干细胞移植治疗睾丸衰老的现状与思考

莫嘉辉; 李欣禹; 陈志宏; 张敏; 邓春华

doi:10.3969/j.issn.1674-7445.2023.03.001

干细胞移植治疗睾丸衰老的现状与思考

doi: 10.3969/j.issn.1674-7445.2023.03.001

510080 广州，中山大学附属第一医院泌尿外科与男科(莫嘉辉、李欣禹、陈志宏、邓春华)，转化医学研究中心(张敏)

基金项目:

国家自然科学基金面上项目 81971314

国家自然科学基金面上项目 82171564

广东省自然科学基金面上项目 2023A1515010286

详细信息

作者简介:

通讯作者:
邓春华(ORCID：0009-0002-3512-4057)，Email：dengchh@mail.sysu.edu.cn

中图分类号: R329.2, R691.5
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出版历程
- 收稿日期: 2023-02-20
- 刊出日期: 2023-05-15

Current status and reflections on stem cell transplantation in the treatment of testicular aging

Department of Urology and Andrology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China

More Information

Corresponding author: Deng Chunhua, Email: dengchh@mail.sysu.edu.cn

摘要

摘要: 睾丸衰老的主要特点为睾酮合成能力以及生精功能逐渐下降，不仅会影响男性生育力，也与衰老相关慢性疾病关系密切。因此，延缓睾丸衰老对于改善中老年男性健康和生活质量至关重要。干细胞是具有强大的自我更新能力和多向分化潜能的细胞群体，近年来，其基础与临床应用研究不断深化，推动了细胞疗法的发展。干细胞移植目前已被用于治疗多种疾病，在衰老与再生医学领域也受到广泛关注。干细胞移植在治疗睾丸衰老中也具有巨大的应用前景。本文将回顾干细胞移植治疗睾丸衰老的相关研究历程与进展，并探讨临床转化面临的瓶颈以及疗效优化策略，以期为睾丸衰老的干细胞疗法研发及临床转化提供新思路。
- 干细胞移植 /
- 睾丸衰老 /
- 睾丸间质干细胞 /
- 精原干细胞 /
- 间充质干细胞 /
- 诱导多能干细胞 /
- 睾酮
Abstract: Testicular aging is mainly characterized by a gradual decline in the capability of testosterone synthesis and spermatogenesis, which not only affects male fertility, but also correlates with aging-related chronic diseases intimately. Therefore, delaying testicular aging plays a significant role in improving the health and quality of life of middle-aged and elderly men. Stem cells are a cell group with potent self-renewal capability and multi-directional differentiation potential. In recent years, the research of stem cells in basic and clinical application has been carried out in-depth, which has accelerated the development of cell therapy. Currently, stem cell transplantation has been employed to treat multiple diseases, which has captivated widespread attention in the field of aging and regenerative medicine. Stem cell transplantation has demonstrated promising prospects in the treatment of testicular aging. In this article, research profile and progress of stem cell transplantation in the treatment of testicular aging were reviewed, and bottleneck issues encountered in clinical translation and strategies for optimizing clinical efficacy were discussed, aiming to provide novel ideas for the research and development and clinical translation of stem cell therapy for testicular aging.
- Stem cell transplantation /
- Testicular aging /
- Stem Leydig cell /
- Spermatogonial stem cell /
- Mesenchymal stem cell /
- Induced pluripotent stem cell /
- Testosterone

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图 1 干细胞移植研究历程的重要进展

Figure 1. The major scientific advances during the history of stem cell transplantation research

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表 1 睾丸衰老的内分泌及抗氧化治疗策略

Table 1. Strategies of endocrinotherapy and antioxidant treatment for testicular aging

