Mezenkimal Kök Hücrelerin Erkek İnfertilitesindeki Rolü

Yazarlar

Büşra Çetinkaya Ün

Özet

İnfertilite, Dünya çapında çiftlerin yaklaşık %15'ini etkileyen önemli bir halk sağlığı sorunudur ve bu vakaların %50-60'ına erkek faktörü eşlik etmektedir. Sigara, alkol, genetik faktörler, Y kromozomu mikrodelesyonları, yüksek reaktif oksijen türleri (ROS) kaynaklı oksidatif stres, kanser tedavileri ve testis torsiyonu erkek infertilitesinin temel nedenleri arasında yer almaktadır. Günümüzde yaygın olarak kullanılan yardımcı üreme teknikleri (YÜT), fonksiyonel gametleri bulunmayan veya çocukluk çağında gonadotoksik tedavilere maruz kalmış hastalar için yetersiz kalabilmektedir. Bu noktada, rejeneratif tıp ve kök hücre teknolojileri kısırlık tedavisinde yeni bir umut kapısı aralamaktadır. Sahip oldukları yüksek çoğalma, kendi kendini yenileme ve parakrin faktörler salgılama yetenekleri sayesinde mezenkimal kök hücreler (MKH), hasarlı testis dokularının iyileştirilmesinde kritik bir rol oynamaktadır. Kemik iliği, göbek kordonu ve yağ dokusu gibi çeşitli kaynaklardan izole edilen MKH'lerin, retinoik asit ve belirli büyüme faktörleri eşliğinde in vitro ortamda germ hücrelerine farklılaşabildiği gösterilmiştir. Deneysel çalışmalar, transplante edilen MKH'lerin veya bunların koşullu ortamlarının (sekretom), oksidatif stresi ve apoptozu azaltarak, sperm motilitesini artırarak ve testis nişini destekleyerek spermatogenezi geri döndürebildiğini ortaya koymaktadır. Sonuç olarak MKH'ler, erkek infertilitesinin hücresel düzeyde tedavisinde güçlü ve yenilikçi bir terapötik alternatif sunmaktadır.

Infertility is a major global public health issue affecting approximately 15% of couples worldwide, with a male factor contributing to 50-60% of cases. The primary causes of male infertility include smoking, alcohol consumption, genetic factors, Y chromosome microdeletions, oxidative stress induced by high reactive oxygen species (ROS), cancer therapies, and testicular torsion. Although assisted reproductive technologies (ART) are widely utilized today, they remain insufficient for patients lacking functional gametes or those who underwent gonadotoxic treatments during childhood. In this regard, regenerative medicine and stem cell technologies offer a new beacon of hope for infertility treatment. Due to their high proliferation, self-renewal capacities, and secretome profile, mesenchymal stem cells (MSCs) play a critical role in healing damaged testicular tissues. Isolated from various sources such as bone marrow, umbilical cord, and adipose tissue, MSCs have been shown to differentiate into germ-like cells in vitro when treated with retinoic acid and specific growth factors. Experimental studies demonstrate that transplanted MSCs or their conditioned media can restore spermatogenesis by reducing oxidative stress and apoptosis, improving sperm motility, and enhancing the testicular niche. Consequently, MSCs provide a powerful and innovative therapeutic alternative for the cellular-level treatment of male infertility.

Referanslar

Inhorn, M.C. and P. Patrizio, Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century. Human Reproduction Update, 2015. 21(4): p. 411-426.

Chehab, M., A. Madala, and J.C. Trussell, On-label and off-label drugs used in the treatment of male infertility. Fertility and Sterility, 2015. 103(3): p. 595-604.

Ring, J.D., A.A. Lwin, and T.S. Kohler, Current medical management of endocrine-related male infertility. Asian J Androl, 2016.

Cocuzza, M. and A. Agarwal, Nonsurgical treatment of male infertility: specific and empiric therapy. Biologics, 2007. 1(3): p. 259-69.

Miyamoto, T., et al., Male infertility and its causes in human. Adv Urol, 2012. 2012: p. 384520.

Organization, W.H., WHO laboratory manual for the examination and processing of human semen. 2010.

Cocuzza, M., C. Alvarenga, and R. Pagani, The epidemiology and etiology of azoospermia. Clinics (Sao Paulo), 2013. 68 Suppl 1: p. 15-26.

