{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T00:29:38Z","timestamp":1794097778023,"version":"4.8.0"},"reference-count":102,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of Chin","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Henan Provincial Natural Science Foundation"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Reprod Biol Endocrinol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>With the global population aging at an accelerated pace, testicular aging and its associated male health issues have garnered increasing attention. Testicular aging encompasses both age-related physiological decline and premature or pathological aging caused by various pathogenic factors. It is primarily characterized by reduced androgen secretion (mainly testosterone) and impaired spermatogenesis. Leydig cells, the key cells in the testes responsible for synthesizing and secreting testosterone, play a critical role in maintaining testicular function, and their dysfunction is one of the major contributors to testicular functional decline. In recent years, stem cell technology has demonstrated significant potential in restoring Leydig cell function. Stem cells possess the ability to differentiate into Leydig-like cells, which can restore testosterone secretion, improve the testicular microenvironment, and promote the regeneration of endogenous Leydig cells. Currently, various types of stem cells, such as stem leydig cells, mesenchymal stem cells, and induced pluripotent stem cells, have been successfully directed to differentiate into Leydig-like cells. This article provides an in-depth analysis of the mechanisms by which testicular aging affects Leydig cells, with a particular focus on the application of stem cell technology in restoring Leydig cell function. Additionally, it explores potential strategies to address these issues, aiming to offer novel perspectives and approaches for the prevention and treatment of testicular aging.<\/jats:p>","DOI":"10.1186\/s12958-025-01487-9","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T09:52:18Z","timestamp":1763545938000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The effects of testicular aging on Leydig cells and the application of stem cells in restoring Leydig cells function"],"prefix":"10.1186","volume":"23","author":[{"given":"Wen-bo","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-bin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang-zhao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zu-long","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-qi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"1487_CR1","first-page":"551","volume":"25","author":"H Qiyang","year":"2019","unstructured":"Qiyang H, Guanghui L, Zhijun B. Expert consensuses of China for aging and antiaging(2019 edition). GeriatrHealth Care. 2019;25:551\u20133.","journal-title":"GeriatrHealth Care"},{"key":"1487_CR2","first-page":"291","volume":"26","author":"CH Deng","year":"2020","unstructured":"Deng CH, Zhang C, Xie Y, Liu GH. Researches on testicular aging: status quo and prospects. Zhonghua Nan Ke Xue = Natl J Androl. 2020;26:291\u20136.","journal-title":"Zhonghua Nan Ke Xue = Natl J Androl"},{"key":"1487_CR3","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1012119","volume":"13","author":"S Dong","year":"2022","unstructured":"Dong S, Chen C, Zhang J, Gao Y, Zeng X, Zhang X. Testicular aging, male fertility and beyond. Front Endocrinol (Lausanne). 2022;13:1012119.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"1487_CR4","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1073\/pnas.1814377116","volume":"116","author":"NK Aryal","year":"2019","unstructured":"Aryal NK, Pant V, Wasylishen AR, Parker-Thornburg J, Baseler L, El-Naggar AK, et al. Constitutive dicer1 phosphorylation accelerates metabolism and aging in vivo. Proc Natl Acad Sci U S A. 2019;116:960\u20139.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"1487_CR5","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1080\/19396368.2017.1391888","volume":"63","author":"K Kotarska","year":"2017","unstructured":"Kotarska K, Doniec A, Bednarska M, Pola\u0144ski Z, Styrna J. Aging deteriorates quality of sperm produced by male mice with partial Yq deletion. Syst Biol Reprod Med. 2017;63(6):360\u20133.","journal-title":"Syst Biol Reprod Med"},{"key":"1487_CR6","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.115.131318","volume":"93","author":"J Selvaratnam","year":"2015","unstructured":"Selvaratnam J, Paul C, Robaire B. Male rat germ cells display age-dependent and cell-specific susceptibility in response to oxidative stress challenges. Biol Reprod. 2015;93:72.","journal-title":"Biol Reprod"},{"key":"1487_CR7","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1095\/biolreprod.111.094219","volume":"85","author":"C Paul","year":"2011","unstructured":"Paul C, Nagano M, Robaire B. Aging results in differential regulation of DNA repair pathways in pachytene spermatocytes in the brown Norway rat. Biol Reprod. 