治疗策略	治疗方法	研究对象
内分泌调节	补充雄激素(睾酮)	人
内分泌调节	补充睾酮+5α还原酶抑制剂	人
内分泌调节	补充促性腺激素及其类似物	人
内分泌调节	补充睾酮前体物质(脱氢表雄酮等)	人
内分泌调节	补充非芳香化雄激素	人
内分泌调节	使用雌激素拮抗剂	人
内分泌调节	补充选择性雄激素受体调节剂	人
抗氧化疗法	补充黄芪端粒酶激活剂-65	大鼠
抗氧化疗法	补充维生素D₃	大鼠
抗氧化疗法	中医药治疗(八子补肾方)	小鼠
抗氧化疗法	补充外源性脂联素	小鼠

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参考文献(57)

[1]	ZHANG J, WEI L, DENG X, et al. Current status and reflections on fertility preservation in China[J]. J Assist Reprod Genet, 2022, 39(12): 2835-2845. DOI: 10.1007/s10815-022-02648-0.
[2]	MATZKIN ME, CALANDRA RS, ROSSI SP, et al. Hallmarks of testicular aging: the challenge of anti-inflammatory and antioxidant therapies using natural and/or pharmacological compounds to improve the physiopathological status of the aged male gonad[J]. Cells, 2021, 10(11): 3114. DOI: 10.3390/cells10113114.
[3]	FRUNGIERI MB, CALANDRA RS, BARTKE A, et al. Male and female gonadal ageing: its impact on health span and life span[J]. Mech Ageing Dev, 2021, 197: 111519. DOI: 10.1016/j.mad.2021.111519.
[4]	李湘平, 邓春华. 男性生殖衰老特征的多角度认识[J]. 中山大学学报(医学科学版), 2022, 43(06): 871-877. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2022.0601. LI XP, DENG CH. Male Reproductive aging characteristics: a multi-perspective understanding[J]. J Sun Yat-sen Univ (Med Sci), 2022, 43(06): 871-877. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2022.0601.
[5]	KUES WA, KUMAR D, SELOKAR NL, et al. Applications of genome editing tools in stem cells towards regenerative medicine: an update[J]. Curr Stem Cell Res Ther, 2022, 17(3): 267-279. DOI: 10.2174/1574888X16666211124095527.
[6]	DE LUCA M, AIUTI A, COSSU G, et al. Advances in stem cell research and therapeutic development[J]. Nat Cell Biol, 2019, 21(7): 801-811. DOI: 10.1038/s41556-019-0344-z.
[7]	SAMADI P, SAKI S, MANOOCHEHRI H, et al. Therapeutic applications of mesenchymal stem cells: a comprehensive review[J]. Curr Stem Cell Res Ther, 2021, 16(3): 323-353. DOI: 10.2174/1574888X15666200914142709.
[8]	WENG Z, WANG Y, OUCHI T, et al. Mesenchymal stem/stromal cell senescence: hallmarks, mechanisms, and combating strategies[J]. Stem Cells Transl Med, 2022, 11(4): 356-371. DOI: 10.1093/stcltm/szac004.
[9]	GUL M, HILDORF S, DONG L, et al. Review of injection techniques for spermatogonial stem cell transplantation[J]. Hum Reprod Update, 2020, 26(3): 368-391. DOI: 10.1093/humupd/dmaa003.
[10]	EYNI H, GHORBANI S, NAZARI H, et al. Advanced bioengineering of male germ stem cells to preserve fertility[J]. J Tissue Eng, 2021, 12: 20417314211060590. DOI: 10.1177/20417314211060590.
[11]	IOACHIMESCU AG. Updates in male hypogonadism[J]. Endocrinol Metab Clin North Am, 2022, 51(1): xiii-xiv. DOI: 10.1016/j.ecl.2021.12.001.
[12]	SALVIO G, CIARLONI A, CUTINI M, et al. Metabolic syndrome and male fertility: beyond heart consequences of a complex cardiometabolic endocrinopathy[J]. Int J Mol Sci, 2022, 23(10): 5497. DOI: 10.3390/ijms23105497.
[13]	LEE TH, KIM DS, KIM DK, et al. Effect of male age on reproductive function: a comparison of young and middle-aged men[J]. Investig Clin Urol, 2023, 64(1): 51-55. DOI: 10.4111/icu.20220302.
