“…The formation of new blood vessels is fundamental to health and disease[1,2,3,4,5]. This formation can occur by two processes: vasculogenesis or angiogenesis.…”
Casitas B lineage lymphoma (c-Cbl) is a multifunctional protein with a ubiquitin E3 ligase activity capable of degrading diverse sets of proteins. Although previous work had focused mainly on c-Cbl mutations in humans with hematological malignancies, recent emerging evidence suggests a critical role of c-Cbl in angiogenesis and human solid organ tumors. The combination of its unique structure, modular function, and ability to channelize cues from a rich network of signaling cascades, empowers c-Cbl to assume a central role in these disease models. This review consolidates the structural and functional insights based on recent studies that highlight c-Cbl as a target with tantalizing therapeutic potential in various models of angiogenesis and tumorigenesis.
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