17β-Estradiol Enhances the Efficacy of Adipose-Derived Mesenchymal Stem Cells on Remyelination in Mouse Model of Multiple Sclerosis
Previous studies have demonstrated the potential of monotherapy with either mesenchymal stem cells (MSCs) or estrogen in autoimmune and cuprizone models of multiple sclerosis (MS). The aim of this study was to examine the effects of co-administration of 17β-estradiol (E2) and adipose-derived mesenchymal stem cells (ADSCs) on remyelination of corpus callosum axons in a cuprizone model of MS. Forty eight male C57BL/6 mice were fed cuprizone (0.2%) for 6 weeks. At day 0 after cuprizone removal, animals were randomly divided into four groups. The E2 monotherapy, ADSCs monotherapy, E2/ADSCs combined therapy and vehicle control. Some mice of the same age were fed with their normal diet to serve as healthy control group. E2 pellets, designed to release 5.0 mg E2 over 10 days, were implanted subcutaneously. 106 PKH26 labeled ADSCs were transplanted into lateral tail. The extent of demyelination, remyelination, and cell type's composition of host brain were examined at 10 days post-transplantation in the body of the corpus callosum. Transplanted cells migrated to the corpus callosum injury. Histological examination revealed efficacy of intravenous ADSCs transplantation in remyelination of mouse cuprizone model of MS can be significantly enhanced by E2 administration. Flow cytometry showed that the mean percentages of expression of Iba-1, Olig2 and O4 were significantly increased in E2/ADSCs combined therapy in comparison with ADSCs monotherapy. In conclusion, the findings of this study revealed that E2 administration enhanced efficacy of intravenous ADSCs transplantation in remyelination of corpus callosum axons in mouse cuprizone model of MS.
Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype,differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007;25(11):2739-49.
Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, Du MQ, Luan SL, Altmann DR, Thompson AJ, Compston A, Scott MA, Miller DH, Chandran S. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol 2012;11(2):150-6.
Einstein O, Friedman-Levi Y, Grigoriadis N, Ben-Hur T. Transplanted neural precursors enhance host brain-derived myelin regeneration. J Neurosci 2009;29(50):15694-702.
Gholipour Z, Ragerdi kashani I, Akbari M, Mahmoudi R, Abbasi M, Nekoonam S. Apoptosis of Rat Adipose- Derived Stem Cells during Transdifferentiation to Schwann-LikeCell. IJMS 2010;35(2):129-35.
Fraser JK, Wulur I, Alfonso Z, Hedrick MH. Fat tissue: an underappreciated source of stem cells for biotechnology. Trends Biotechnol 2006;24:150-4.
Constantin G, Marconi S, Rossi B, Angiari S, Calderan L, Anghileri E, Gini B, Bach SD, Martinello M, Bifari F, Galiè M, Turano E,Budui S, Sbarbati A, KramperaM, Bonetti B. Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis. Stem Cells 2009; 27(10):2624-35.
De Ugarte DA, Alfonso Z, Zuk PA, Elbarbary A, Zhu M, Ashjian P, Benhaim P, Hedrick MH, Fraser JK. Differential expression of stem cell mobilizationassociated molecules on multi-lineage cells from adipose tissue and bone marrow. Immunol Lett 2003;89(2-3):267-70.
Barnard AL, Chidgey AP, Bernard CC, Boyd RL. Androgen depletion increases the efficacy of bone marrow transplantation in ameliorating experimental autoimmune encephalomyelitis. Blood 2009;113(1):204-13.
Burt RK, Burns WH, Miller SD. Bone marrow transplantation for multiple sclerosis: returning to Pandora's box. Immunol Today 1997; 18(12):559-61.
Aghajanova L, Horcajadas JA, Esteban FJ, Giudice LC. The bone marrow-derived human mesenchymal stem cell: potential progenitor of the endometrial stromal fibroblast. Biol Reprod 2010;82(6):1076-87.
Sicotte NL, Liva SM, Klutch R, Pfeiffer P, Bouvier S, Odesa S, Wu TC, Voskuhl RR. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol 2002;52(4):421-8.