[14]	JANECZKO D, HOŁOWCZUK M, ORZEŁ A, et al. Paternal age is affected by genetic abnormalities, perinatal complications and mental health of the offspring[J]. Biomed Rep, 2020, 12(3): 83-88. DOI: 10.3892/br.2019.1266.
[15]	TSAMETIS CP, ISIDORI AM. Testosterone replacement therapy: for whom, when and how?[J]. Metabolism, 2018, 86: 69-78. DOI: 10.1016/j.metabol.2018.03.007.
[16]	TWITCHELL DK, PASTUSZAK AW, KHERA M. Controversies in testosterone therapy[J]. Sex Med Rev, 2021, 9(1): 149-159. DOI: 10.1016/j.sxmr.2020.09.004.
[17]	CHONG YH, PANKHURST MW, MCLENNAN IS. The testicular hormones AMH, InhB, INSL3, and testosterone can be independently deficient in older men[J]. J Gerontol A Biol Sci Med Sci, 2017, 72(4): 548-553. DOI: 10.1093/gerona/glw143.
[18]	RODRIGUES DOS SANTOS M, BHASIN S. Benefits and risks of testosterone treatment in men with age-related decline in testosterone[J]. Annu Rev Med, 2021, 72: 75-91. DOI: 10.1146/annurev-med-050219-034711.
[19]	LEVIT GS, HOSSFELD U. Ernst Haeckel in the history of biology[J]. Curr Biol, 2019, 29(24): R1276-R1284. DOI: 10.1016/j.cub.2019.10.064.
[20]	LIU G, DAVID BT, TRAWCZYNSKI M, et al. Advances in pluripotent stem cells: history, mechanisms, technologies, and applications[J]. Stem Cell Rev Rep, 2020, 16(1): 3-32. DOI: 10.1007/s12015-019-09935-x.
[21]	DING L, YAN G, WANG B, et al. Transplantation of UC-MSCs on collagen scaffold activates follicles in dormant ovaries of POF patients with long history of infertility[J]. Sci China Life Sci, 2018, 61(12): 1554-1565. DOI: 10.1007/s11427-017-9272-2.
[22]	DIAO L, TUREK PJ, JOHN CM, et al. Roles of spermatogonial stem cells in spermatogenesis and fertility restoration[J]. Front Endocrinol (Lausanne), 2022, 13: 895528. DOI: 10.3389/fendo.2022.895528.
[23]	BRINSTER RL, AVARBOCK MR. Germline transmission of donor haplotype following spermatogonial transplantation[J]. Proc Natl Acad Sci U S A, 1994, 91(24): 11303-11307. DOI: 10.1073/pnas.91.24.11303.
[24]	HERMANN BP, SUKHWANI M, WINKLER F, et al. Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm[J]. Cell Stem Cell, 2012, 11(5): 715-726. DOI: 10.1016/j.stem.2012.07.017.
[25]	SANOU I, VAN MAAREN J, ELIVELD J, et al. Spermatogonial stem cell-based therapies: taking preclinical research to the next level[J]. Front Endocrinol (Lausanne), 2022, 13: 850219. DOI: 10.3389/fendo.2022.850219.
[26]	CHEN P, ZIRKIN BR, CHEN H. Stem Leydig cells in the adult testis: characterization, regulation and potential applications[J]. Endocr Rev, 2020, 41(1): 22-32. DOI: 10.1210/endrev/bnz013.
[27]	SANTIAGO J, SILVA JV, ALVES MG, et al. Testicular aging: an overview of ultrastructural, cellular, and molecular alterations[J]. J Gerontol A Biol Sci Med Sci, 2019, 74(6): 860-871. DOI: 10.1093/gerona/gly082.
[28]	GE RS, DONG Q, SOTTAS CM, et al. In search of rat stem Leydig cells: identification, isolation, and lineage-specific development[J]. Proc Natl Acad Sci U S A, 2006, 103(8): 2719-2724. DOI: 10.1073/pnas.0507692103.