Sansone, A., et al., Smoke, alcohol and drug addiction and male fertility. Reprod Biol Endocrinol, 2018. 16(1): p. 3.

Hirsh, A., Male subfertility. BMJ, 2003. 327(7416): p. 669-72.

Agarwal, A., et al., Effect of oxidative stress on male reproduction. World J Mens Health, 2014. 32(1): p. 1-17.

Khourdaji, I., H. Lee, and R.P. Smith, Frontiers in hormone therapy for male infertility. Translational Andrology and Urology, 2018. 7: p. S353-S366.

Host, E., S. Lindenberg, and S. Smidt-Jensen, The role of DNA strand breaks in human spermatozoa used for IVF and ICSI. Acta Obstet Gynecol Scand, 2000. 79(7): p. 559-63.

Fang, F., et al., Human induced pluripotent stem cells and male infertility: an overview of current progress and perspectives. Hum Reprod, 2018. 33(2): p. 188-195.

Volarevic, V., et al., Stem cells as new agents for the treatment of infertility: current and future perspectives and challenges. Biomed Res Int, 2014. 2014: p. 507234.

Lindroos, B., R. Suuronen, and S. Miettinen, The potential of adipose stem cells in regenerative medicine. Stem Cell Rev Rep, 2011. 7(2): p. 269-91.

Castillo, M., et al., The immune properties of mesenchymal stem cells. Int J Biomed Sci, 2007. 3(2): p. 76-80.

Harlev, A., et al., Smoking and Male Infertility: An Evidence-Based Review. World J Mens Health, 2015. 33(3): p. 143-60.

Dai, J.B., Z.X. Wang, and Z.D. Qiao, The hazardous effects of tobacco smoking on male fertility. Asian J Androl, 2015. 17(6): p. 954-60.

Ramlau-Hansen, C.H., et al., Is smoking a risk factor for decreased semen quality? A cross-sectional analysis. Hum Reprod, 2007. 22(1): p. 188-96.

Zavos, P.M., et al., An electron microscope study of the axonemal ultrastructure in human spermatozoa from male smokers and nonsmokers. Fertil Steril, 1998. 69(3): p. 430-4.

Zalata, A.A., et al., Relationship between acrosin activity of human spermatozoa and oxidative stress. Asian J Androl, 2004. 6(4): p. 313-8.

Shenker, N.S., et al., DNA methylation as a long-term biomarker of exposure to tobacco smoke. Epidemiology, 2013. 24(5): p. 712-6.

Ghaffari, M.A. and M. Rostami, The effect of cigarette smoking on human sperm creatine kinase activity: as an ATP buffering system in sperm. Int J Fertil Steril, 2013. 6(4): p. 258-65.

Sobinoff, A.P., et al., Damaging legacy: maternal cigarette smoking has long-term consequences for male offspring fertility. Hum Reprod, 2014. 29(12): p. 2719-35.

Jana, K., et al., Ethanol induces mouse spermatogenic cell apoptosis in vivo through over-expression of Fas/Fas-L, p53, and caspase-3 along with cytochrome c translocation and glutathione depletion. Mol Reprod Dev, 2010. 77(9): p. 820-33.

Ramlau-Hansen, C.H., et al., Maternal alcohol consumption during pregnancy and semen quality in the male offspring: two decades of follow-up. Hum Reprod, 2010. 25(9): p. 2340-5.

Ferlin, A., et al., Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-year experience in Italy. J Clin Endocrinol Metab, 2007. 92(3): p. 762-70.

Vogt, P.H., et al., Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet, 1996. 5(7): p. 933-43.

Reijo, R., et al., Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet, 1995. 10(4): p. 383-93.

Elliott, D.J., et al., Expression of RBM in the nuclei of human germ cells is dependent on a critical region of the Y chromosome long arm. Proc Natl Acad Sci U S A, 1997. 94(8): p. 3848-53.

Aitken, R.J. and M.A. Baker, Oxidative stress, sperm survival and fertility control. Mol Cell Endocrinol, 2006. 250(1-2): p. 66-9.

Makker, K., A. Agarwal, and R. Sharma, Oxidative stress & male infertility. Indian J Med Res, 2009. 129(4): p. 357-67.

Koksal, I.T., et al., Potential role of reactive oxygen species on testicular pathology associated with infertility. Asian J Androl, 2003. 5(2): p. 95-9.

