Spermatogonial stem cells(SSCs)are essential for initiating and maintaining normal spermatogenesis,and notably,they have important applications in both reproduction and regenerative medicine.Nevertheless,the molecular...Spermatogonial stem cells(SSCs)are essential for initiating and maintaining normal spermatogenesis,and notably,they have important applications in both reproduction and regenerative medicine.Nevertheless,the molecular mechanisms controlling the fate determinations of human SSCs remain elusive.In this study,we identified a selective expression of APBB1 in dormant human SSCs.We demonstrated for the first time that APBB1 interacted with KAT5,which led to the suppression of GDF15 expression and consequent inhibition of human SSC proliferation.Intriguingly,Apbb1^(-/-)mice assumed the disrupted spermatogenesis and markedly reduced fertility.SSC transplantation assays revealed that Apbb1 silencing enhanced SSC colonization and impeded their differentiation,which resulted in the impaired spermatogenesis.Notably,4 deleterious APBB1 mutation sites were identified in 2,047 patients with non-obstructive azoospermia(NOA),and patients with the c.1940C>G mutation had a similar testicular phenotype with Apbb1^(-/-)mice.Additionally,we observed lower expression levels of APBB1 in NOA patients with spermatogenic arrest than in obstructive azoospermia patients with normal spermatogenesis.Collectively,our findings highlight an essential role of APBB1/KAT5/GDF15 in governing human SSC fate decisions and maintaining normal spermatogenesis and underscore them as therapeutic targets for treating male infertility.展开更多
基金supported by grants from the National Natural Science Foundation of China(nos.82201771,32270912,and 32170862)Natural Science Foundation of Hunan Province(nos.2024JJ6083 and 2023JJ31018)+4 种基金Health Research Project of Hunan Provincial Health Commission(nos.W20243143 and 20231769)Natural Science Foundation of Changsha(nos.kq2202491 and kq2502312)Science and Technology Innovation Project of Hunan Province(no.2021SK53204)Clinical Medical Technology Demonstration Base for Genetic Research of Fetal Congenital Heart Disease in Hunan Province(no.2021SK4036)Hunan Province Children’s Safe Medication Clinical Medical Technology Demonstration Base(no.2023SK4083).
文摘Spermatogonial stem cells(SSCs)are essential for initiating and maintaining normal spermatogenesis,and notably,they have important applications in both reproduction and regenerative medicine.Nevertheless,the molecular mechanisms controlling the fate determinations of human SSCs remain elusive.In this study,we identified a selective expression of APBB1 in dormant human SSCs.We demonstrated for the first time that APBB1 interacted with KAT5,which led to the suppression of GDF15 expression and consequent inhibition of human SSC proliferation.Intriguingly,Apbb1^(-/-)mice assumed the disrupted spermatogenesis and markedly reduced fertility.SSC transplantation assays revealed that Apbb1 silencing enhanced SSC colonization and impeded their differentiation,which resulted in the impaired spermatogenesis.Notably,4 deleterious APBB1 mutation sites were identified in 2,047 patients with non-obstructive azoospermia(NOA),and patients with the c.1940C>G mutation had a similar testicular phenotype with Apbb1^(-/-)mice.Additionally,we observed lower expression levels of APBB1 in NOA patients with spermatogenic arrest than in obstructive azoospermia patients with normal spermatogenesis.Collectively,our findings highlight an essential role of APBB1/KAT5/GDF15 in governing human SSC fate decisions and maintaining normal spermatogenesis and underscore them as therapeutic targets for treating male infertility.
