It is becoming increasingly evident that selecting an optimal source of mesenchymal stromal cells (MSCs) is crucial for the successful outcome of MSC-based therapies. During the search for cells with potent regenerative properties, Sertoli cells (SCs) have been proven to modulate immune response in both in vitro and in vivo models. Based on morphological properties and expression of surface markers, it has been suggested that SCs could be a kind of MSCs, however, this hypothesis has not been fully confirmed. Therefore, we compared several parameters of MSCs and SCs, with the aim to evaluate the therapeutic potential of SCs in regenerative medicine. We showed that SCs successfully underwent osteogenic, chondrogenic and adipogenic differentiation and determined the expression profile of canonical MSC markers on the SC surface. Besides, SCs rescued T helper (Th) cells from undergoing apoptosis, promoted the anti-inflammatory phenotype of these cells, but did not regulate Th cell proliferation. MSCs impaired the Th17-mediated response; on the other hand, SCs suppressed the inflammatory polarisation in general. SCs induced M2 macrophage polarisation more effectively than MSCs. For the first time, we demonstrated here the ability of SCs to transfer mitochondria to immune cells. Our results indicate that SCs are a type of MSCs and modulate the reactivity of the immune system. Therefore, we suggest that SCs are promising candidates for application in regenerative medicine due to their anti-inflammatory and protective effects, especially in the therapies for diseases associated with testicular tissue inflammation.

Department of Cell Biology Faculty of Science Charles University Vinicna 7 Prague 2 128 43 Vídeňská Czech Republic

Department of Nanotoxicology and Molecular Epidemiology Institute of Experimental Medicine of the Czech Academy of Sciences Prague 4 142 20 Vídeňská 1083 Czech Republic

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Richardson, S. M., Kalamegam, G., Pushparaj, P. N., Matta, C., Memic, A., Khademhosseini, A., Mobasheri, R., Poletti, F. L., Hoyland, J. A., & Mobasheri, A. (2016). Mesenchymal stem cells in regenerative medicine: Focus on articular cartilage and intervertebral disc regeneration. Methods, 99, 69–80. PubMed DOI

Wegmeyer, H., Bröske, A. M., Leddin, M., Kuentzer, K., Nisslbeck, A. K., Hupfeld, J., Wiechmann, K., Kuhlen, J., von Schwerin, C., Stein, C., Knothe, S., Funk, J., Huss, R., & Neubauer, M. (2013). Mesenchymal stromal cell characteristics vary depending on their origin. Stem Cells and Development, 22(19), 2606–2618. PubMed DOI PMC

Gomez-Salazar, M., Gonzalez-Galofre, Z. N., Casamitjana, J., Crisan, M., James, A. W., & Péault, B. (2020). Five Decades Later, Are Mesenchymal Stem Cells Still Relevant? Frontiers in Bioengineering and Biotechnology, 8, 148. PubMed DOI PMC

Fitzsimmons, R. E. B., Mazurek, M. S., Soos, A., & Simmons, C. A. (2018). Mesenchymal Stromal/Stem Cells in Regenerative Medicine and Tissue Engineering. Stem Cells International, 2018, 8031718. PubMed DOI PMC

Viswanathan, S., Shi, Y., Galipeau, J., Krampera, M., Leblanc, K., Martin, I., Nolta, J., Phinney, D. G., & Sensebe, L. (2019). Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT®) Mesenchymal Stromal Cell committee position statement on nomenclature. Cytotherapy, 21(10), 1019–1024. PubMed DOI

Tarulli, G. A., Stanton, P. G., & Meachem, S. J. (2012). Is the Adult Sertoli Cell Terminally Differentiated? Biology of Reproduction, 87(1), 13, 1–11.

França, L. R., Hess, R. A., Dufour, J. M., Hofmann, M. C., & Griswold, M. D. (2016). The Sertoli cell: One hundred fifty years of beauty and plasticity. Andrology, 4(2), 189–212. PubMed DOI PMC

Chikhovskaya, J. V., van Daalen, S. K. M., Korver, C. M., Repping, S., & van Pelt, A. M. M. (2014). Mesenchymal origin of multipotent human testis-derived stem cells in human testicular cell cultures. Molecular Human Reproduction, 20(2), 155–167. PubMed DOI

Sadeghian-Nodoushan, F., Aflatoonian, R., Borzouie, Z., Akyash, F., Fesahat, F., Soleimani, M., Aghajanpour, S., Moore, H. D., & Aflatoonian, B. (2016). Pluripotency and differentiation of cells from human testicular sperm extraction: An investigation of cell stemness. Molecular Reproduction and Development, 83(4), 312–323. PubMed DOI

