PTN from Leydig cells activates SDC2 and modulates human spermatogonial stem cell proliferation and survival via GFRA1.
Male
Humans
Cell Proliferation
/ physiology
Leydig Cells
/ metabolism
Cytokines
/ metabolism
Glial Cell Line-Derived Neurotrophic Factor Receptors
/ metabolism
Syndecan-2
/ metabolism
Carrier Proteins
/ metabolism
Cell Survival
/ physiology
Spermatogonia
/ metabolism
Signal Transduction
/ physiology
Adult Germline Stem Cells
/ metabolism
Apoptosis
Pleiotrophin
Proliferation
Self-renewal
Spermatogonial stem cells
Syndecan-2
Journal
Biological research
ISSN: 0717-6287
Titre abrégé: Biol Res
Pays: England
ID NLM: 9308271
Informations de publication
Date de publication:
16 Sep 2024
16 Sep 2024
Historique:
received:
23
01
2024
accepted:
02
09
2024
medline:
17
9
2024
pubmed:
17
9
2024
entrez:
16
9
2024
Statut:
epublish
Résumé
Spermatogonial stem cells (SSCs) are essential for the maintenance and initiation of male spermatogenesis. Despite the advances in understanding SSC biology in mouse models, the mechanisms underlying human SSC development remain elusive. Here, we analyzed the signaling pathways involved in SSC regulation by testicular somatic cells using single-cell sequencing data (GEO datasets: GSE149512 and GSE112013) and identified that Leydig cells communicate with SSCs through pleiotrophin (PTN) and its receptor syndecan-2 (SDC2). Immunofluorescence, STRING prediction, and protein immunoprecipitation assays confirmed the interaction between PTN and SDC2 in spermatogonia, but their co-localization was observed only in approximately 50% of the cells. The knockdown of SDC2 in human SSC lines impaired cell proliferation, DNA synthesis, and the expression of PLZF, a key marker for SSC self-renewal. Transcriptome analysis revealed that SDC2 knockdown downregulated the expression of GFRA1, a crucial factor for SSC proliferation and self-renewal, and inhibited the HIF-1 signaling pathway. Exogenous PTN rescued the proliferation and GFRA1 expression in SDC2 knockdown SSC lines. In addition, we found downregulation of PTN and SDC2 as well as altered localization in non-obstructive azoospermia (NOA) patients, suggesting that downregulation of PTN and SDC2 may be associated with impaired spermatogenesis. Our results uncover a novel mechanism of human SSC regulation by the testicular microenvironment and suggest a potential therapeutic target for male infertility.
Sections du résumé
BACKGROUND
BACKGROUND
Spermatogonial stem cells (SSCs) are essential for the maintenance and initiation of male spermatogenesis. Despite the advances in understanding SSC biology in mouse models, the mechanisms underlying human SSC development remain elusive.
RESULTS
RESULTS
Here, we analyzed the signaling pathways involved in SSC regulation by testicular somatic cells using single-cell sequencing data (GEO datasets: GSE149512 and GSE112013) and identified that Leydig cells communicate with SSCs through pleiotrophin (PTN) and its receptor syndecan-2 (SDC2). Immunofluorescence, STRING prediction, and protein immunoprecipitation assays confirmed the interaction between PTN and SDC2 in spermatogonia, but their co-localization was observed only in approximately 50% of the cells. The knockdown of SDC2 in human SSC lines impaired cell proliferation, DNA synthesis, and the expression of PLZF, a key marker for SSC self-renewal. Transcriptome analysis revealed that SDC2 knockdown downregulated the expression of GFRA1, a crucial factor for SSC proliferation and self-renewal, and inhibited the HIF-1 signaling pathway. Exogenous PTN rescued the proliferation and GFRA1 expression in SDC2 knockdown SSC lines. In addition, we found downregulation of PTN and SDC2 as well as altered localization in non-obstructive azoospermia (NOA) patients, suggesting that downregulation of PTN and SDC2 may be associated with impaired spermatogenesis.
CONCLUSIONS
CONCLUSIONS
Our results uncover a novel mechanism of human SSC regulation by the testicular microenvironment and suggest a potential therapeutic target for male infertility.
Identifiants
pubmed: 39285301
doi: 10.1186/s40659-024-00546-6
pii: 10.1186/s40659-024-00546-6
doi:
Substances chimiques
pleiotrophin
134034-50-7
Cytokines
0
Glial Cell Line-Derived Neurotrophic Factor Receptors
0
Syndecan-2
149769-25-5
Carrier Proteins
0
GFRA1 protein, human
0
SDC2 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
66Subventions
Organisme : National Natural Science Foundation for Young Scholars of China
ID : 82201771
Organisme : Natural Science Foundation of Hunan Province
ID : 2024JJ6083
Organisme : Natural Science Foundation of Hunan Province
ID : 2023JJ31018
Organisme : Health Research Project of Hunan Provincial Health Commission
ID : W20243143
Organisme : Health Research Project of Hunan Provincial Health Commission
ID : 20231769
Organisme : Natural Science Foundation of Changsha
ID : kq2202491
Organisme : Science and Technology Innovation Project of Hunan Province
ID : 2021SK53204
Informations de copyright
© 2024. The Author(s).
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