Stem Cell Reviews and Reports

, Volume 11, Issue 3, pp 474–486 | Cite as

Immunomodulation in Stem Cell Differentiation into Neurons and Brain Repair

  • Henning UlrichEmail author
  • Isis Cristina do Nascimento
  • Jozsef Bocsi
  • Attila TárnokEmail author


Immunomodulators regulate stem cell activity at all stages of development as well as during adulthood. Embryonic stem cell (ESC) proliferation as well as neurogenic processes during embryonic development are controlled by factors of the immune system. We review here immunophenotypic expression patterns of  different stem cell types, including ESC, neural (NSC) and tissue-specific mesenchymal stem cells (MSC), and focus on immunodulatory properties of these cells. Immune and inflammatory responses, involving actions of cytokines as well as toll-like receptor (TLR) signaling are known to affect the differentiation capacity of NSC and MSC. Secretion of pro- and anti-inflammatory messengers by MSC have been observed as the consequence of TLR and cytokine activation and promotion of differentiation into specified phenotypes. As result of augmented differentiation capacity, stem cells secrete angiogenic factors including vascular endothelial growth factor, resulting in multifactorial actions in tissue repair. Immunoregulatory properties of tissue specific adult stem cells are put into the context of possible clinical applications.


Stem cells Phenotypic marker expression Neurogenesis Immunomodulation Cytokines 



Embryonic stem cells


Hematopoietic stem cells


Mesenchymal stem cells


Neural progenitor cells


Neural stem cells



H.U. acknowledges grant support by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and the Provost’s Office for Research of the University of São Paulo, Grant number: 2011.1.9333.1.3 (NAPNA-USP), Brazil. I.C.N.’s postdoctoral research is supported by a CNPq fellowship. A.T. acknowledges grant support from the German Federal Ministry of Education and Research (BMBF 1315883; BMBF 01DN13037). J.B. acknowledges support from MaDaKos (BMBF, 16N10872, 990101-088).

Conflict of Interest

The authors declare no potential conflicts of interest.