Gong, D., Zhang, C., Li, T., Zhang, J., Zhang, N., Tao, Z., Zhu, W., & Sun, X. (2017). Are Sertoli cells a kind of mesenchymal stem cells? American Journal of Translational Research, 9(3), 1067–1074. PubMed PMC

Holan, V., Hermankova, B., Bohacova, P., Kossl, J., Chudickova, M., Hajkova, M., Krulova, M., Zajicova, A., & Javorkova, E. (2016). Distinct Immunoregulatory Mechanisms in Mesenchymal Stem Cells: Role of the Cytokine Environment. Stem Cell Reviews and Reports, 12(6), 654–663. PubMed DOI

Mital, P., Kaur, G., & Dufour, J. M. (2010). Immunoprotective Sertoli cells: Making allogeneic and xenogeneic transplantation feasible. Reproduction, 139(3), 495–504. PubMed DOI

Lee, H. M., Byoung, C. O., Lim, D. P., Lee, D. S., Lim, H. G., Chun, S. P., & Jeong, R. L. (2008). Mechanism of humoral and cellular immune modulation provided by porcine Sertoli cells. Journal of Korean Medical Science, 23(3), 514–520. PubMed DOI PMC

Campese, A. F., Grazioli, P., de Cesaris, P., Riccioli, A., Bellavia, D., Pelullo, M., Noce, C., Verkhovskaia, S., Filippini, A., Latella, G., Screpanti, I., Ziparo, E., & Starace, D. (2014). Mouse Sertoli Cells Sustain De Novo Generation of Regulatory T Cells by Triggering the Notch Pathway Through Soluble JAGGED11. Biology of Reproduction, 90(3), 53–54. PubMed DOI

Zhao, S., Zhu, W., Xue, S., & Han, D. (2014). Testicular defense systems: Immune privilege and innate immunity. Cellular and Molecular Immunology, 11(5), 428–437. PubMed DOI PMC

Dufour, J. M., Rajotte, R. V., Kin, T., & Korbutt, G. S. (2003). Immunoprotection of rat islet xenografts by cotransplantation with Sertoli cells and a single injection of antilymphocyte serum1. Transplantation, 75(9), 1594–1596. PubMed DOI

Shamekh, R., El-Badri, N. S., Saporta, S., Pascual, C., Sanberg, P. R., & Cameron, D. F. (2006). Sertoli cells induce systemic donor-specific tolerance in xenogenic transplantation model. Cell Transplantation, 15(1), 45–53. PubMed DOI

Aliaghaei, A., Meymand, A. Z., Boroujeni, E., Khodagoli, F., Meftahi, G. H., Hadipour, M. M., Abdollahifar, M. A., Mesgar, S., Ahmadi, H., Danyali, S., Hasani, S., & Sadeghi, Y. (2019). Neuro-restorative effect of Sertoli cell transplants in a rat model of amyloid beta toxicity. Behavioural Brain Research, 367, 158–165. PubMed DOI

Paliwal, S., Chaudhuri, R., Agrawal, A., & Mohanty, S. (2018). Regenerative abilities of mesenchymal stem cells through mitochondrial transfer. Journal of Biomedical Science, 25(1), 31. PubMed DOI PMC

Luz-Crawford, P., Hernandez, J., Djouad, F., Luque-Campos, N., Caicedo, A., Carrère-Kremer, S., Brondello, J. M., Vignais, M. L., Pène, J., & Jorgensen, C. (2019). Mesenchymal stem cell repression of Th17 cells is triggered by mitochondrial transfer. Stem Cell Research and Therapy, 10(1), 232. PubMed DOI PMC

Plotnikov, E. Y., Khryapenkova, T. G., Vasileva, A. K., Marey, M. V., Galkina, S. I., Isaev, N. K., Sheval, E. V., Polyakov, V. Y., Sukhikh, G. T., & Zorov, D. B. (2008). Cell-to-cell cross-talk between mesenchymal stem cells and cardiomyocytes in co-culture. Journal of Cellular and Molecular Medicine, 12(5A), 1622–1631. PubMed DOI

Ahmad, T., Mukherjee, S., Pattnaik, B., Kumar, M., Singh, S., Rehman, R., & …& Agrawal, A. . (2014). Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. EMBO Journal, 33(9), 994–1010.

