Busulfan Suppresses Autophagy in Mouse Spermatogonial Progenitor Cells via mTOR of AKT and p53 Signaling Pathways

Wei, Rui; Zhang, Xiaoyu; Cai, Yihui; Li, Hongyang; Wang, Bingyuan; Zhao, Xiaodong; Zou, Kang

doi:10.1007/s12015-020-10027-4

Cited by 18 publications

(8 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To study the role of E-cadherin, SPCs were purified using THY1.2 + MACS from neonatal mouse testis, and grape-like clones were observed after 2 passages on MEF feeder layers (Fig. 1 D), which were able to be stably maintained in vitro for more than 30 passages [ 26 ]. The expression of SPC markers, including Plzf , Cdh1 , Gfra1 and Id4 , was examined to characterize their identities using RT-PCR (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Testicular cells were extracted from 5 days postpartum mice generally following previous protocol [ 26 ]. Briefly, testes were cut into small particles and followed by collagenase IV and trypsin digestion and centrifugation, and cell pellet was resuspended and were filtered with 70-µm cell filter and subsequently sorted using mouse THY-1.2 antibody coated magnetic beads (BD, Cat.551518).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

E-cadherin maintains the undifferentiated state of mouse spermatogonial progenitor cells via β-catenin

Song

Zhang

et al. 2022

Cell Biosci

Self Cite

View full text Add to dashboard Cite

Background Cadherins play a pivotal role in facilitating intercellular interactions between spermatogonial progenitor cells (SPCs) and their surrounding microenvironment. Specifically, E-cadherin serves as a cellular marker of SPCs in many species. Depletion of E-cadherin in mouse SPCs showed no obvious effect on SPCs homing and spermatogenesis. Results Here, we investigated the regulatory role of E-cadherin in regulating SPCs fate. Specific deletion of E-cadherin in germ cells was shown to promote SPCs differentiation, evidencing by reduced PLZF+ population and increased c-Kit+ population in mouse testes. E-cadherin loss down-regulated the expression level of β-catenin, leading to the reduced β-catenin in nuclear localization for transcriptional activity. Remarkably, increasing expression level of Cadherin-22 (CDH22) appeared specifically after E-cadherin deletion, indicating CDH22 played a synergistic effect with E-cadherin in SPCs. By searching for the binding partners of β-catenin, Lymphoid enhancer-binding factor 1 (LEF1), T-cell factor (TCF3), histone deacetylase 4 (HDAC4) and signal transducer and activator 3 (STAT3) were identified as suppressors of SPCs differentiation by regulating acetylation of differentiation genes with PLZF. Conclusions Two surface markers of SPCs, E-cadherin and Cadherin-22, synergically maintain the undifferentiation of SPCs via the pivotal intermediate molecule β-catenin. LEF1, TCF3, STAT3 and HDAC4 were identified as co-regulatory factors of β-catenin in regulation of SPC fate. These observations revealed a novel regulatory pattern of cadherins on SPCs fate.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

E-cadherin maintains the undifferentiated state of mouse spermatogonial progenitor cells via β-catenin

Song

Zhang

et al. 2022

Cell Biosci

Self Cite

View full text Add to dashboard Cite

show abstract

“…The functional analysis of these genes, using the KEGG database revealed that many are involved in the TP53 signaling pathway and cellular senescence ( CCND1 , FAS , MDM2 , TNFRSF10B , CALML6 ). This result can be explained by the response of the cells to the toxic effect of busulfan and its metabolites which might also play a role in SOS [ 50 ]. In addition, TP53 regulated genes were significantly upregulated in our gene expression analysis such as MDM2 , and the pro-apoptotic genes BBC3 and GADD45A .…”