2011;85:1269\u201378.","journal-title":"Biol Reprod"},{"key":"1487_CR8","doi-asserted-by":"publisher","first-page":"12528","DOI":"10.1096\/fj.201901089R","volume":"33","author":"H Wu","year":"2019","unstructured":"Wu H, Jiang X, Gao Y, Liu W, Wang F, Gong M, et al. Mumps virus infection disrupts blood-testis barrier through the induction of TNF-\u03b1 in Sertoli cells. FASEB J. 2019;33:12528\u201340.","journal-title":"FASEB J"},{"key":"1487_CR9","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2023.165938","volume":"901","author":"D Sarkar","year":"2023","unstructured":"Sarkar D, Midha P, Shanti SS, Singh SK. A comprehensive review on the Decabromodiphenyl ether (BDE-209)-induced male reproductive toxicity: evidences from rodent studies. Sci Total Environ. 2023;901:165938.","journal-title":"Sci Total Environ"},{"key":"1487_CR10","first-page":"96","volume":"156","author":"R Barakat","year":"2017","unstructured":"Barakat R, Lin PP, Rattan S, Brehm E, Canisso IF, Abosalum ME, et al. Prenatal exposure to DEHP induces premature reproductive senescence in male mice. Toxicol Sci. 2017;156:96\u2013108.","journal-title":"Toxicol Sci"},{"key":"1487_CR11","doi-asserted-by":"publisher","first-page":"758","DOI":"10.2174\/1386207323999200918124639","volume":"24","author":"JS Ajarem","year":"2021","unstructured":"Ajarem JS, Hegazy AK, Allam GA, Allam AA, Maodaa SN, Mahmoud AM. Effect of visnagin on altered steroidogenesis and spermatogenesis, and testicular injury induced by the heavy metal lead. Comb Chem High Throughput Screen. 2021;24:758\u201366.","journal-title":"Comb Chem High Throughput Screen"},{"issue":"3","key":"1487_CR12","volume":"21","author":"H Sayg\u0131n","year":"2023","unstructured":"Sayg\u0131n H, Korgal\u0131 E, Ko\u00e7 T, Do\u011fan K. The effect of smoking and electronic cigarettes on rat testicles. Revista Int Androl. 2023;21(3):100365.","journal-title":"Revista Int Androl"},{"key":"1487_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2024.114463","volume":"185","author":"P Nie","year":"2024","unstructured":"Nie P, Wen S, Wang M, Xu H. Exploration of Lactiplantibacillus plantarum p101 ameliorated the alcohol-induced testicular dysfunction based on metabolome analysis. Food Chem Toxicol. 2024;185:114463.","journal-title":"Food Chem Toxicol"},{"key":"1487_CR14","doi-asserted-by":"publisher","DOI":"10.3390\/antiox14020150","author":"RJ Moreira","year":"2025","unstructured":"Moreira RJ, Oliveira PF, Spadella MA, Ferreira R, Alves MG. Do lifestyle interventions mitigate the oxidative damage and inflammation induced by obesity in the testis? Antioxidants. 2025. https:\/\/doi.org\/10.3390\/antiox14020150.","journal-title":"Antioxidants"},{"key":"1487_CR15","doi-asserted-by":"publisher","first-page":"e823","DOI":"10.1210\/clinem\/dgad097","volume":"108","author":"M Rosimont","year":"2023","unstructured":"Rosimont M, Kariyawasam D, Samara-Boustani D, Giani E, Beltrand J, Bolle S, et al. Assessment of puberty and hypothalamic-pituitary-gonadal axis function after childhood brain tumor treatment. J Clin Endocrinol Metab. 2023;108:e823\u201331.","journal-title":"J Clin Endocrinol Metab"},{"key":"1487_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.yfrne.2021.100953","volume":"64","author":"YL Son","year":"2022","unstructured":"Son YL, Ubuka T, Tsutsui K. Regulation of stress response on the hypothalamic-pituitary-gonadal axis via gonadotropin-inhibitory hormone. Front Neuroendocrinol. 2022;64:100953.","journal-title":"Front Neuroendocrinol"},{"key":"1487_CR17","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23073535","author":"B Barone","year":"2022","unstructured":"Barone B, Napolitano L, Abate M, Cirillo L, Reccia P, Passaro F, et al. The role of testosterone in the elderly: what do we know? Int J Mol Sci. 2022. https:\/\/doi.org\/10.3390\/ijms23073535.","journal-title":"Int J Mol Sci"},{"key":"1487_CR18","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1038\/nrendo.2013.135","volume":"9","author":"A Ferlin","year":"2013","unstructured":"Ferlin A, Selice R, Carraro U, Foresta C. Testicular function and bone metabolism\u2013beyond testosterone. Nat Rev Endocrinol. 2013;9:548\u201354.","journal-title":"Nat Rev Endocrinol"},{"key":"1487_CR19","doi-asserted-by":"publisher","DOI":"10.3390\/nu14163438","author":"K Romejko","year":"2022","unstructured":"Romejko K, Rymarz A, Sadownik H, Niemczyk S. Testosterone deficiency as one of the major endocrine disorders in chronic kidney disease. Nutrients. 2022. https:\/\/doi.org\/10.3390\/nu14163438.","journal-title":"Nutrients"},{"key":"1487_CR20","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyg.2017.01722","volume":"8","author":"A Walther","year":"2017","unstructured":"Walther A, Waldvogel P, Noser E, Ruppen J, Ehlert U. Emotions and steroid secretion in aging men: a multi-study report. Front Psychol. 