Abstract
Spermatogonial stem cells (SSCs) are germline stem cells located along the basement membrane of seminiferous tubules in testes. Recently, SSCs were shown to be reprogrammed into multipotent SSCs (mSSCs). However, both the key factors and biological networks underlying this reprogramming remain elusive. Here, we present transcriptional regulatory networks (TRNs) that control cellular processes related to the SSC-to-mSSC reprogramming. Previously, we established intermediate SSCs (iSSCs) undergoing the transition to mSSCs and generated gene expression profiles of SSCs, iSSCs and mSSCs. By comparing these profiles, we identified 2643 genes that were up-regulated during the reprogramming process and 15 key transcription factors (TFs) that regulate these genes. Using the TF-target relationships, we developed TRNs describing how these TFs regulate three pluripotency-related processes (cell proliferation, stem cell maintenance and epigenetic regulation) during the reprogramming. The TRNs showed that 4 of the 15 TFs (Oct4/Pou5f1, Cux1, Zfp143 and E2f4) regulated cell proliferation during the early stages of reprogramming, whereas 11 TFs (Oct4/Pou5f1, Foxm1, Cux1, Zfp143, Trp53, E2f4, Esrrb, Nfyb, Nanog, Sox2 and Klf4) regulated the three pluripotency-related processes during the late stages of reprogramming. Our TRNs provide a model for the temporally coordinated transcriptional regulation of pluripotency-related processes during the SSC-to-mSSC reprogramming, which can be further tested in detailed functional studies.
Highlights
Spermatogonial stem cells (SSCs) are the germline stem cells located along the basement membrane of seminiferous tubules in mammalian testes
Gene expression signatures related to the reprogramming of SSCs to multipotent SSCs (mSSCs) To understand the reprogramming of SSCs to mSSCs, we first developed mSSCs derived from SSCs as previously described.[28]
In this study, we attempted to decode the transcriptional regulatory networks (TRNs) underlying the reprogramming of SSCs to mSSCs through a comparative analysis of gene expression profiles obtained from SSCs, intermediate SSCs (iSSCs) and mSSCs and an integrative analysis of (1) differentially expressed genes (DEGs) during the SSC reprogramming and (2) transcription factors (TFs)-target information
Summary
Spermatogonial stem cells (SSCs) are the germline stem cells located along the basement membrane of seminiferous tubules in mammalian testes. SSCs are self-renewing and undifferentiated cells in the testicular microenvironment. Recent studies have shown that these unipotent SSCs can be reprogrammed into multipotent SSCs (mSSCs) under defined culture conditions.[1,2,3,4,5,6] Unlike embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) that have several issues, such as tumorigenic potential and ethical concerns, hindering their application in regenerative medicine, these mSSCs can serve as a pluripotent stem cell source free from these issues. Previous studies have focused on both the generation and characterization of mSSCs. Comparative analyses of gene expression profiles revealed that mSSCs were similar to ESCs, compared with iPSCs, SSCs and neural stem cells (NSCs).[6,7]
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