  1. 1.
    Nery, A. A., Nascimento, I. C., Glaser, T., Bassaneze, V., Krieger, J. E., & Ulrich, H. (2013). Human mesenchymal stem cells: from immunophenotyping by flow cytometry to clinical applications. Cytometry. Part A, 83, 48–61.Google Scholar
  2. 2.
    Ardeshiry Lajimi, A., Hagh, M. F., Saki, N., Mortaz, E., Soleimani, M., & Rahim, F. (2013). Feasibility of cell therapy in multiple sclerosis: a systematic review of 83 studies. International Journal of Hematology-Oncology and Stem Cell Research, 7, 15–33.PubMedCentralPubMedGoogle Scholar
  3. 3.
    Fibbe, W. E. (2002). Mesenchymal stem cells. A potential source for skeletal repair. Annals of the Rheumatic Diseases, 6, ii29–ii31.Google Scholar
  4. 4.
    Lo, K. C., Chuang, W. W., & Lamb, D. J. (2003). Stem cell research: the facts, the myths and the promises. The Journal of Urology, 170, 2453–2458.PubMedGoogle Scholar
  5. 5.
    Aoshima, K., Baba, A., Makino, Y., & Okada, Y. (2013). Establishment of alternative culture method for spermatogonial stem cells using knockout serum replacement. PLoS One, 8, e77715.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., & Jones, J. M. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282, 1145–1147.PubMedGoogle Scholar
  7. 7.
    Reubinoff, B. E., Pera, M. F., Fong, C. Y., Trounson, A., & Bongso, A. (2000). Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nature Biotechnology, 18, 399–404.PubMedGoogle Scholar
  8. 8.
    Chen, L., & Daley, G. Q. (2008). Molecular basis of pluripotency. Human Molecular Genetics, 17, R23–R27.PubMedGoogle Scholar
  9. 9.
    Rogers, M. B., Hosler, B. A., & Gudas, L. J. (1991). Specific expression of a retinoic acid-regulated, zinc-finger gene, Rex-1, in preimplantation embryos, trophoblast and spermatocytes. Development, 113, 815–824.PubMedGoogle Scholar
  10. 10.
    Shi, W., Wang, H., Pan, G., Geng, Y., Guo, Y., & Pei, D. (2006). Regulation of the pluripotency marker Rex-1 by Nanog and Sox2. The Journal of Biological Chemistry, 281, 23319–23325.PubMedGoogle Scholar
  11. 11.
    Guallar, D., Pérez-Palacios, R., Climent, M., Martínez-Abadía, I., Larraga, A., Fernández-Juan, M., et al. (2012). Expression of endogenous retroviruses is negatively regulated by the pluripotency marker Rex1/Zfp42. Nucleic Acids Research, 40, 8993–9007.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Tondeur, S., Assou, S., Nadal, L., Hamamah, S., & De Vos, J. (2008). Biology and potential of human embryonic stem cells. Annales de Biologie Clinique, 66, 241–247.PubMedGoogle Scholar
  13. 13.
    Arduini, B. L., & Brivanlou, A. H. (2012). Modulation of FOXD3 activity in human embryonic stem cells directs pluripotency and paraxial mesoderm fates. Stem Cells, 30, 2188–2198.PubMedGoogle Scholar
  14. 14.
    Zhang, X., Rielland, M., Yalcin, S., & Ghaffari, S. (2011). Regulation and function of FoxO transcription factors in normal and cancer stem cells: what have we learned? Current Drug Targets, 12, 1267–1283.PubMedGoogle Scholar
  15. 15.
    Draper, J. S., Pigott, C., Thomson, J. A., & Andrews, P. W. (2002). Surface antigens of human embryonic stem cells: changes upon differentiation in culture. Journal of Anatomy, 200, 249–258.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Guest, D. J., & Allen, W. R. (2007). Expression of cell-surface antigens and embryonic stem cell pluripotency genes in equine blastocysts. Stem Cells and Development, 16, 789–796.PubMedGoogle Scholar
  17. 17.
    Rao, R. R., Johnson, A. V., & Stice, S. L. (2007). Cell surface markers in human embryonic stem cells. Methods in Molecular Biology, 407, 51–61.PubMedGoogle Scholar
  18. 18.
    Nagano, K., Yoshida, Y., & Isobe, T. (2008). Cell surface biomarkers of embryonic stem cells. Proteomics, 8, 4025–4035.PubMedGoogle Scholar
  19. 19.
    Li, L., Bennett, S. A., & Wang, L. (2012). Role of E-cadherin and other cell adhesion molecules in survival and differentiation of human pluripotent stem cells. Cell Adhesion & Migration, 6, 59–70.Google Scholar
  20. 20.
    Zhao, W., Ji, X., Zhang, F., Li, L., & Ma, L. (2012). Embryonic stem cell markers. Molecules, 17, 6196–6236.PubMedGoogle Scholar
  21. 21.
    O’Connor, M. D., Kardel, M. D., Iosfina, I., Youssef, D., Lu, M., Li, M. M., et al. (2008). Alkaline phosphatase-positive colony formation is a sensitive, specific, and quantitative indicator of undifferentiated human embryonic stem cells. Stem Cells, 26, 1109–1116.PubMedGoogle Scholar
  22. 22.
    Hoffmeyer, K., Raggioli, A., Rudloff, S., Anton, R., Hierholzer, A., Del Valle, I., et al. (2012). Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science, 336, 1549–1554.PubMedGoogle Scholar
  23. 23.