Kumar, M., et al., Radioprotective effect of Panax ginseng on the phosphatases and lipid peroxidation level in testes of Swiss albino mice. Biol Pharm Bull, 2003. 26(3): p. 308-12.

Agarwal, A., R.A. Saleh, and M.A. Bedaiwy, Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil Steril, 2003. 79(4): p. 829-43.

Novotny, J., et al., The occurrence of reactive oxygen species in the semen of males from infertile couples. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2003. 147(2): p. 173-6.

Sikka, S.C., Relative impact of oxidative stress on male reproductive function. Curr Med Chem, 2001. 8(7): p. 851-62.

Agarwal, A. and S.A. Prabakaran, Mechanism, measurement, and prevention of oxidative stress in male reproductive physiology. Indian J Exp Biol, 2005. 43(11): p. 963-74.

Moustafa, M.H., et al., Relationship between ROS production, apoptosis and DNA denaturation in spermatozoa from patients examined for infertility. Hum Reprod, 2004. 19(1): p. 129-38.

Agarwal, A. and T.M. Said, Role of sperm chromatin abnormalities and DNA damage in male infertility. Hum Reprod Update, 2003. 9(4): p. 331-45.

Carroll, P.R., et al., Endocrine and exocrine profiles of men with testicular tumors before orchiectomy. J Urol, 1987. 137(3): p. 420-3.

Hansen, P.V., et al., Germ cell function and hormonal status in patients with testicular cancer. Cancer, 1989. 64(4): p. 956-61.

Oeffinger, K.C., P.C. Nathan, and L.C.M. Kremer, Challenges after curative treatment for childhood cancer and long-term follow up of survivors. Pediatric Clinics of North America, 2008. 55(1): p. 251-+.

Coward, R.M., et al., Fertility Preservation in Young Men Treated for Malignancies: Options for Precancer Treatment. Sex Med Rev, 2013. 1(3): p. 123-134.

Howell, S. and S. Shalet, Gonadal damage from chemotherapy and radiotherapy. Endocrinol Metab Clin North Am, 1998. 27(4): p. 927-43.

Rowley, M.J., et al., Effect of graded doses of ionizing radiation on the human testis. Radiat Res, 1974. 59(3): p. 665-78.

Howell, S.J. and S.M. Shalet, Spermatogenesis after cancer treatment: damage and recovery. J Natl Cancer Inst Monogr, 2005(34): p. 12-7.

Brennemann, W., et al., Attempted protection of spermatogenesis from irradiation in patients with seminoma by D-Tryptophan-6 luteinizing hormone releasing hormone. Clin Investig, 1994. 72(11): p. 838-42.

Lee, S.J., et al., American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol, 2006. 24(18): p. 2917-31.

Mansky, P., et al., Treatment late effects in long-term survivors of pediatric sarcoma. Pediatr Blood Cancer, 2007. 48(2): p. 192-9.

van Beek, R.D., et al., Inhibin B is superior to FSH as a serum marker for spermatogenesis in men treated for Hodgkin's lymphoma with chemotherapy during childhood. Hum Reprod, 2007. 22(12): p. 3215-22.

Whitehead, E., et al., The effects of Hodgkin's disease and combination chemotherapy on gonadal function in the adult male. Cancer, 1982. 49(3): p. 418-22.

Turner, T.T. and K.J. Brown, Spermatic cord torsion: loss of spermatogenesis despite return of blood flow. Biol Reprod, 1993. 49(2): p. 401-7.

Mansbach, J.M., P. Forbes, and C. Peters, Testicular torsion and risk factors for orchiectomy. Arch Pediatr Adolesc Med, 2005. 159(12): p. 1167-71.

Serakinci, N. and W.N. Keith, Therapeutic potential of adult stem cells. Eur J Cancer, 2006. 42(9): p. 1243-6.

Can, A. (2009) Kök Hücre Biyolojisi ve Klinik Uygulamalar. 1. Baskı ed., Ankara: Tüba.

Liu, Z.J., Y. Zhuge, and O.C. Velazquez, Trafficking and differentiation of mesenchymal stem cells. J Cell Biochem, 2009. 106(6): p. 984-91.

Dominici, M., et al., Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 2006. 8(4): p. 315-7.

Bianco, P., P.G. Robey, and P.J. Simmons, Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell, 2008. 2(4): p. 313-9.

Zuk, P.A., et al., Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell, 2002. 13(12): p. 4279-95.

