DOI QR코드

DOI QR Code

Gender-independent efficacy of mesenchymal stem cell therapy in sex hormone-deficient bone loss via immunosuppression and resident stem cell recovery

  • Sui, Bing-Dong (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University) ;
  • Chen, Ji (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University) ;
  • Zhang, Xin-Yi (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University) ;
  • He, Tao (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University) ;
  • Zhao, Pan (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University) ;
  • Zheng, Chen-Xi (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University) ;
  • Li, Meng (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University) ;
  • Hu, Cheng-Hu (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University) ;
  • Jin, Yan (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University)
  • Received : 2018.01.08
  • Accepted : 2018.10.01
  • Published : 2018.12.30

Abstract

Osteoporosis develops with high prevalence in both postmenopausal women and hypogonadal men. Osteoporosis results in significant morbidity, but no cure has been established. Mesenchymal stem cells (MSCs) critically contribute to bone homeostasis and possess potent immunomodulatory/anti-inflammatory capability. Here, we investigated the therapeutic efficacy of using an infusion of MSCs to treat sex hormone-deficient bone loss and its underlying mechanisms. In particular, we compared the impacts of MSC cytotherapy in the two genders with the aim of examining potential gender differences. Using the gonadectomy (GNX) model, we confirmed that the osteoporotic phenotypes were substantially consistent between female and male mice. Importantly, systemic MSC transplantation (MSCT) not only rescued trabecular bone loss in GNX mice but also restored cortical bone mass and bone quality. Unexpectedly, no differences were detected between the genders. Furthermore, MSCT demonstrated an equal efficiency in rectifying the bone remodeling balance in both genders of GNX animals, as proven by the comparable recovery of bone formation and parallel normalization of bone resorption. Mechanistically, using green fluorescent protein (GFP)-based cell-tracing, we demonstrated rapid engraftment but poor inhabitation of donor MSCs in the GNX recipient bone marrow of each gender. Alternatively, MSCT uniformly reduced the $CD3^+T$-cell population and suppressed the serum levels of inflammatory cytokines in reversing female and male GNX osteoporosis, which was attributed to the ability of the MSC to induce T-cell apoptosis. Immunosuppression in the microenvironment eventually led to functional recovery of endogenous MSCs, which resulted in restored osteogenesis and normalized behavior to modulate osteoclastogenesis. Collectively, these data revealed recipient sexually monomorphic responses to MSC therapy in gonadal steroid deficiency-induced osteoporosis via immunosuppression/anti-inflammation and resident stem cell recovery.

