Glucagon-like peptide-1 promotes Leydig cell regeneration from stem cells in rats

in Reproduction
Authors:
Xiaoheng LiDepartment of Anesthesiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Institute of Reproductive Biomedicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

Search for other papers by Xiaoheng Li in
Current site
Google Scholar
PubMed
Close
,
Lanlan ChenDepartment of Anesthesiology, Taizhou People’s Hospital, The Fifth Hospital Affiliated Nantong University, Taizhou, Jiangsu, China

Search for other papers by Lanlan Chen in
Current site
Google Scholar
PubMed
Close
,
Yiyan WangDepartment of Anesthesiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Institute of Reproductive Biomedicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

Search for other papers by Yiyan Wang in
Current site
Google Scholar
PubMed
Close
,
Huitao LiDepartment of Anesthesiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Institute of Reproductive Biomedicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

Search for other papers by Huitao Li in
Current site
Google Scholar
PubMed
Close
,
Qiqi ZhuDepartment of Anesthesiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Institute of Reproductive Biomedicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

Search for other papers by Qiqi Zhu in
Current site
Google Scholar
PubMed
Close
, and
Ren-Shan GeDepartment of Anesthesiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Institute of Reproductive Biomedicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

Search for other papers by Ren-Shan Ge in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0002-3448-9823
View More View Less

Correspondence should be addressed to R-S Ge; Email: r_ge@yahoo.com

*(X Li and L Chen contributed equally to this work)

Restricted access

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $1.00
USD  $1.00

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $0.01
USD  $0.01

USD  $1.00
USD  $1.00

USD  $1.00
USD  $1.00

In brief

Glucagon-like peptide-1 stimulates stem Leydig cell development. Glucagon-like peptide-1 stimulates stem Leydig cell differentiation without affecting its proliferation.

Abstract

The regulators of stem Leydig cell (SLC) development remain largely unknown. The effect of glucagon-like peptide-1 (GLP-1) on rat SLC proliferation and differentiation was investigated using a 3D tissue culture system and an ethane dimethane sulfonate (EDS)-treated in vivo LC regeneration model. RNA-seq analysis was performed to analyze pathways in which GLP-1 may be involved. GLP-1 (3 and 30 nmol/L) significantly increased medium testosterone abundances and upregulated the expression of Scarb1, Cyp11a1, and Hsd11b1. GLP-1 in vitro did not affect SLC proliferation by 5-Ethynyl-2’- deoxyuridine (EdU) incorporation assay. Intratesticular injection of GLP-1 (10 and 100 ng/testis) into the LC-depleted testis from day 14 to day 28 post-EDS significantly increased serum testosterone abundances and upregulated the expression of Cyp11a1, Hsd3b1, and Hsd11b1. It did not affect the number of HSD11B1+ and CYP11A1+ LCs. RNA-seq analysis revealed that GLP-1 upregulated several pathways, including cAMP-PKA-EPAC1 and MEK/ERK1/2. GLP-1 stimulates SLC differentiation without affecting its proliferation, showing its novel action and mechanism on rat SLC development.

 

  • Collapse
  • Expand
  • Annes JP, Ryu JH, Lam K, Carolan PJ, Utz K, Hollister-Lock J, Arvanites AC, Rubin LL, Weir G & Melton DA 2012 Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication. PNAS 109 39153920. (https://doi.org/10.1073/pnas.1201149109)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Caltabiano R, Condorelli D, Panza S, Boitani C, Musso N, Ježek D, Memeo L, Colarossi L, Rago V & Mularoni V et al.2020 Glucagon-like peptide-1 receptor is expressed in human and rodent testis. Andrology 8 19351945. (https://doi.org/10.1111/andr.12871)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Campbell JE & Drucker DJ 2013 Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metabolism 17 819837. (https://doi.org/10.1016/j.cmet.2013.04.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen P, Zirkin BR & Chen H 2020 Stem Leydig cells in the adult testis: characterization, regulation and potential applications. Endocrine Reviews 41 2232. (https://doi.org/10.1210/endrev/bnz013)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A & Bos JL 1998 Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396 474477. (https://doi.org/10.1038/24884)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • du Toit T & Swart AC 2021 Turning the spotlight on the C11-oxy androgens in human fetal development. Journal of Steroid Biochemistry and Molecular Biology 212 105946. (https://doi.org/10.1016/j.jsbmb.2021.105946)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eliveld J, van den Berg EA, Chikhovskaya JV, van Daalen SKM, de Winter-Korver CM, van der Veen F, Repping S, Teerds K & van Pelt AMM 2019 Primary human testicular PDGFRalpha+ cells are multipotent and can be differentiated into cells with Leydig cell characteristics in vitro. Human Reproduction 34 16211631. (https://doi.org/10.1093/humrep/dez131)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fujimoto K, Shibasaki T, Yokoi N, Kashima Y, Matsumoto M, Sasaki T, Tajima N, Iwanaga T & Seino S 2002 Piccolo, a Ca2+ sensor in pancreatic β-cells. Journal of Biological Chemistry 277 5049750502. (https://doi.org/10.1074/jbc.M210146200)