Wagner, W., et al., Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol, 2005. 33(11): p. 1402-16.

Friedman, R., et al., Umbilical cord mesenchymal stem cells: adjuvants for human cell transplantation. Biol Blood Marrow Transplant, 2007. 13(12): p. 1477-86.

Barry, F.P. and J.M. Murphy, Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol, 2004. 36(4): p. 568-84.

Minguell, J.J., A. Erices, and P. Conget, Mesenchymal stem cells. Exp Biol Med (Maywood), 2001. 226(6): p. 507-20.

Kinnaird, T., et al., Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res, 2004. 94(5): p. 678-85.

da Silva Meirelles, L., A.I. Caplan, and N.B. Nardi, In search of the in vivo identity of mesenchymal stem cells. Stem Cells, 2008. 26(9): p. 2287-99.

Pawitan, J.A., Prospect of stem cell conditioned medium in regenerative medicine. Biomed Res Int, 2014. 2014: p. 965849.

Baglio, S.R., D.M. Pegtel, and N. Baldini, Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol, 2012. 3: p. 359.

Makridakis, M., M.G. Roubelakis, and A. Vlahou, Stem cells: insights into the secretome. Biochim Biophys Acta, 2013. 1834(11): p. 2380-4.

Yang, D., et al., The relative contribution of paracine effect versus direct differentiation on adipose-derived stem cell transplantation mediated cardiac repair. PLoS One, 2013. 8(3): p. e59020.

Sagaradze, G.D., et al., Application of rat cryptorchidism model for the evaluation of mesenchymal stromal cell secretome regenerative potential. Biomed Pharmacother, 2019. 109: p. 1428-1436.

Shirzeyli, M.H., et al., Bones Morphogenic Protein-4 and retinoic acid combined treatment comparative analysis for in vitro differentiation potential of murine mesenchymal stem cells derived from bone marrow and adipose tissue into germ cells. Microsc Res Tech, 2017. 80(11): p. 1151-1160.

Newson, A.J. and A.C. Smajdor, Artificial gametes: new paths to parenthood? J Med Ethics, 2005. 31(3): p. 184-6.

Chen, W., et al., Retinoic acid regulates germ cell differentiation in mouse embryonic stem cells through a Smad-dependent pathway. Biochemical and biophysical research communications, 2012. 418(3): p. 571-577.

Huang, P., et al., Differentiation of human umbilical cord Wharton's jelly‐derived mesenchymal stem cells into germ‐like cells in vitro. Journal of cellular biochemistry, 2010. 109(4): p. 747-754.

Gely-Pernot, A., et al., Retinoic Acid Receptors Control Spermatogonia Cell-Fate and Induce Expression of the SALL4A Transcription Factor. PLoS Genet, 2015. 11(10): p. e1005501.

Ghasemzadeh-Hasankolaei, M., et al., Comparison of the efficacy of three concentrations of retinoic acid for transdifferentiation induction in sheep marrow-derived mesenchymal stem cells into male germ cells. Andrologia, 2014. 46(1): p. 24-35.

Ghasemzadeh-Hasankolaei, M., M.A. Sedighi-Gilani, and M.B. Eslaminejad, Induction of ram bone marrow mesenchymal stem cells into germ cell lineage using transforming growth factor-beta superfamily growth factors. Reprod Domest Anim, 2014. 49(4): p. 588-598.

Cakici, C., et al., Recovery of fertility in azoospermia rats after injection of adipose-tissue-derived mesenchymal stem cells: the sperm generation. Biomed Res Int, 2013. 2013: p. 529589.

Chen, H., et al., Differentiation of human umbilical cord mesenchymal stem cells into germ-like cells in mouse seminiferous tubules. Mol Med Rep, 2015. 12(1): p. 819-28.

Maghen, L., et al., Human umbilical perivascular cells: a novel source of MSCs to support testicular niche regeneration. Reproduction, 2016.

Hsiao, C.H., et al., Local injection of mesenchymal stem cells protects testicular torsion-induced germ cell injury. Stem Cell Res Ther, 2015. 6: p. 113.

Hsiao, C.H., et al., Mesenchymal stem cells restore the sperm motility from testicular torsion-detorsion injury by regulation of glucose metabolism in sperm. Stem Cell Res Ther, 2019. 10(1): p. 270.

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25 Mart 2022

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