Keywords

Acknowledgement

Supported by : National Natural Science Foundation of China

References

  1. Jackson, J. A. & Kleerekoper, M. Osteoporosis in men: diagnosis, pathophysiology, and prevention. Medicine 69, 137-152 (1990). https://doi.org/10.1097/00005792-199005000-00002
  2. Hannan, M. T., Felson, D. T. & Anderson, J. J. Bone mineral density in elderly men and women: results from the Framingham osteoporosis study. J. Bone Miner. Res. 7, 547-553 (1992).
  3. Pacifici, R. Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J. Bone Miner. Res. 11, 1043-1051 (1996).
  4. Sui BD, et al. Stem cell-based bone regeneration in diseased microenvironments: Challenges and solutions. Biomaterials 2017; e-pub ahead of print 30 October 2017. https://doi.org/10.1016/j.biomaterials.2017.10.046.
  5. Sui, B. D., Hu, C. H., Zheng, C. X. & Jin, Y. Microenvironmental Views on Mesenchymal Stem Cell Differentiation in Aging. J. Dent. Res. 95, 1333-1340 (2016). https://doi.org/10.1177/0022034516653589
  6. Liu, Y., Wu, J., Zhu, Y. & Han, J. Therapeutic application of mesenchymal stem cells in bone and joint diseases. Clin. Exp. Med. 14, 13-24 (2014). https://doi.org/10.1007/s10238-012-0218-1
  7. Shi, Y. et al. Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res. 20, 510-518 (2010). https://doi.org/10.1038/cr.2010.44
  8. Sui, B. D. et al. Recipient Glycemic Micro-environments Govern Therapeutic Effects of Mesenchymal Stem Cell Infusion on Osteopenia. Theranostics 7, 1225-1244 (2017). https://doi.org/10.7150/thno.18181
  9. Liu, Y. et al. Transplantation of SHED prevents bone loss in the early phase of ovariectomy-induced osteoporosis. J. Dent. Res. 93, 1124-1132 (2014). https://doi.org/10.1177/0022034514552675
  10. Cho, S. W. et al. Transplantation of mesenchymal stem cells overexpressing RANK-Fc or CXCR4 prevents bone loss in ovariectomized mice. Mol. Ther. 17, 1979-1987 (2009). https://doi.org/10.1038/mt.2009.153
  11. Lee, K. et al. Systemic transplantation of human adipose-derived stem cells stimulates bone repair by promoting osteoblast and osteoclast function. J. Cell. Mol. Med. 15, 2082-2094 (2011). https://doi.org/10.1111/j.1582-4934.2010.01230.x
  12. An, J. H. et al. Transplantation of human umbilical cord blood-derived mesenchymal stem cells or their conditioned medium prevents bone loss in ovariectomized nude mice. Tissue Eng. Part. A. 19, 685-696 (2013). https://doi.org/10.1089/ten.tea.2012.0047
  13. Nielson, C. M., Klein, R. F. & Orwoll, E. S. Sex and the single nucleotide polymorphism: exploring the genetic causes of skeletal sex differences. J. Bone Miner. Res. 27, 2047-2050 (2012). https://doi.org/10.1002/jbmr.1723
  14. Sui, B. et al. Allogeneic mesenchymal stem cell therapy promotes osteoblastogenesis and prevents glucocorticoid-induced osteoporosis. Stem Cells Transl. Med. 5, 1238-1246 (2016). https://doi.org/10.5966/sctm.2015-0347
  15. Lien, C. Y., Chih-Yuan, Ho. K., Lee,O. K., Blunn,G. W. & Su, Y. Restoration of bone mass and strength in glucocorticoid-treated mice by systemic transplantation of CXCR4 and cbfa-1 co-expressing mesenchymal stem cells. J. Bone Miner. Res. 24, 837-848 (2009). https://doi.org/10.1359/jbmr.081257
  16. Ma, L. et al. Transplantation of mesenchymal stem cells ameliorates secondary osteoporosis through interleukin-17-impaired functions of recipient bone marrow mesenchymal stem cells in MRL/lpr mice. Stem Cell Res. Ther. 6, 104 (2015). https://doi.org/10.1186/s13287-015-0091-4
  17. Akiyama, K. et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell. Stem Cell 10, 544-555 (2012). https://doi.org/10.1016/j.stem.2012.03.007
  18. Yang, N. et al. Tumor necrosis factor alpha suppresses the mesenchymal stem cell osteogenesis promoter miR-21 in estrogen deficiency-induced osteoporosis. J. Bone Miner. Res. 28, 559-573 (2013). https://doi.org/10.1002/jbmr.1798
  19. Liao, L. et al. TNF-alpha Inhibits FoxO1 by Upregulating miR-705 to Aggravate Oxidative Damage in Bone Marrow-Derived Mesenchymal Stem Cells during Osteoporosis. Stem Cells 34, 1054-1067 (2016). https://doi.org/10.1002/stem.2274
  20. Sui, B. et al. Mesenchymal progenitors in osteopenias of diverse pathologies: differential characteristics in the common shift from osteoblastogenesis to adipogenesis. Sci. Rep. 6, 30186 (2016). https://doi.org/10.1038/srep30186