2017;8:1722.","journal-title":"Front Psychol"},{"key":"1487_CR21","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1177\/1756287215612961","volume":"8","author":"JA Mcbride","year":"2016","unstructured":"Mcbride JA, Carson CCR, Coward RM. Testosterone deficiency in the aging male. Ther Adv Urol. 2016;8:47\u201360.","journal-title":"Ther Adv Urol"},{"key":"1487_CR22","doi-asserted-by":"publisher","first-page":"1506","DOI":"10.1111\/andr.12719","volume":"8","author":"E Nieschlag","year":"2020","unstructured":"Nieschlag E. Late-onset hypogonadism: a concept comes of age. Andrology. 2020;8:1506\u201311.","journal-title":"Andrology"},{"key":"1487_CR23","doi-asserted-by":"publisher","first-page":"M76","DOI":"10.1093\/gerona\/57.2.M76","volume":"57","author":"AM Matsumoto","year":"2002","unstructured":"Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol Biol Sci Med Sci. 2002;57:M76\u201399.","journal-title":"J Gerontol Biol Sci Med Sci"},{"key":"1487_CR24","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1016\/j.jacc.2015.12.005","volume":"67","author":"RA Kloner","year":"2016","unstructured":"Kloner RA, Carson CR, Dobs A, Kopecky S, Mohler ERR. Testosterone and cardiovascular disease. J Am Coll Cardiol. 2016;67:545\u201357.","journal-title":"J Am Coll Cardiol"},{"key":"1487_CR25","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1007\/s11154-022-09746-5","volume":"23","author":"G Wittert","year":"2022","unstructured":"Wittert G, Grossmann M. Obesity, type 2 diabetes, and testosterone in ageing men. Rev Endocr Metab Disord. 2022;23:1233\u201342.","journal-title":"Rev Endocr Metab Disord"},{"key":"1487_CR26","first-page":"1\u201357","volume":"2","author":"F Leydig","year":"1850","unstructured":"Leydig F. Zur Anatomie der m\u00e4nnlichen Geschlechtsorgane und Analdr\u00fcsen der S\u00e4ugethiere. Zeitschrift f Wiss Zool. 1850;2:1\u201357.","journal-title":"Zeitschrift f Wiss Zool"},{"key":"1487_CR27","first-page":"437","volume":"4","author":"P Bouin","year":"1903","unstructured":"Bouin P. Recherches Sur les cellules interstitielles du testicule des mammif\u00e8res. Arch De Zo\u00f6l Exp Et G\u00e9n. 1903;4:437.","journal-title":"Arch De Zo\u00f6l Exp Et G\u00e9n"},{"key":"1487_CR28","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1210\/endo-84-3-488","volume":"84","author":"PF Hall","year":"1969","unstructured":"Hall PF, Irby DC, De Kretser DM. Conversion of cholesterol to androgens by rat testes: comparison of interstitial cells and seminiferous tubules. Endocrinology. 1969;84:488\u201396.","journal-title":"Endocrinology"},{"key":"1487_CR29","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1093\/biolre\/ioy059","volume":"99","author":"BR Zirkin","year":"2018","unstructured":"Zirkin BR, Papadopoulos V. Leydig cells: formation, function, and regulation. Biol Reprod. 2018;99:101\u201311.","journal-title":"Biol Reprod"},{"key":"1487_CR30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000200077","volume":"3","author":"SL Griswold","year":"2009","unstructured":"Griswold SL, Behringer RR. Fetal Leydig cell origin and development. Sex Dev. 2009;3:1\u201315.","journal-title":"Sex Dev"},{"key":"1487_CR31","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1046\/j.1439-0272.2003.00540.x","volume":"35","author":"V Rouiller-Fabre","year":"2003","unstructured":"Rouiller-Fabre V, Levacher C, Pairault C, Racine C, Moreau E, Olaso R, et al. Development of the foetal and neonatal testis. Andrologia. 2003;35:79\u201383.","journal-title":"Andrologia"},{"key":"1487_CR32","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1242\/dev.103.3.535","volume":"103","author":"JB Kerr","year":"1988","unstructured":"Kerr JB, Knell CM. The fate of fetal Leydig cells during the development of the fetal and postnatal rat testis. Development. 1988;103:535\u201344.","journal-title":"Development"},{"key":"1487_CR33","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1095\/biolreprod65.3.660","volume":"65","author":"SM Mendis-Handagama","year":"2001","unstructured":"Mendis-Handagama SM, Ariyaratne HB. Differentiation of the adult Leydig cell population in the postnatal testis. Biol Reprod. 2001;65:660\u201371.","journal-title":"Biol Reprod"},{"key":"1487_CR34","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1002\/jcp.21231","volume":"213","author":"X Wu","year":"2007","unstructured":"Wu X, Wan S, Lee MM. Key factors in the regulation of fetal and postnatal Leydig cell development. J Cell Physiol. 2007;213:429\u201333.","journal-title":"J Cell Physiol"},{"key":"1487_CR35","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1095\/biolreprod.109.082099","volume":"82","author":"DK Griffin","year":"2010","unstructured":"Griffin DK, Ellis PJ, Dunmore B, Bauer J, Abel MH, Affara NA. Transcriptional profiling of luteinizing hormone receptor-deficient mice before and after testosterone treatment provides insight into the hormonal control of postnatal testicular development and Leydig cell differentiation. Biol Reprod. 2010;82:1139\u201350.","journal-title":"Biol Reprod"},{"key":"1487_CR36","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1196\/annals.1411.016","volume":"1120","author":"L Dong","year":"2007","unstructured":"Dong L, Jelinsky SA, Finger JN, Johnston DS, Kopf GS, Sottas CM, et al. Gene expression during development of fetal and adult Leydig cells. Ann N Y Acad Sci. 2007;1120:16\u201335.","journal-title":"Ann N Y Acad Sci"},{"key":"1487_CR37","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/S0074-7696(04)33005-6","volume":"233","author":"SG Haider","year":"2004","unstructured":"Haider SG. Cell biology of Leydig cells in the testis. Int Rev Cytol. 