[29]	KUANG S, HE F, LIU G, et al. CCR2-engineered mesenchymal stromal cells accelerate diabetic wound healing by restoring immunological homeostasis[J]. Biomaterials, 2021, 275: 120963. DOI: 10.1016/j.biomaterials.2021.120963.
[30]	AITKEN RJ, BAKER MA. Causes and consequences of apoptosis in spermatozoa; contributions to infertility and impacts on development[J]. Int J Dev Biol, 2013, 57(2/3/4): 265-272. DOI: 10.1387/ijdb.130146ja.
[31]	HSIAO CH, JI AT, CHANG CC, et al. Local injection of mesenchymal stem cells protects testicular torsion-induced germ cell injury[J]. Stem Cell Res Ther, 2015, 6(1): 113. DOI: 10.1186/s13287-015-0079-0.
[32]	SHERIF IO, SABRY D, ABDEL-AZIZ A, et al. The role of mesenchymal stem cells in chemotherapy-induced gonadotoxicity[J]. Stem Cell Res Ther, 2018, 9(1): 196. DOI: 10.1186/s13287-018-0946-6.
[33]	GE RS, LI X, WANG Y. Leydig cell and spermatogenesis[J]. Adv Exp Med Biol, 2021, 1288: 111-129. DOI: 10.1007/978-3-030-77779-1_6.
[34]	LI L, PAPADOPOULOS V. Advances in stem cell research for the treatment of primary hypogonadism[J]. Nat Rev Urol, 2021, 18(8): 487-507. DOI: 10.1038/s41585-021-00480-2.
[35]	LO KC, LEI Z, RAO CHV, et al. De novo testosterone production in luteinizing hormone receptor knockout mice after transplantation of Leydig stem cells[J]. Endocrinology, 2004, 145(9): 4011-4015. DOI: 10.1210/en.2003-1729.
[36]	ZANG ZJ, WANG J, CHEN Z, et al Transplantation of CD51⁺ stem Leydig cells: a new strategy for the treatment of testosterone deficiency[J]. Stem Cells, 2017, 35(5): 1222-1232. DOI: 10.1002/stem.2569.
[37]	JIANG MH, CAI B, TUO Y, et al. Characterization of nestin-positive stem Leydig cells as a potential source for the treatment of testicular Leydig cell dysfunction[J]. Cell Res, 2014, 24(12): 1466-1485. DOI: 10.1038/cr.2014.149.
[38]	ZHANG M, WANG J, DENG C, et al. Transplanted human p75-positive stem Leydig cells replace disrupted Leydig cells for testosterone production[J]. Cell Death Dis, 2017, 8(10): e3123. DOI: 10.1038/cddis.2017.531.
[39]	XIA K, MA Y, FENG X, et al. Endosialin defines human stem Leydig cells with regenerative potential[J]. Hum Reprod, 2020, 35(10): 2197-2212. DOI: 10.1093/humrep/deaa174.
[40]	XIA K, CHEN H, WANG J, et al. Restorative functions of autologous stem Leydig cell transplantation in a testosterone-deficient non-human primate model[J]. Theranostics, 2020, 10(19): 8705-8720. DOI: 10.7150/thno.46854.
[41]	ALFANO M, TASCINI AS, PEDERZOLI F, et al. Aging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia[J]. Nat Commun, 2021, 12(1): 5205. DOI: 10.1038/s41467-021-25544-0.
[42]	YAZAWA T, MIZUTANI T, YAMADA K, et al. Differentiation of adult stem cells derived from bone marrow stroma into Leydig or adrenocortical cells[J]. Endocrinology, 2006, 147(9): 4104-4111. DOI: 10.1210/en.2006-0162.
[43]	HOU L, DONG Q, WU YJ, et al. Gonadotropins facilitate potential differentiation of human bone marrow mesenchymal stem cells into Leydig cells in vitro[J]. Kaohsiung J Med Sci, 2016, 32(1): 1-9. DOI: 10.1016/j.kjms.2015.10.008.