    • Search Google Scholar
    • Export Citation
  • Ge RS & Hardy MP 1998 Variation in the end products of androgen biosynthesis and metabolism during postnatal differentiation of rat Leydig cells. Endocrinology 139 37873795. (https://doi.org/10.1210/endo.139.9.6183)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ge RS, Hardy DO, Catterall JF & Hardy MP 1997 Developmental changes in glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase oxidative and reductive activities in rat Leydig cells. Endocrinology 138 50895095. (https://doi.org/10.1210/endo.138.12.5614)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ge RS, Dong Q, Sottas CM, Papadopoulos V, Zirkin BR & Hardy MP 2006 In search of rat stem Leydig cells: identification, isolation, and lineage-specific development. PNAS 103 27192724. (https://doi.org/10.1073/pnas.0507692103)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Graaf Cd, Donnelly D, Wootten D, Lau J, Sexton PM, Miller LJ, Ahn JM, Liao J, Fletcher MM & Yang D et al.2016 Glucagon-like peptide-1 and its class B G protein-coupled receptors: a long march to therapeutic successes. Pharmacological Reviews 68 9541013. (https://doi.org/10.1124/pr.115.011395)

    • Search Google Scholar
    • Export Citation
  • Guo J, Zhou H, Su Z, Chen B, Wang G, Wang CQ, Xu Y & Ge RS 2013 Comparison of cell types in the rat Leydig cell lineage after ethane dimethanesulfonate treatment. Reproduction 145 371380. (https://doi.org/10.1530/REP-12-0465)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hardy MP, Zirkin BR & Ewing LL 1989 Kinetic studies on the development of the adult population of Leydig cells in testes of the pubertal rat. Endocrinology 124 762770. (https://doi.org/10.1210/endo-124-2-762)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hossain MN, Sakemura R, Fujii M & Ayusawa D 2006 G-protein gamma subunit GNG11 strongly regulates cellular senescence. Biochemical and Biophysical Research Communications 351 645650. (https://doi.org/10.1016/j.bbrc.2006.10.112)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ivell R, Agoulnik AI & Anand-Ivell R 2017 Relaxin-like peptides in male reproduction – a human perspective. British Journal of Pharmacology 174 9901001. (https://doi.org/10.1111/bph.13689)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jiang MH, Cai B, Tuo Y, Wang J, Zang ZJ, Tu X, Gao Y, Su Z, Li W & Li G et al.2014 Characterization of Nestin-positive stem Leydig cells as a potential source for the treatment of testicular Leydig cell dysfunction. Cell Research 24 14661485. (https://doi.org/10.1038/cr.2014.149)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kashima Y, Miki T, Shibasaki T, Ozaki N, Miyazaki M, Yano H & Seino S 2001 Critical role of cAMP–GEFII–Rim2 complex in incretin-potentiated insulin secretion. Journal of Biological Chemistry 276 4604646053. (https://doi.org/10.1074/jbc.M108378200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kieffer TJ & Habener JF 1999 The glucagon-like peptides. Endocrine Reviews 20 876913. (https://doi.org/10.1210/edrv.20.6.0385)

  • Landschulz KT, Pathak RK, Rigotti A, Krieger M & Hobbs HH 1996 Regulation of scavenger receptor, class B, type I, a high density lipoprotein receptor, in liver and steroidogenic tissues of the rat. Journal of Clinical Investigation 98 984995. (https://doi.org/10.1172/JCI118883)