2004;233:181\u2013241.","journal-title":"Int Rev Cytol"},{"key":"1487_CR38","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.semcdb.2016.03.003","volume":"59","author":"Q Wen","year":"2016","unstructured":"Wen Q, Cheng CY, Liu Y. Development, function and fate of fetal Leydig cells. Semin Cell Dev Biol. 2016;59:89\u201398.","journal-title":"Semin Cell Dev Biol"},{"key":"1487_CR39","doi-asserted-by":"publisher","first-page":"2719","DOI":"10.1073\/pnas.0507692103","volume":"103","author":"R Ge","year":"2006","unstructured":"Ge R, Dong Q, Sottas CM, Papadopoulos V, Zirkin BR, Hardy MP. In search of rat stem Leydig cells: identification, isolation, and lineage-specific development. Proc Natl Acad Sci U S A. 2006;103:2719\u201324.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1487_CR40","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.mce.2009.01.023","volume":"306","author":"H Chen","year":"2009","unstructured":"Chen H, Ge R, Zirkin BR. Leydig cells: from stem cells to aging. Mol Cell Endocrinol. 2009;306:9\u201316.","journal-title":"Mol Cell Endocrinol"},{"key":"1487_CR41","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.852661","volume":"13","author":"G Grande","year":"2022","unstructured":"Grande G, Barrachina F, Soler-Ventura A, Jodar M, Mancini F, Marana R, et al. The role of testosterone in spermatogenesis: lessons from proteome profiling of human spermatozoa in testosterone deficiency. Front Endocrinol (Lausanne). 2022;13:852661.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"1487_CR42","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1002\/j.1939-4640.2001.tb02165.x","volume":"22","author":"L Luo","year":"2001","unstructured":"Luo L, Chen H, Zirkin BR. Leydig cell aging: steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme. J Androl. 2001;22:149\u201356.","journal-title":"J Androl"},{"key":"1487_CR43","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1530\/EJE-12-0890","volume":"168","author":"EM Camacho","year":"2013","unstructured":"Camacho EM, Huhtaniemi IT, O\u2019Neill TW, Finn JD, Pye SR, Lee DM, et al. Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European male ageing study. Eur J Endocrinol. 2013;168:445\u201355.","journal-title":"Eur J Endocrinol"},{"key":"1487_CR44","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1002\/j.1939-4640.1994.tb00498.x","volume":"15","author":"H Chen","year":"1994","unstructured":"Chen H, Hardy MP, Huhtaniemi I, Zirkin BR. Age-related decreased Leydig cell testosterone production in the brown Norway rat. J Androl. 1994;15:551\u20137.","journal-title":"J Androl"},{"key":"1487_CR45","doi-asserted-by":"publisher","first-page":"6859","DOI":"10.1111\/jcmm.14569","volume":"23","author":"X Su","year":"2019","unstructured":"Su X, Lin D, Luo D, Sun M, Wang X, Ye J, et al. Cyclophilin d participates in the inhibitory effect of high-fat diet on the expression of steroidogenic acute regulatory protein. J Cell Mol Med. 2019;23:6859\u201371.","journal-title":"J Cell Mol Med"},{"key":"1487_CR46","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1088249","volume":"14","author":"D Luo","year":"2023","unstructured":"Luo D, Qi X, Xu X, Yang L, Yu C, Guan Q. Involvement of p38 MAPK in Leydig cell aging and age-related decline in testosterone. Front Endocrinol (Lausanne). 2023;14:1088249.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"1487_CR47","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1007\/s00204-015-1472-2","volume":"89","author":"EK Kim","year":"2015","unstructured":"Kim EK, Choi E. Compromised MAPK signaling in human diseases: an update. Arch Toxicol. 2015;89:867\u201382.","journal-title":"Arch Toxicol"},{"key":"1487_CR48","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1152\/physrev.00028.2011","volume":"92","author":"JM Kyriakis","year":"2012","unstructured":"Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev. 2012;92:689\u2013737.","journal-title":"Physiol Rev"},{"key":"1487_CR49","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glaf004","author":"M Zhao","year":"2025","unstructured":"Zhao M, Wei J, Geng Y, Zhang Y, Zhao J, Yang H, et al. Age-associated increase in at1r expression in human testis and its intervention effects on Leydig cell senescence in aged rodents. J Gerontol Biol Sci Med Sci. 2025;80(6). https:\/\/doi.org\/10.1093\/gerona\/glaf004","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"1487_CR50","doi-asserted-by":"publisher","first-page":"5070","DOI":"10.1016\/S0021-9258(18)60680-5","volume":"263","author":"A Khanum","year":"1988","unstructured":"Khanum A, Dufau ML. Angiotensin II receptors and inhibitory actions in Leydig cells. J Biol Chem. 1988;263:5070\u20134.","journal-title":"J Biol Chem"},{"key":"1487_CR51","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1161\/HYPERTENSIONAHA.120.11941","volume":"77","author":"N Fatima","year":"2021","unstructured":"Fatima N, Patel SN, Hussain T. Angiotensin II type 2 receptor: a target for protection against hypertension, metabolic dysfunction, and organ remodeling. Hypertension. 