Islam, M. N., Das, S. R., Emin, M. T., Wei, M., Sun, L., Westphalen, K., Tiwari, B. K., Jha, K. A., Barhanpurkar, A. P., Wani, M. R., Roy, S. S., Mabalirajan, U., Ghosh, B., & Bhattacharya, J. (2012). Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nature Medicine, 18(5), 759–765. PubMed DOI PMC

Brehm, R., Zeiler, M., Rüttinger, C., Herde, K., Kibschull, M., Winterhager, E., Willecke, K., Guillou, F., Lécureuil, C., Steger, K., Konrad, L., Biermann, K., Failing, K., & Bergmann, M. (2007). A sertoli cell-specific knockout of connexin43 prevents initiation of spermatogenesis. The American journal of pathology, 171(1), 19–31. PubMed DOI PMC

Sagaradze, G., Basalova, N., Kirpatovsky, V., Ohobotov, D., Nimiritsky, P., Grigorieva, O., Popov, V., Kamalov, A., Tkachuk, V., & Efimenko, A. (2019). A magic kick for regeneration: Role of mesenchymal stromal cell secretome in spermatogonial stem cell niche recovery. Stem Cell Research and Therapy, 10(1), 1–10. DOI

Anand, S., Bhartiya, D., Sriraman, K., & Mallick, A. (2016). Underlying Mechanisms that Restore Spermatogenesis on Transplanting Healthy Niche Cells in Busulphan Treated Mouse Testis. Stem Cell Reviews and Reports, 12(6), 682–697. PubMed DOI

Gauthier-Fisher, A., Kauffman, A., & Librach, C. L. (2020). Potential use of stem cells for fertility preservation. Andrology, 8(4), 862–878. PubMed DOI

Hajkova, M., Hermankova, B., Javorkova, E., Bohacova, P., Zajicova, A., Holan, V., & Krulova, M. (2017). Mesenchymal Stem Cells Attenuate the Adverse Effects of Immunosuppressive Drugs on Distinct T Cell Subopulations. Stem Cell Reviews and Reports, 13(1), 104–115. PubMed DOI

Krulová, M., Zajícová, A., Frič, J., & Holáň, V. (2002). Alloantigen-induced, T-cell-dependent production of nitric oxide by macrophages infiltrating skin allografts in mice. Transplant International, 15(2–3), 108–116. PubMed DOI

Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F. C., Krause, D. S., Deans, R., Keating, A., Prockop, D., & Horwitz, E. M. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8(4), 315–317.

Duffy, M. M., Ritter, T., Ceredig, R., & Griffin, M. D. (2011). Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Research and Therapy, 2(4), 34. PubMed DOI PMC

Murray, P. J. (2017). Macrophage Polarisation. Annual Review of Physiology, 79, 541–566. PubMed DOI

Court, A. C., Le‐Gatt, A., Luz‐Crawford, P., Parra, E., Aliaga‐Tobar, V., Bátiz, L. F., Contreras, R. A., Ortúzar, M. I., Kurte, M., Elizondo-Vega, R., Maracaja-Coutinho, V., Pino-Lagos, K., Figueroa, F. E., & Khoury, M. (2020). Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response. EMBO Reports, 21(2), e48052.

Jackson, M. V., Morrison, T. J., Doherty, D. F., McAuley, D. F., Matthay, M. A., Kissenpfennig, A., O’Kane, C. M., & Krasnodembskaya, A. D. (2016). Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS. Stem Cells, 34(8), 2210–2223. PubMed DOI PMC

Meligy, F. Y., Abo Elgheed, A. T., & Alghareeb, S. M. (2019). Therapeutic effect of adipose-derived mesenchymal stem cells on Cisplatin induced testicular damage in adult male albino rat. Ultrastructural Pathology, 43(1), 28–55. PubMed DOI

Hsiao, C. H., Ji, A. T. Q., Chang, C. C., Chien, M. H., Lee, L. M., & Ho, J. H. C. (2019). Mesenchymal stem cells restore the sperm motility from testicular torsion-detorsion injury by regulation of glucose metabolism in sperm. Stem Cell Research and Therapy, 10(1), 270. PubMed DOI PMC

Kaur, G., Thompson, L. A., & Dufour, J. M. (2014). Sertoli cells-Immunological sentinels of spermatogenesis. Seminars in Cell & Developmental Biology, 30, 36–44. DOI

Bryan, E. R., Kim, J., Beagley, K. W., & Carey, A. J. (2020). Testicular inflammation and infertility: Could chlamydial infections be contributing? American Journal of Reproductive Immunology, 84(3), e13286.