    • Search Google Scholar
    • Export Citation
  • Li X, Wang Z, Jiang Z, Guo J, Zhang Y, Li C, Chung J, Folmer J, Liu J & Lian Q et al.2016 Regulation of seminiferous tubule-associated stem Leydig cells in adult rat testes. PNAS 113 26662671. (https://doi.org/10.1073/pnas.1519395113)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Martins AD, Monteiro MP, Silva BM, Barros A, Sousa M, Carvalho RA, Oliveira PF & Alves MG 2019 Metabolic dynamics of human Sertoli cells are differentially modulated by physiological and pharmacological concentrations of GLP-1. Toxicology and Applied Pharmacology 362 18. (https://doi.org/10.1016/j.taap.2018.10.009)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Oda S, Ashida K, Uchiyama M, Sakamoto S, Hasuzawa N, Nagayama A, Wang L, Nagata H, Sakamoto R & Kishimoto J et al.2021 An open-label Phase I/IIa clinical trial of 11beta-HSD1 inhibitor for Cushing’s syndrome and autonomous cortisol secretion. Journal of Clinical Endocrinology and Metabolism 106 e3865–e3880. (https://doi.org/10.1210/clinem/dgab450)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ozaki N, Shibasaki T, Kashima Y, Miki T, Takahashi K, Ueno H, Sunaga Y, Yano H, Matsuura Y & Iwanaga T et al.2000 cAMP-GEFII is a direct target of cAMP in regulated exocytosis. Nature Cell Biology 2 805811. (https://doi.org/10.1038/35041046)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Peverelli E, Ermetici F, Corbetta S, Gozzini E, Avagliano L, Zappa MA, Bulfamante G, Beck-Peccoz P, Spada A & Mantovani G 2013 PKA regulatory subunit R2B is required for murine and human adipocyte differentiation. Endocrine Connections 2 196207. (https://doi.org/10.1530/EC-13-0049)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rago V, De Rose D, Santoro M, Panza S, Malivindi R, Ando S, D’Agata R & Aquila S 2020 Human sperm express the receptor for glucagon-like peptide-1 (GLP-1), which affects sperm function and metabolism. Endocrinology 161 bqaa031. (https://doi.org/10.1210/endocr/bqaa031)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sassone-Corsi P 2012 The cyclic AMP pathway. Cold Spring Harbor Perspectives in Biology 4 a011148. (https://doi.org/10.1101/cshperspect.a011148)

  • Smith LB, O’Shaughnessy PJ & Rebourcet D 2015 Cell-specific ablation in the testis: what have we learned? Andrology 3 10351049. (https://doi.org/10.1111/andr.12107)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stanley E, Lin CY, Jin S, Liu J, Sottas CM, Ge R, Zirkin BR & Chen H 2012 Identification, proliferation, and differentiation of adult Leydig stem cells. Endocrinology 153 50025010. (https://doi.org/10.1210/en.2012-1417)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stojkov NJ, Janjic MM, Kostic TS & Andric SA 2013 Orally applied doxazosin disturbed testosterone homeostasis and changed the transcriptional profile of steroidogenic machinery, cAMP/cGMP signalling and adrenergic receptors in Leydig cells of adult rats. Andrology 1 332347. (https://doi.org/10.1111/j.2047-2927.2012.00035.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Takaya J 2021 Calcium-deficiency during pregnancy affects insulin resistance in offspring. International Journal of Molecular Sciences 22 7008. (https://doi.org/10.3390/ijms22137008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Teerds KJ, De Rooij DG, Rommerts FF & Wensing CJ 1988 The regulation of the proliferation and differentiation of rat Leydig cell precursor cells after EDS administration or daily HCG treatment. Journal of Andrology 9 343351. (https://doi.org/10.1002/j.1939-4640.1988.tb01061.x)

    • Search Google Scholar
    • Export Citation
  • Wang Y, Xie L, Tian E, Li X, Wen Z, Li L, Chen L, Zhong Y & Ge RS 2019 Oncostatin M inhibits differentiation of rat stem Leydig cells in vivo and in vitro. Journal of Cellular and Molecular Medicine 23 426438. (https://doi.org/10.1111/jcmm.13946)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu N, Katz DA & An G 2021 A target-mediated drug disposition model to explain nonlinear pharmacokinetics of the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor SPI-62 in healthy adults. Journal of Clinical Pharmacology 61 14421453. (https://doi.org/10.1002/jcph.1925)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ye L, Li X, Li L, Chen H & Ge RS 2017 Insights into the development of the adult Leydig cell lineage from stem Leydig cells. Frontiers in Physiology 8 430. (https://doi.org/10.3389/fphys.2017.00430)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang E, Xu F, Liang H, Yan J, Xu H, Li Z, Wen X & Weng J 2015a GLP-1 receptor agonist exenatide attenuates the detrimental effects of obesity on inflammatory profile in testis and sperm quality in mice. American Journal of Reproductive Immunology 74 457466. (https://doi.org/10.1111/aji.12420)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang YF, Yuan KM, Liang Y, Chu YH, Lian QQ, Ge YF, Zhen W, Sottas CM, Su ZJ & Ge RS 2015b Alterations of gene profiles in Leydig-cell-regenerating adult rat testis after ethane dimethane sulfonate-treatment. Asian Journal of Andrology 17 253260. (https://doi.org/10.4103/1008-682X.136447)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang M, Wang J, Deng C, Jiang MH, Feng X, Xia K, Li W, Lai X, Xiao H & Ge RS et al.2017 Transplanted human p75-positive stem Leydig cells replace disrupted Leydig cells for testosterone production. Cell Death and Disease 8 e3123. (https://doi.org/10.1038/cddis.2017.531)

    • PubMed
    • Search Google Scholar
    • Export Citation