2021;77:1845\u201356.","journal-title":"Hypertension"},{"key":"1487_CR52","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1093\/gerona\/glaa132","volume":"76","author":"SJ Sokanovic","year":"2021","unstructured":"Sokanovic SJ, Baburski AZ, Kojic Z, Medar MLJ, Andric SA, Kostic TS. Aging-related increase of cGMP disrupts mitochondrial homeostasis in Leydig cells. J Gerontol Biol Sci Med Sci. 2021;76:177\u201386.","journal-title":"J Gerontol Biol Sci Med Sci"},{"key":"1487_CR53","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1096\/fj.201800612R","volume":"33","author":"M Curley","year":"2019","unstructured":"Curley M, Milne L, Smith S, J\u00f8rgensen A, Frederiksen H, Hadoke P, et al. A young testicular microenvironment protects Leydig cells against age-related dysfunction in a mouse model of premature aging. Faseb J. 2019;33:978\u201395.","journal-title":"Faseb J"},{"key":"1487_CR54","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1038\/s43587-025-00824-2","volume":"5","author":"L Cui","year":"2025","unstructured":"Cui L, Nie X, Guo Y, Ren P, Guo Y, Wang X, et al. Single-cell transcriptomic atlas of the human testis across the reproductive lifespan. Nat Aging. 2025;5:658\u201374.","journal-title":"Nat Aging"},{"key":"1487_CR55","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1016\/j.devcel.2022.04.004","volume":"57","author":"X Nie","year":"2022","unstructured":"Nie X, Munyoki SK, Sukhwani M, Schmid N, Missel A, Emery BR, et al. Single-cell analysis of human testis aging and correlation with elevated body mass index. Dev Cell. 2022;57:1160\u201376.","journal-title":"Dev Cell"},{"key":"1487_CR56","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.1093\/humrep\/deae199","volume":"39","author":"K Xia","year":"2024","unstructured":"Xia K, Luo P, Yu J, He S, Dong L, Gao F, et al. Single-cell RNA sequencing reveals transcriptomic landscape and potential targets for human testicular ageing. Hum Reprod. 2024;39:2189\u2013209.","journal-title":"Hum Reprod"},{"key":"1487_CR57","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/s41585-021-00480-2","volume":"18","author":"L Li","year":"2021","unstructured":"Li L, Papadopoulos V. Advances in stem cell research for the treatment of primary hypogonadism. Nat Rev Urol. 2021;18:487\u2013507.","journal-title":"Nat Rev Urol"},{"key":"1487_CR58","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1461-0","volume":"10","author":"X Chen","year":"2019","unstructured":"Chen X, Li C, Chen Y, Xi H, Zhao S, Ma L, et al. Differentiation of human induced pluripotent stem cells into leydig-like cells with molecular compounds. Cell Death Dis. 2019;10:220.","journal-title":"Cell Death Dis"},{"key":"1487_CR59","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1007\/s12015-021-10133-x","volume":"17","author":"Z Liu","year":"2021","unstructured":"Liu Z, Liu Y, Huang S, Zang Z. Insights into the regulation on proliferation and differentiation of stem Leydig cells. Stem Cell Rev Rep. 2021;17:1521\u201333.","journal-title":"Stem Cell Rev Rep"},{"key":"1487_CR60","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.mce.2016.10.010","volume":"445","author":"H Chen","year":"2017","unstructured":"Chen H, Wang Y, Ge R, Zirkin BR. Leydig cell stem cells: identification, proliferation and differentiation. Mol Cell Endocrinol. 2017;445:65\u201373.","journal-title":"Mol Cell Endocrinol"},{"key":"1487_CR61","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1002\/stem.2569","volume":"35","author":"ZJ Zang","year":"2017","unstructured":"Zang ZJ, Wang J, Chen Z, Zhang Y, Gao Y, Su Z, et al. Transplantation of CD51(+) stem Leydig cells: a new strategy for the treatment of testosterone deficiency. Stem Cells. 2017;35:1222\u201332.","journal-title":"Stem Cells"},{"key":"1487_CR62","doi-asserted-by":"publisher","first-page":"306","DOI":"10.4252\/wjsc.v8.i10.306","volume":"8","author":"TC Peak","year":"2016","unstructured":"Peak TC, Haney NM, Wang W, Delay KJ, Hellstrom WJ. Stem cell therapy for the treatment of Leydig cell dysfunction in primary hypogonadism. World J Stem Cells. 2016;8:306\u201315.","journal-title":"World J Stem Cells"},{"key":"1487_CR63","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1097\/MED.0000000000000580","volume":"27","author":"JK Achua","year":"2020","unstructured":"Achua JK, Frech FS, Ramasamy R. Leydig stem cells and future therapies for hypogonadism. Curr Opin Endocrinol Diabetes Obes. 2020;27:419\u201323.","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"key":"1487_CR64","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46190-2","volume":"15","author":"A Chi","year":"2024","unstructured":"Chi A, Yang B, Dai H, Li X, Mo J, Gao Y, et al. Stem leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice. Nat Commun. 