  21. Shao, B. et al. Estrogen preserves Fas ligand levels by inhibiting microRNA-181a in bone marrow-derived mesenchymal stem cells to maintain bone remodeling balance. FASEB J. 29, 3935-3944 (2015). https://doi.org/10.1096/fj.15-272823
  22. Zheng, C., Sui, B., Hu, C. & Jin, Y. Vitamin C promotes in vitro proliferation of bone marrow mesenchymal stem cells derived from aging mice. Nan. Fang. Yi. Ke. Da. Xue. Xue. Bao. 35, 1689-1693 (2015).
  23. Sui, B., Hu, C. & Jin, Y. Mitochondrial metabolic failure in telomere attritionprovoked aging of bone marrow mesenchymal stem cells. Biogerontology 17, 267-279 (2016). https://doi.org/10.1007/s10522-015-9609-5
  24. Chen, N. et al. microRNA-21 Contributes to Orthodontic Tooth Movement. J. Dent. Res. 95, 1425-1433 (2016). https://doi.org/10.1177/0022034516657043
  25. Hu, C. H. et al. miR-21 deficiency inhibits osteoclast function and prevents bone loss in mice. Sci. Rep. 7, 43191 (2017). https://doi.org/10.1038/srep43191
  26. Bouxsein, M. L. et al. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J. Bone Miner. Res. 25, 1468-1486 (2010). https://doi.org/10.1002/jbmr.141
  27. Dempster, D. W. et al. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J. Bone Miner. Res. 28, 2-17 (2013). https://doi.org/10.1002/jbmr.1805
  28. Zhao, P. et al. Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application. Aging Cell 16, 1083-1093 (2017). https://doi.org/10.1111/acel.12635
  29. Liao, L. et al. Redundant miR-3077-5p and miR-705 mediate the shift of mesenchymal stem cell lineage commitment to adipocyte in osteoporosis bone marrow. Cell Death Dis. 4, e600 (2013). https://doi.org/10.1038/cddis.2013.130
  30. Moverare-Skrtic, S. et al. Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. Nat. Med. 20, 1279-1288 (2014). https://doi.org/10.1038/nm.3654
  31. Yuan, X. et al. Psoralen and isopsoralen Ameliorate sex hormone deficiencyinduced osteoporosis in female and male mice. Biomed. Res. Int. 2016, 6869452 (2016).
  32. Fujita, T. et al. Breadth of the mandibular condyle affected by disturbances of the sex hormones in ovariectomized and orchiectomized mice. Clin. Orthod. Res. 4, 172-176 (2001). https://doi.org/10.1034/j.1600-0544.2001.040307.x
  33. Cenci, S. et al. Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator. Proc. Natl Acad. Sci. USA 100, 10405-10410 (2003). https://doi.org/10.1073/pnas.1533207100
  34. Cenci, S. et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J. Clin. Invest. 106, 1229-1237 (2000). https://doi.org/10.1172/JCI11066
  35. Wang, L. et al. IFN-gamma and TNF-alpha synergistically induce mesenchymal stem cell impairment and tumorigenesis via NFkappaB signaling. Stem Cells 31, 1383-1395 (2013). https://doi.org/10.1002/stem.1388
  36. Cawthon, P. M. Gender differences in osteoporosis and fractures. Clin. Orthop. Relat. Res. 469, 1900-1905 (2011). https://doi.org/10.1007/s11999-011-1780-7
  37. Rupich, R. C., Specker, B. L., Lieuw-A-Fa, M. & Ho, M. Gender and race differences in bone mass during infancy. Calcif. Tissue Int. 58, 395-397 (1996). https://doi.org/10.1007/BF02509436
  38. Gilsanz, V. et al. Gender differences in vertebral body sizes in children and adolescents. Radiology 190, 673-677 (1994). https://doi.org/10.1148/radiology.190.3.8115609
  39. Aaron, J. E., Makins, N. B. & Sagreiya, K. The microanatomy of trabecular bone loss in normal aging men and women. Clin. Orthop. Relat. Res. 215, 260-271 (1987).
  40. Seeman, E. During aging, men lose less bone than women because they gain more periosteal bone, not because they resorb less endosteal bone. Calcif. Tissue Int. 69, 205-208 (2001). https://doi.org/10.1007/s00223-001-1040-z
  41. Most, W., van der Wee-Pals, L., Ederveen, A., Papapoulos, S. & Lowik, C. Ovariectomy and orchidectomy induce a transient increase in the osteoclastogenic potential of bone marrow cells in the mouse. Bone 20, 27-30 (1997). https://doi.org/10.1016/S8756-3282(96)00309-2
  42. Turner, R. T., Wakley, G. K. & Hannon, K. S. Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats. J. Orthop. Res. 8, 612-617 (1990). https://doi.org/10.1002/jor.1100080418