[44]	NGUYEN THANH L, DAM PTM, NGUYEN HP, et al. Can autologous adipose-derived mesenchymal stem cell transplantation improve sexual function in people with sexual functional deficiency?[J]. Stem Cell Rev Rep, 2021, 17(6): 2153-2163. DOI: 10.1007/s12015-021-10196-w.
[45]	LI L, LI Y, SOTTAS C, et al. Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells[J]. Proc Natl Acad Sci U S A, 2019, 116(46): 23274-23283. DOI: 10.1073/pnas.1908207116.
[46]	CHEN X, LI C, CHEN Y, et al. Differentiation of human induced pluripotent stem cells into Leydig-like cells with molecular compounds[J]. Cell Death Dis, 2019, 10(3): 220. DOI: 10.1038/s41419-019-1461-0.
[47]	ZHAO X, WAN W, ZHANG X, et al. Spermatogonial stem cell transplantation in large animals[J]. Animals (Basel), 2021, 11(4): 918. DOI: 10.3390/ani11040918.
[48]	KADAM P, NTEMOU E, BAERT Y, et al. Co-transplantation of mesenchymal stem cells improves spermatogonial stem cell transplantation efficiency in mice[J]. Stem Cell Res Ther, 2018, 9(1): 317. DOI: 10.1186/s13287-018-1065-0.
[49]	LI X, TIAN E, WANG Y, et al. Stem Leydig cells: current research and future prospects of regenerative medicine of male reproductive health[J]. Semin Cell Dev Biol, 2022, 121: 63-70. DOI: 10.1016/j.semcdb.2021.05.007.
[50]	MOEINABADI-BIDGOLI K, BABAJANI A, YAZDANPANAH G, et al. Translational insights into stem cell preconditioning: from molecular mechanisms to preclinical applications[J]. Biomed Pharmacother, 2021, 142: 112026. DOI: 10.1016/j.biopha.2021.112026.
[51]	HUANG ML, MICHALAK AL, FISHER CJ, et al. Small molecule antagonist of cell surface glycosaminoglycans restricts mouse embryonic stem cells in a pluripotent state[J]. Stem Cells, 2018, 36(1): 45-54. DOI: 10.1002/stem.2714.
[52]	LIU H, ZHU X, CAO X, et al. IL-1β-primed mesenchymal stromal cells exert enhanced therapeutic effects to alleviate chronic prostatitis/chronic pelvic pain syndrome through systemic immunity[J]. Stem Cell Res Ther, 2021, 12(1): 514. DOI: 10.1186/s13287-021-02579-0.
[53]	KARPOVA T, RAVICHANDIRAN K, INSISIENMAY L, et al. Steroidogenic factor 1 differentially regulates fetal and adult Leydig cell development in male mice[J]. Biol Reprod, 2015, 93(4): 83. DOI: 10.1095/biolreprod.115.131193.
[54]	SHEN YC, SHAMI AN, MORITZ L, et al. TCF21+ mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration in mice[J]. Nat Commun, 2021, 12(1): 3876. DOI: 10.1038/s41467-021-24130-8.
[55]	PIPREK RP, KOLASA M, PODKOWA D, et al. Transcriptional profiling validates involvement of extracellular matrix and proteinases genes in mouse gonad development[J]. Mech Dev, 2018, 149: 9-19. DOI: 10.1016/j.mod.2017.11.001.
[56]	KHAYAMBASHI P, IYER J, PILLAI S, et al. Hydrogel encapsulation of mesenchymal stem cells and their derived exosomes for tissue engineering[J]. Int J Mol Sci, 2021, 22(2): 684. DOI: 10.3390/ijms22020684.
[57]	BAERT Y, DE KOCK J, ALVES-LOPES JP, et al. Primary human testicular cells self-organize into organoids with testicular properties[J]. Stem Cell Reports, 2017, 8(1): 30-38. DOI: 10.1016/j.stemcr.2016.11.012.