2024;15:2120.","journal-title":"Nat Commun"},{"key":"1487_CR65","doi-asserted-by":"publisher","first-page":"1466","DOI":"10.1038\/cr.2014.149","volume":"24","author":"MH Jiang","year":"2014","unstructured":"Jiang MH, Cai B, Tuo Y, Wang J, Zang ZJ, Tu X, et al. Characterization of nestin-positive stem Leydig cells as a potential source for the treatment of testicular Leydig cell dysfunction. Cell Res. 2014;24:1466\u201385.","journal-title":"Cell Res"},{"key":"1487_CR66","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.semcdb.2021.05.007","volume":"121","author":"X Li","year":"2022","unstructured":"Li X, Tian E, Wang Y, Wen Z, Lei Z, Zhong Y, et al. Stem Leydig cells: current research and future prospects of regenerative medicine of male reproductive health. Semin Cell Dev Biol. 2022;121:63\u201370.","journal-title":"Semin Cell Dev Biol"},{"key":"1487_CR67","doi-asserted-by":"publisher","first-page":"8705","DOI":"10.7150\/thno.46854","volume":"10","author":"K Xia","year":"2020","unstructured":"Xia K, Chen H, Wang J, Feng X, Gao Y, Wang Y, et al. Restorative functions of autologous stem Leydig cell transplantation in a testosterone-deficient non-human primate model. Theranostics. 2020;10:8705\u201320.","journal-title":"Theranostics"},{"key":"1487_CR68","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.531","volume":"8","author":"M Zhang","year":"2017","unstructured":"Zhang M, Wang J, Deng C, Jiang MH, Feng X, Xia K, et al. Transplanted human p75-positive stem Leydig cells replace disrupted Leydig cells for testosterone production. Cell Death Dis. 2017;8:e3123.","journal-title":"Cell Death Dis"},{"key":"1487_CR69","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.kjms.2015.10.008","volume":"32","author":"L Hou","year":"2016","unstructured":"Hou L, Dong Q, Wu Y, Sun Y, Guo Y, Huo Y. Gonadotropins facilitate potential differentiation of human bone marrow mesenchymal stem cells into Leydig cells in vitro. Kaohsiung J Med Sci. 2016;32:1\u20139.","journal-title":"Kaohsiung J Med Sci"},{"key":"1487_CR70","doi-asserted-by":"publisher","first-page":"4104","DOI":"10.1210\/en.2006-0162","volume":"147","author":"T Yazawa","year":"2006","unstructured":"Yazawa T, Mizutani T, Yamada K, Kawata H, Sekiguchi T, Yoshino M, et al. Differentiation of adult stem cells derived from bone marrow stroma into Leydig or adrenocortical cells. Endocrinology. 2006;147:4104\u201311.","journal-title":"Endocrinology"},{"key":"1487_CR71","doi-asserted-by":"publisher","first-page":"2153","DOI":"10.1007\/s12015-021-10196-w","volume":"17","author":"L Nguyen Thanh","year":"2021","unstructured":"Nguyen Thanh L, Dam PTM, Nguyen H, Nguyen TT, To HM, Nguyen HB, et al. Can autologous adipose-derived mesenchymal stem cell transplantation improve sexual function in people with sexual functional deficiency? Stem Cell Rev Rep. 2021;17:2153\u201363.","journal-title":"Stem Cell Rev Rep"},{"key":"1487_CR72","doi-asserted-by":"publisher","first-page":"23274","DOI":"10.1073\/pnas.1908207116","volume":"116","author":"L Li","year":"2019","unstructured":"Li L, Li Y, Sottas C, Culty M, Fan J, Hu Y, et al. Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells. Proc Natl Acad Sci USA. 2019;116:23274\u201383.","journal-title":"Proc Natl Acad Sci USA"},{"key":"1487_CR73","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abq3173","volume":"9","author":"C Jin","year":"2023","unstructured":"Jin C, Wang Z, Li P, Tang J, Jiao T, Li Y, et al. Decoding the spermatogonial stem cell niche under physiological and recovery conditions in adult mice and humans. Sci Adv. 2023;9:eabq3173.","journal-title":"Sci Adv"},{"key":"1487_CR74","doi-asserted-by":"publisher","first-page":"R159","DOI":"10.1530\/REP-14-0481","volume":"149","author":"S Chen","year":"2015","unstructured":"Chen S, Liu Y. Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling. Reproduction. 2015;149:R159-67.","journal-title":"Reproduction"},{"key":"1487_CR75","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1007\/s11255-013-0610-0","volume":"46","author":"H Jiang","year":"2014","unstructured":"Jiang H, Zhu W, Li J, Chen Q, Liang W, Gu Y. Quantitative histological analysis and ultrastructure of the aging human testis. Int Urol Nephrol. 2014;46:879\u201385.","journal-title":"Int Urol Nephrol"},{"key":"1487_CR76","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1210\/endrev\/bnz013","volume":"41","author":"P Chen","year":"2020","unstructured":"Chen P, Zirkin BR, Chen H. Stem leydig cells in the adult testis: characterization, regulation and potential applications. Endocr Rev. 2020;41:22\u201332.","journal-title":"Endocr Rev"},{"key":"1487_CR77","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25544-0","volume":"12","author":"M Alfano","year":"2021","unstructured":"Alfano M, Tascini AS, Pederzoli F, Locatelli I, Nebuloni M, Giannese F, et al. Aging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia. Nat Commun. 2021;12:5205.","journal-title":"Nat Commun"},{"key":"1487_CR78","first-page":"319","volume":"14","author":"M Jiahui","year":"2023","unstructured":"Jiahui M, Xinyu L, Zhihong C, Min Z, Chunhua D, Andrology DOUA, et al. Current status and reflections on stem cell transplantation in the treatment of testicular aging. Organ Transplantation. 