  43. Khosla, S., Oursler, M. J. & Monroe, D. G. Estrogen and the skeleton. Trends Endocrinol. Metab. 23, 576-581 (2012). https://doi.org/10.1016/j.tem.2012.03.008
  44. Novack, D. V. Estrogen and bone: osteoclasts take center stage. Cell. Metab. 6, 254-256 (2007). https://doi.org/10.1016/j.cmet.2007.09.007
  45. Weitzmann, M. N. & Pacifici, R. Estrogen deficiency and bone loss: an inflammatory tale. J. Clin. Invest. 116, 1186-1194 (2006). https://doi.org/10.1172/JCI28550
  46. Clowes, J. A., Riggs, B. L. & Khosla, S. The role of the immune system in the pathophysiology of osteoporosis. Immunol. Rev. 208, 207-227 (2005). https://doi.org/10.1111/j.0105-2896.2005.00334.x
  47. Pfeilschifter, J., Koditz, R., Pfohl, M. & Schatz, H. Changes in proinflammatory cytokine activity after menopause. Endocr. Rev. 23, 90-119 (2002). https://doi.org/10.1210/edrv.23.1.0456
  48. Vandenput, L. & Ohlsson, C. Estrogens as regulators of bone health in men. Nat. Rev. Endocrinol. 5, 437-443 (2009). https://doi.org/10.1038/nrendo.2009.112
  49. Francis, R. M. Androgen replacement in aging men. Calcif. Tissue Int. 69, 235-238 (2001). https://doi.org/10.1007/s00223-001-1051-9
  50. Finkelstein, J. S. et al. Osteoporosis in men with idiopathic hypogonadotropic hypogonadism. Ann. Intern Med 106, 354-361 (1987). https://doi.org/10.7326/0003-4819-106-3-
  51. Stepan, J. J., Lachman, M., Zverina, J., Pacovsky, V. & Baylink, D. J. Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling. J. Clin. Endocrinol. Metab. 69, 523-527 (1989). https://doi.org/10.1210/jcem-69-3-523
  52. Alibhai, S. M., Gogov, S. & Allibhai, Z. Long-term side effects of androgen deprivation therapy in men with non-metastatic prostate cancer: a systematic literature review. Crit. Rev. Oncol. Hematol. 60, 201-215 (2006). https://doi.org/10.1016/j.critrevonc.2006.06.006
  53. Baillie, S. P., Davison, C. E., Johnson, F. J. & Francis, R. M. Pathogenesis of vertebral crush fractures in men. Age Ageing 21, 139-141 (1992). https://doi.org/10.1093/ageing/21.2.139
  54. Gunness, M. & Orwoll, E. Early induction of alterations in cancellous and cortical bone histology after orchiectomy in mature rats. J. Bone Miner. Res. 10, 1735-1744 (1995).
  55. Zhang, X. S. et al. Local ex vivo gene therapy with bone marrow stromal cells expressing human BMP4 promotes endosteal bone formation in mice. J. Gene Med. 6, 4-15 (2004). https://doi.org/10.1002/jgm.477
  56. Mirsaidi, A. et al. Therapeutic potential of adipose-derived stromal cells in agerelated osteoporosis. Biomaterials 35, 7326-7335 (2014). https://doi.org/10.1016/j.biomaterials.2014.05.016
  57. Liu, S. et al. MSC Transplantation Improves Osteopenia via Epigenetic Regulation of Notch Signaling in Lupus. Cell. Metab. 22, 606-618 (2015). https://doi.org/10.1016/j.cmet.2015.08.018
  58. Chen, C. et al. Mesenchymal stem cell transplantation in tight-skin mice identifies miR-151-5p as a therapeutic target for systemic sclerosis. Cell Res. 27, 559-577 (2017). https://doi.org/10.1038/cr.2017.11
  59. Tan, R. et al. GAPDH is critical for superior efficacy of female bone marrowderived mesenchymal stem cells on pulmonary hypertension. Cardiovasc. Res. 100, 19-27 (2013). https://doi.org/10.1093/cvr/cvt165
  60. Sammour, I. et al. The Effect of Gender on Mesenchymal Stem Cell (MSC) Efficacy in Neonatal Hyperoxia-Induced Lung Injury. PLoS ONE 11, e0164269 (2016). https://doi.org/10.1371/journal.pone.0164269

Cited by

  1. Stem cell-based bone and dental regeneration: a view of microenvironmental modulation vol.11, pp.3, 2019, https://doi.org/10.1038/s41368-019-0060-3
  2. Sex, not gender. A plea for accuracy vol.51, pp.11, 2018, https://doi.org/10.1038/s12276-019-0341-0
  3. Defective Proliferation and Osteogenic Potential with Altered Immunoregulatory phenotype of Native Bone marrow-Multipotential Stromal Cells in Atrophic Fracture Non-Union vol.9, pp.1, 2018, https://doi.org/10.1038/s41598-019-53927-3
  4. Trophic effects of multiple administration of mesenchymal stem cells in children with osteogenesis imperfecta vol.11, pp.4, 2021, https://doi.org/10.1002/ctm2.385
  5. Bone Marrow Multipotent Mesenchymal Stromal Cells as Autologous Therapy for Osteonecrosis: Effects of Age and Underlying Causes vol.8, pp.5, 2021, https://doi.org/10.3390/bioengineering8050069