    Simerman, A. A., Perone, M. J., Gimeno, M. L., Dumesic, D. A., & Chazenbalk, G. D. (2014). A mystery unraveled: nontumorigenic pluripotent stem cells in human adult tissues. Expert Opinion on Biological Therapy, 14, 917–929.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Kucia, M. J., Wysoczynski, M., Wu, W., Zuba-Surma, E. K., Ratajczak, J., & Ratajczak, M. Z. (2008). Evidence that very small embryonic-like stem cells are mobilized into peripheral blood. Stem Cells, 26, 2083–2092.PubMedGoogle Scholar
  25. 25.
    Ratajczak, M. Z., Zuba-Surma, E. K., Shin, D. M., Ratajczak, J., & Kucia, M. (2008). Very small embryonic-like (VSEL) stem cells in adult organs and their potential role in rejuvenation of tissues and longevity. Experimental Gerontology, 43, 1009–1017.PubMedCentralPubMedGoogle Scholar
  26. 26.
    De Coppi, P., Bartsch, G., Jr., Siddiqui, M. M., Xu, T., Santos, C. C., Perin, L., et al. (2007). Isolation of amniotic stem cell lines with potential for therapy. Nature Biotechnology, 25, 100–106.PubMedGoogle Scholar
  27. 27.
    Pappa, K. I., & Anagnou, N. P. (2009). Novel sources of fetal stem cells: where do they fit on the developmental continuum? Regenerative Medicine, 4, 423–433.PubMedGoogle Scholar
  28. 28.
    Nichols, J., & Smith, A. (2009). Naive and primed pluripotent states. Cell Stem Cell, 4, 487–492.PubMedGoogle Scholar
  29. 29.
    Obokata, H., Wakayama, T., Sasai, Y., Kojima, K., Vacanti, M. P., Niwa, H., et al. (2014). Stimulus-triggered fate conversion of somatic cells into pluripotency. Nature, 505, 641–647.PubMedGoogle Scholar
  30. 30.
    Keller, R. (2005). Cell migration during gastrulation. Current Opinion in Cell Biology, 17, 533–541.PubMedGoogle Scholar
  31. 31.
    Sumi, T., Tsuneyoshi, N., Nakatsuji, N., & Suemori, H. (2008). Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/beta-catenin, Activin/Nodal and BMP signaling. Development, 135, 2969–2979.PubMedGoogle Scholar
  32. 32.
    Gadue, P., Huber, T. L., Nostro, M. C., Kattman, S., & Keller, G. M. (2005). Germ layer induction from embryonic stem cells. Experimental Hematology, 33, 955–964.PubMedGoogle Scholar
  33. 33.
    Williams, M., Burdsal, C., Periasamy, A., Lewandoski, M., & Sutherland, A. (2012). Mouse primitive streak forms in situ by initiation of epithelial to mesenchymal transition without migration of a cell population. Developmental Dynamics: An Official Publication of the American Association of Anatomists, 241, 270–283.Google Scholar
  34. 34.
    Thomson, M., Liu, S. J., Zou, L. N., Smith, Z., Meissner, A., & Ramanathan, S. (2011). Pluripotency factors in embryonic stem cells regulate differentiation into germ layers. Cell, 145, 875–889.PubMedGoogle Scholar
  35. 35.
    Hatano, S. Y., Tada, M., Kimura, H., Yamaguchi, S., Kono, T., Nakano, T., et al. (2005). Pluripotential competence of cells associated with Nanog activity. Mechanisms of Development, 122, 67–79.PubMedGoogle Scholar
  36. 36.
    Kanai-Azuma, M., Kanai, Y., Gad, J. M., Tajima, Y., Taya, C., Kurohmaru, M., et al. (2002). Depletion of definitive gut endoderm in Sox17-null mutant mice. Development, 129, 2367–2379.PubMedGoogle Scholar
  37. 37.
    Kim, P. T., & Ong, C. J. (2012). Differentiation of definitive endoderm from mouse embryonic stem cells. Results and Problems in Cell Differentiation, 55, 303–319.PubMedGoogle Scholar
  38. 38.
    Suter, D. M., Tirefort, D., Julien, S., & Krause, K. H. (2009). A Sox1 to Pax6 switch drives neuroectoderm to radial glia progression during differentiation of mouse embryonic stem cells. Stem Cells, 27, 49–58.PubMedGoogle Scholar
  39. 39.
    Evseenko, D., Zhu, Y., Schenke-Layland, K., Kuo, J., Latour, B., Ge, S., et al. (2010). Mapping the first stages of mesoderm commitment during differentiation of human embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 107, 13742–13747.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Brignier, A. C., & Gewirtz, A. M. (2010). Embryonic and adult stem cell therapy. The Journal of Allergy and Clinical Immunology, 125, S336–S344.PubMedGoogle Scholar
  41. 41.
    Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126, 663–676.PubMedGoogle Scholar
  42. 42.
    Beltrão-Braga, P. C., Pignatari, G. C., Russo, F. B., Fernandes, I. R., & Muotri, A. R. (2013). In-a-dish: induced pluripotent stem cells as a novel model for human diseases. Cytometry. Part A, 83, 11–17.Google Scholar
  43. 43.
    Tárnok, A., Ulrich, H., & Bocsi, J. (2010). Phenotypes of stem cells from diverse origin. Cytometry. Part A, 77, 6–10.Google Scholar
  44. 44.
    Zimmerlin, L., Donnenberg, V. S., Rubin, J. P., & Donnenberg, A. D. (2013). Mesenchymal markers on human adipose stem/progenitor cells. Cytometry. Part A, 83, 134–140.Google Scholar