2023;14:319\u201326.","journal-title":"Organ Transplantation"},{"key":"1487_CR79","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1007\/s13577-020-00324-y","volume":"33","author":"W Ji","year":"2020","unstructured":"Ji W, Chen Y, Wang L, Xu Z, Ahmed J, Ge R, et al. Differentiation of human umbilical cord mesenchymal stem cells into leydig-like cells with defined molecular compounds. Hum Cell. 2020;33:318\u201329.","journal-title":"Hum Cell"},{"key":"1487_CR80","doi-asserted-by":"publisher","first-page":"1917","DOI":"10.1126\/science.1151526","volume":"318","author":"J Yu","year":"2007","unstructured":"Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917\u201320.","journal-title":"Science"},{"key":"1487_CR81","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqab202","author":"T Ishida","year":"2021","unstructured":"Ishida T, Koyanagi-Aoi M, Yamamiya D, Onishi A, Sato K, Uehara K, et al. Differentiation of human induced pluripotent stem cells into testosterone-producing leydig-like cells. Endocrinology. 2021. https:\/\/doi.org\/10.1210\/endocr\/bqab202.","journal-title":"Endocrinology"},{"key":"1487_CR82","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1007\/s12015-018-9811-3","volume":"14","author":"R Ben Jehuda","year":"2018","unstructured":"Ben Jehuda R, Shemer Y, Binah O. Genome editing in induced pluripotent stem cells using CRISPR\/cas9. Stem Cell Rev Rep. 2018;14:323\u201336.","journal-title":"Stem Cell Rev Rep"},{"key":"1487_CR83","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.895528","volume":"13","author":"LD Pj","year":"2022","unstructured":"Pj LD, Cm T, Ra JFF. Roles of spermatogonial stem cells in spermatogenesis and fertility restoration. Front Endocrinol (Lausanne). 2022;13:895528.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"1487_CR84","doi-asserted-by":"publisher","first-page":"R151","DOI":"10.1530\/REP-16-0588","volume":"153","author":"SJ Potter","year":"2017","unstructured":"Potter SJ, Defalco T. Role of the testis interstitial compartment in spermatogonial stem cell function. Reproduction. 2017;153:R151\u201362.","journal-title":"Reproduction"},{"key":"1487_CR85","doi-asserted-by":"publisher","first-page":"544","DOI":"10.2174\/1574888X12666170623095457","volume":"12","author":"A Shams","year":"2017","unstructured":"Shams A, Eslahi N, Movahedin M, Izadyar F, Asgari H, Koruji M. Future of spermatogonial stem cell culture: application of nanofiber scaffolds. Curr Stem Cell Res Ther. 2017;12:544\u201353.","journal-title":"Curr Stem Cell Res Ther"},{"key":"1487_CR86","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.850219","volume":"13","author":"I Sanou","year":"2022","unstructured":"Sanou I, van Maaren J, Eliveld J, Lei Q, Mei\u00dfner A, de Melker AA, et al. Spermatogonial stem cell-based therapies: taking preclinical research to the next level. Front Endocrinol (Lausanne). 2022;13:850219.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"1487_CR87","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.2174\/1574888X18666221223104859","volume":"18","author":"B Pourjabbar","year":"2023","unstructured":"Pourjabbar B, Shams F, Moghadam M, Ahani-Nahayati M, Azari A, Sefat F, et al. Recent emerging trend in stem cell therapy risk factors. Curr Stem Cell Res Ther. 2023;18:1076\u201389.","journal-title":"Curr Stem Cell Res Ther"},{"key":"1487_CR88","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1056\/NEJMp1613723","volume":"376","author":"PW Marks","year":"2017","unstructured":"Marks PW, Witten CM, Califf RM. Clarifying stem-cell therapy\u2019s benefits and risks. N Engl J Med. 2017;376:1007\u20139.","journal-title":"N Engl J Med"},{"key":"1487_CR89","first-page":"261","volume":"10","author":"M L\u00fc","year":"2018","unstructured":"L\u00fc M, Huang X, Wu Y. Research progress on the effects of traditional Chinese medicine on stem cells. Res Integr Tradit Chin West Med. 2018;10:261\u20134.","journal-title":"Res Integr Tradit Chin West Med"},{"key":"1487_CR90","first-page":"324","volume":"19","author":"L Guangwang","year":"2013","unstructured":"Guangwang L, Juan G, Hanjun G, Weiling H, Chao M, Ming C, et al. Effect of invigorating kidney and nourishing essence Chinese medicine containing serum on wnt\/\u03b2-catenin osteogenic differentiation signal pathway in BMSCs in ovariectomized mice. Chin J Osteoporos. 