Section: Discussionmentioning

confidence: 99%

A novel integrative multi-omics approach to unravel the genetic determinants of rare diseases with application in sinusoidal obstruction syndrome

et al. 2023

View full text Add to dashboard Cite

Background Genotype-phenotype analyses of rare diseases often suffer from a lack of power, due to small sample size, which makes identifying significant associations difficult. Sinusoidal obstruction syndrome (SOS) of the liver is a rare but life-threatening complication of hematopoietic stem cell transplantation (HSCT). The alkylating agent busulfan is commonly used in HSCT and known to trigger SOS. We developed a novel pipeline to identify genetic determinants in rare diseases by combining in vitro information with clinical whole-exome sequencing (WES) data and applied it in SOS patients and controls. Methods First, we analysed differential gene expression in six lymphoblastoid cell lines (LCLs) before and after incubation with busulfan. Second, we used WES data from 87 HSCT patients and estimated the association with SOS at the SNP and the gene levels. We then combined the results of the expression and the association analyses into an association statistic at the gene level. We used an over-representation analysis to functionally characterize the genes that were associated with a significant combined test statistic. Results After treatment of LCLs with busulfan, 1708 genes were significantly up-, and 1385 down-regulated. The combination of the expression experiment and the association analysis of WES data into a single test statistic revealed 35 genes associated with the outcome. These genes are involved in various biological functions and processes, such as “Cell growth and death”, “Signalling molecules and interaction”, “Cancer”, and “Infectious disease”. Conclusions This novel data analysis pipeline integrates two independent omics datasets and increases statistical power for identifying genotype-phenotype associations. The analysis of the transcriptomics profile of cell lines treated with busulfan and WES data from HSCT patients allowed us to identify potential genetic contributors to SOS. Our pipeline could be useful for identifying genetic contributors to other rare diseases where limited power renders genome-wide analyses unpromising. Trial registration For the clinical dataset: Clinicaltrials.gov: NCT01257854. https://clinicaltrials.gov/ct2/history/NCT01257854.

show abstract

“…It has long been known that these drugs can interfere with testicular function and spermatogenesis [ 200 ]. Based on this fact, different animal models have been used in studies to identify autophagy-based therapies for these chemotherapy-induced side effects [ 201 – 203 ]. For instance, moderate induction of autophagy using rapamycin was shown to protect mouse spermatogonial progenitor cells (SPCs) from the cytotoxic effects of busulfan.…”

Section: Autophagy Modulation As a New Therapeutic Approachmentioning

confidence: 99%

Autophagy, a critical element in the aging male reproductive disorders and prostate cancer: a therapeutic point of view

Raee,

Tan,

Najafi

et al. 2023

Reprod Biol Endocrinol

View full text Add to dashboard Cite

Autophagy is a highly conserved, lysosome-dependent biological mechanism involved in the degradation and recycling of cellular components. There is growing evidence that autophagy is related to male reproductive biology, particularly spermatogenic and endocrinologic processes closely associated with male sexual and reproductive health. In recent decades, problems such as decreasing sperm count, erectile dysfunction, and infertility have worsened. In addition, reproductive health is closely related to overall health and comorbidity in aging men. In this review, we will outline the role of autophagy as a new player in aging male reproductive dysfunction and prostate cancer. We first provide an overview of the mechanisms of autophagy and its role in regulating male reproductive cells. We then focus on the link between autophagy and aging-related diseases. This is followed by a discussion of therapeutic strategies targeting autophagy before we end with limitations of current studies and suggestions for future developments in the field.

show abstract

Busulfan Suppresses Autophagy in Mouse Spermatogonial Progenitor Cells via mTOR of AKT and p53 Signaling Pathways

Cited by 18 publications

References 80 publications

E-cadherin maintains the undifferentiated state of mouse spermatogonial progenitor cells via β-catenin

E-cadherin maintains the undifferentiated state of mouse spermatogonial progenitor cells via β-catenin

A novel integrative multi-omics approach to unravel the genetic determinants of rare diseases with application in sinusoidal obstruction syndrome

Autophagy, a critical element in the aging male reproductive disorders and prostate cancer: a therapeutic point of view

Contact Info

Product

Resources

About