Luca, G., Arato, I., Sorci, G., Cameron, D. F., Hansen, B. C., Baroni, T., Donato, R., White, D. G. J., & Calafiore, R. (2018). Sertoli cells for cell transplantation: Pre-clinical studies and future perspectives. Andrology, 6(3), 385–395. PubMed DOI

Hemendinger, R., Wang, J., Malik, S., Persinski, R., Copeland, J., Emerich, D., Gores, P., Halberstadt, C., & Rosenfeld, J. (2005). Sertoli cells improve survival of motor neurons in SOD1 transgenic mice, a model of amyotrophic lateral sclerosis. Experimental Neurology, 196(2), 235–243. PubMed DOI

Glennie, S., Soeiro, I., Dyson, P. J., Lam, E. W. F., & Dazzi, F. (2005). Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood, 105(7), 2821–2827. PubMed DOI

da Silva Meirelles, L., Fontes, A. M., Covas, D. T., & Caplan, A. I. (2009). Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine and Growth Factor Reviews, 20(5–6), 419–427. DOI

Mohammadzadeh, A., Pourfathollah, A. A., Shahrokhi, S., Hashemi, S. M., Moradi, S. L. A., & Soleimani, M. (2014). Immunomodulatory effects of adipose-derived mesenchymal stem cells on the gene expression of major transcription factors of T cell subsets. International Immunopharmacology, 20(2), 316–321. PubMed DOI

Svobodova, E., Krulova, M., Zajicova, A., Pokorna, K., Prochazkova, J., Trosan, P., & Holan, V. (2012). The role of mouse mesenchymal stem cells in differentiation of naive T-cells into anti-inflammatory regulatory T-cell or pro-inflammatory helper T-cell 17 population. Stem Cells and Development, 21(6), 901–910. PubMed DOI

Aggarwal, S., & Pittenger, M. F. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105(4), 1815–1822. PubMed DOI

Hermankova, B., Zajicova, A., Javorkova, E., Chudickova, M., Trosan, P., Hajkova, M., Krulova, M., Zajicova, A., & Holan, V. (2016). Suppression of IL-10 production by activated B cells via a cell contact-dependent cyclooxygenase-2 pathway upregulated in IFN-γ-treated mesenchymal stem cells. Immunobiology, 221(2), 129–136. PubMed DOI

Philipp, D., Suhr, L., Wahlers, T., Choi, Y.-H., & Paunel-Görgülü, A. (2018). Preconditioning of bone marrow-derived mesenchymal stem cells highly strengthens their potential to promote IL-6-dependent M2b polarisation. Stem Cell Research & Therapy, 9(1), 286. DOI

Hajkova, M., Javorkova, E., Zajicova, A., Trosan, P., Holan, V., & Krulova, M. (2017). A local application of mesenchymal stem cells and cyclosporine A attenuates immune response by a switch in macrophage phenotype. Journal of Tissue Engineering and Regenerative Medicine, 11(5), 1456–1465. PubMed DOI

Mossadegh-Keller, N., & Sieweke, M. H. (2018). Testicular macrophages: Guardians of fertility. Cellular Immunology, 330, 120–125. PubMed DOI

O’Neill, L. A. J., Kishton, R. J., & Rathmell, J. (2016). A guide to immunometabolism for immunologists. Nature Reviews Immunology, 16(9), 553–565. PubMed DOI PMC

Rodriguez, A. M., Nakhle, J., Griessinger, E., & Vignais, M. L. (2018). Intercellular mitochondria trafficking highlighting the dual role of mesenchymal stem cells as both sensors and rescuers of tissue injury. Cell Cycle, 17(6), 712–721. PubMed DOI PMC

Morrison, T. J., Jackson, M. V., Cunningham, E. K., Kissenpfennig, A., McAuley, D. F., O’Kane, C. M., & Krasnodembskaya, A. D. (2017). Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer. American Journal of Respiratory and Critical Care Medicine, 196(10), 1275–1286. PubMed DOI PMC

Kaushik, A., & Bhartiya, D. (2020). Additional Evidence to Establish Existence of Two Stem Cell Populations Including VSELs and SSCs in Adult Mouse Testes. Stem Cell Reviews and Reports, 16(5), 992–1004. PubMed DOI PMC

Ratajczak, M. Z., Ratajczak, J., & Kucia, M. (2019). Very Small Embryonic-Like Stem Cells (VSELs): An Update and Future Directions. Circulation Research, 124(2), 208–210. PubMed DOI PMC

Kaushik, A., & Bhartiya, D. (2018). Pluripotent Very Small Embryonic-Like Stem Cells in Adult Testes – An Alternate Premise to Explain Testicular Germ Cell Tumors. Stem Cell Reviews and Reports, 14(6), 793–800. PubMed DOI

Bhartiya, D., Kasiviswananthan, S., & Shaikh, A. (2012). Cellular origin of testis-derived pluripotent stem cells: A case for very small embryonic-like stem cells. Stem Cells and Development, 21(5), 670–674. PubMed DOI

Immunomodulatory role of Xenopus tropicalis immature Sertoli cells in tadpole muscle regeneration via macrophage response modulation

Therapeutic potential of Sertoli cells in vivo: alleviation of acute inflammation and improvement of sperm quality

Metal Nanoparticles with Antimicrobial Properties: The Toxicity Response in Mouse Mesenchymal Stem Cells