2013;19:324\u20139.","journal-title":"Chin J Osteoporos"},{"key":"1487_CR91","first-page":"612","volume":"30","author":"G Tang","year":"2014","unstructured":"Tang G, Zhan X, Li M, Hu F, Pan X, Chen M, et al. Effect and mechanism of Angelica Decoction for replenishing blood on the proliferation of bone marrow mesenchymal stem cells. J Guangdong Pharm Univ. 2014;30:612\u20135.","journal-title":"J Guangdong Pharm Univ"},{"key":"1487_CR92","first-page":"343","volume":"38","author":"J Huang","year":"2011","unstructured":"Huang J, Zhang J, Xu Z. Effect of astragalus polysaccharide on the proliferation of bone marrow mesenchymal stem cells and the expression of stem cell factor invitro. Fudan Univ J Med Sci. 2011;38:343\u20138.","journal-title":"Fudan Univ J Med Sci"},{"key":"1487_CR93","first-page":"158","volume":"39","author":"C Jian-Ping","year":"2012","unstructured":"Jian-Ping C, Ai-Guo Z, Xiangling T, Xiaowei Q, Baoman X. Effects of five kinds of traditional Chinese medicine on proliferation activity in vitro of bone marrow mesenchymal stem cells in rats. Liaoning J Traditional Chin Med. 2012;39:158\u201361.","journal-title":"Liaoning J Traditional Chin Med"},{"key":"1487_CR94","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1002\/stem.2714","volume":"36","author":"ML Huang","year":"2018","unstructured":"Huang ML, Michalak AL, Fisher CJ, Christy M, Smith RAA, Godula K. Small molecule antagonist of cell surface glycosaminoglycans restricts mouse embryonic stem cells in a pluripotent state. Stem Cells. 2018;36:45\u201354.","journal-title":"Stem Cells"},{"key":"1487_CR95","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-021-02579-0","volume":"12","author":"H Liu","year":"2021","unstructured":"Liu H, Zhu X, Cao X, Chi A, Dai J, Wang Z, et al. IL-1\u03b2-primed mesenchymal stromal cells exert enhanced therapeutic effects to alleviate chronic prostatitis\/chronic pelvic pain syndrome through systemic immunity. Stem Cell Res Ther. 2021;12:514.","journal-title":"Stem Cell Res Ther"},{"key":"1487_CR96","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.112026","volume":"142","author":"K Moeinabadi-Bidgoli","year":"2021","unstructured":"Moeinabadi-Bidgoli K, Babajani A, Yazdanpanah G, Farhadihosseinabadi B, Jamshidi E, Bahrami S, et al. Translational insights into stem cell preconditioning: from molecular mechanisms to preclinical applications. Biomed Pharmacother. 2021;142:112026.","journal-title":"Biomed Pharmacother"},{"key":"1487_CR97","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.115.131193","volume":"93","author":"T Karpova","year":"2015","unstructured":"Karpova T, Ravichandiran K, Insisienmay L, Rice D, Agbor V, Heckert LL. Steroidogenic factor 1 differentially regulates fetal and adult Leydig cell development in male mice. Biol Reprod. 2015;93:83.","journal-title":"Biol Reprod"},{"key":"1487_CR98","doi-asserted-by":"publisher","first-page":"267","DOI":"10.2174\/1574888X16666211124095527","volume":"17","author":"WA Kues","year":"2022","unstructured":"Kues WA, Kumar D, Selokar NL, Talluri TR. Applications of genome editing tools in stem cells towards regenerative medicine: an update. Curr Stem Cell Res Ther. 2022;17:267\u201379.","journal-title":"Curr Stem Cell Res Ther"},{"key":"1487_CR99","doi-asserted-by":"publisher","first-page":"1758550894","DOI":"10.1177\/20417314211060590","volume":"12","author":"H Eyni","year":"2021","unstructured":"Eyni H, Ghorbani S, Nazari H, Hajialyani M, Razavi Bazaz S, Mohaqiq M, et al. Advanced bioengineering of male germ stem cells to preserve fertility. J Tissue Eng. 2021;12:1758550894.","journal-title":"J Tissue Eng"},{"key":"1487_CR100","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22020684","author":"P Khayambashi","year":"2021","unstructured":"Khayambashi P, Iyer J, Pillai S, Upadhyay A, Zhang Y, Tran SD. Hydrogel encapsulation of mesenchymal stem cells and their derived exosomes for tissue engineering. Int J Mol Sci. 2021. https:\/\/doi.org\/10.3390\/ijms22020684.","journal-title":"Int J Mol Sci"},{"key":"1487_CR101","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.mod.2017.11.001","volume":"149","author":"RP Piprek","year":"2018","unstructured":"Piprek RP, Kolasa M, Podkowa D, Kloc M, Kubiak JZ. Transcriptional profiling validates involvement of extracellular matrix and proteinases genes in mouse gonad development. Mech Dev. 2018;149:9\u201319.","journal-title":"Mech Dev"},{"key":"1487_CR102","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1007\/s13770-021-00359-8","volume":"18","author":"E Shin","year":"2021","unstructured":"Shin E, Park S, Choi WY, Lee DR. Rapid differentiation of human embryonic stem cells into testosterone-producing Leydig cell-like cells in vitro. Tissue Eng Regen Med. 2021;18:651\u201362.","journal-title":"Tissue Eng Regen Med"}],"container-title":["Reproductive Biology and Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12958-025-01487-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12958-025-01487-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12958-025-01487-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T13:12:30Z","timestamp":1781615550000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12958-025-01487-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":102,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1487"],"URL":"https:\/\/doi.org\/10.1186\/s12958-025-01487-9","relation":{},"ISSN":["1477-7827"],"issn-type":[{"value":"1477-7827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,19]]},"assertion":[{"value":"22 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Consent for publication was taken from all individuals.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"147"}}