Soldan SS, Alvarez Retuerto AI, Sicotte NL, Voskuhl RR. Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol 2003;171(11):6267-74.
Nomura M, Korach KS, Pfaff DW, Ogawa S. Estrogen receptor beta (ERbeta) protein levels in neurons depend on estrogen receptor alpha (ERalpha) gene expression and on its ligand in a brain region-specific manner. Brain Res Mol Brain Res 2003;110(1):7-14.
Short MA, Campanale N, Litwak S, Bernard CC. Quantitative and phenotypic analysis of bone marrowderived cells in the intact and inflamed central nervous system. Cell Adh Migr 2011;5(5):373-81.
Stidworthy MF, Genoud S, Suter U, Mantei N, Franklin RJ. Quantifying the early stages of remyelination following cuprizone-induced demyelination. Brain Pathol 2003;13(3):329-39.
Crocker SJ, Bajpai R, Moore CS, Frausto RF, Brown GD,Pagarigan RR, Whitton JL, Terskikh AV. Intravenous administration of human embryonic stem cell-derived neural precursor cells attenuates cuprizone-induced central nervous system (CNS) demyelination. Neuropathol Appl Neurobiol 2011;37(6):643-53.
Chopp M, Li Y. Treatment of neural injury with marrow stromal cells. Lancet Neurol 2002;1(2):92-100.
Acs P, Kipp M, Norkute A, Johann S, Clarner T, Braun A, Berente Z, Komoly S, Beyer C. 17beta-estradiol and progesterone prevent cuprizone provoked demyelination of corpus callosum in male mice. Glia 2009; 57(8):807-14.
Romagnani P, Lasagni L, Mazzinghi B, Lazzeri E, Romagnani S. Pharmacological modulation of stem cell. Curr Med Chem 2007;14(10):1129-39.
Marin-Husstege M, Muggironi M, Raban D, Skoff RP, Casaccia-Bonnefil P. Oligodendrocyte progenitor proliferation and maturation is differentially regulated by male and female sex steroid hormones. Dev Neurosci 2004;26(2-4):245-54.
Ray R, Novotny NM, Crisostomo PR, Lahm T, Abarbanell A, Meldrum DR. Sex steroids and stem cell function. Mol Med 2008;14(7-8):493-501.
Suzuki T, Mandai M, Akimoto M, Yoshimura N, Takahashi M.The simultaneous treatment of MMP-2 stimulants in retinal transplantation enhances grafted cell migration into the host retina. Stem Cells 2006; 24(11):2406-11.
Vu TH, Werb Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev 2000; 14(17):2123-33.
Guccione M, Silbiger S, Lei J, Neugarten J. Estradiol upregulates mesangial cell MMP-2 activity via thetranscription factor AP-2. Am J Physiol Renal Physiol 2002;282(1):F164-9.
Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci U S A 1997;94(8):4080-5.
Tambuyzer BR, Bergwerf I, De Vocht N, Reekmans K,Daans J, Jorens PG, Goossens H, Ysebaert DK, Chatterjee S, Van Marck E, Berneman ZN, Ponsaerts P. Allogeneic stromal cell implantation in brain tissue leads to robust microglial activation. Immunol Cell Biol 2009;87(4):267-73.
Bergwerf I, Tambuyzer B, De Vocht N, Reekmans K, Praet J, Daans J, Chatterjee S, Pauwels P, Van der Linden A, Berneman ZN, Ponsaerts P. Recognition of cellular implants by the brain's innate immune system. ImmunolCell Biol 2011;89(4):511-6.
Sutton C, Brereton C, Keogh B, Mills KH, Lavelle EC. A crucial role for interleukin (IL)-1 in the induction of IL-17- producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 2006;203(7):1685-91.
Miljkovic D, Momcilovic M, Stojanovic I, Stosic-Grujicic S, Ramic Z, Mostarica-Stojkovic M. Astrocytes stimulate interleukin-17 and interferon-gamma production in vitro. J Neurosci Res 2007;85(16):3598-606.
Bai L, Lennon DP, Eaton V, Maier K, Caplan AI, Miller SD, Miller RH. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 2009;57(11):1192-203.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.