  45. 45.
    Han, B., Li, J., Li, Z., Guo, L., Wang, S., Liu, P., & Wu, Y. (2013). Trichostatin A stabilizes the expression of pluripotent genes in human mesenchymal stem cells during ex vivo expansion. PLoS One, 8, e81781.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Mundra, V., Gerling, I. C., & Mahato, R. I. (2013). Mesenchymal stem cell-based therapy. Molecular Pharmaceutics, 10, 77–89.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Pierelli, L., Scambia, G., Fattorossi, A., Bonanno, G., Battaglia, A., Rumi, C., et al. (1998). Functional, phenotypic and molecular characterization of cytokine low-responding circulating CD34+ haemopoietic progenitors. British Journal of Haematology, 102, 1139–1150.PubMedGoogle Scholar
  48. 48.
    Mayle, A., Luo, M., Jeong, M., & Goodell, M. A. (2013). Flow cytometry analysis of murine hematopoietic stem cells. Cytometry. Part A, 83, 27–37.Google Scholar
  49. 49.
    Bottai, D., Fiocco, R., Gelain, F., Defilippis, L., Galli, R., Gritti, A., & Vescovi, L. A. (2003). Neural stem cells in the adult nervous system. Journal of Hematotherapy & Stem Cell Research, 12, 655–670.Google Scholar
  50. 50.
    Oliveira, S. L., Pillat, M. M., Cheffer, A., Lameu, C., Schwindt, T. T., & Ulrich, H. (2013). Functions of neurotrophins and growth factors in neurogenesis and brain repair. Cytometry. Part A, 83, 76–89.Google Scholar
  51. 51.
    Hemmati, H. D., Nakano, I., Lazareff, J. A., Masterman-Smith, M., Geschwind, D. H., Bronner-Fraser, M., & Kornblum, H. I. (2003). Cancerous stem cells can arise from pediatric brain tumors. Proceedings of the National Academy of Sciences of the United States of America, 100, 15178–15183.PubMedCentralPubMedGoogle Scholar
  52. 52.
    Nakatani, Y., Yanagisawa, M., Suzuki, Y., & Yu, R. K. (2010). Characterization of GD3 ganglioside as a novel biomarker of mouse neural stem cells. Glycobiology, 20, 78–86.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Li, H., Jin, G., Qin, J., Tian, M., Shi, J., Yang, W., et al. (2011). Characterization and identification of Sox2+ radial glia cells derived from rat embryonic cerebral cortex. Histochemistry and Cell Biology, 136, 515–526.PubMedGoogle Scholar
  54. 54.
    Sordi, V., & Piemonti, L. (2011). Therapeutic plasticity of stem cells and allograft tolerance. Cytotherapy, 13, 647–660.PubMedGoogle Scholar
  55. 55.
    Martino, G., & Pluchino, S. (2006). The therapeutic potential of neural stem cells. Nature Reviews. Neuroscience, 7, 395–406.PubMedGoogle Scholar
  56. 56.
    Moonen, J. R., Harmsen, M. C., & Krenning, G. (2012). Cellular plasticity: the good, the bad, and the ugly? Microenvironmental influences on progenitor cell therapy. Canadian Journal of Physiology and Pharmacology, 90, 275–285.PubMedGoogle Scholar
  57. 57.
    Emborg, M. E., Zhang, Z., Joers, V., Brunner, K., Bondarenko, V., Ohshima, S., & Zhang, S. C. (2013). Intracerebral transplantation of differentiated human embryonic stem cells to hemiparkinsonian monkeys. Cell Transplantation, 22, 83831–83838.Google Scholar
  58. 58.
    Aikawa, H., Tamai, M., Mitamura, K., Itmainati, F., Barber, G. N., & Tagawa, Y. I. (2014). Innate immunity in an in vitro murine blastocyst model using embryonic and trophoblast stem cells. Journal of Bioscience and Bioengineering, 117, 358–365.PubMedGoogle Scholar
  59. 59.
    Bilbo, S. D., & Schwarz, J. M. (2012). The immune system and developmental programming of brain and behavior. Frontiers in Neuroendocrinology, 33, 267–286.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Trujillo, C. A., Schwindt, T. T., Martins, A. H., Alves, J. M., Mello, L. E., & Ulrich, H. (2009). Novel perspectives of neural stem cell differentiation: from neurotransmitters to therapeutics. Cytometry. Part A, 75, 38–53.Google Scholar
  61. 61.
    Guillemot, F. (2007). Cell fate specification in the mammalian telencephalon. Progress in Neurobiology, 83, 37–52.PubMedGoogle Scholar
  62. 62.
    Kriegstein, A., & Alvarez-Buylla, A. (2009). The glial nature of embryonic and adult neural stem cells. Annual Review of Neuroscience, 32, 149–184.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Marthiens, V., Kazanis, I., Moss, L., Long, K., & Ffrench-Constant, C. (2010). Adhesion molecules in the stem cell niche–more than just staying in shape? Journal of Cell Science, 123, 1613–1622.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Wang, C. C., Wu, C. H., Shieh, J. Y., & Wen, C. Y. (2002). Microglial distribution and apoptosis in fetal rat brain. Brain Research. Developmental Brain Research, 139, 337–342.PubMedGoogle Scholar
  65. 65.
    Cunningham, C. L., Martínez-Cerdeño, V., & Noctor, S. C. (2013). Microglia regulate the number of neural precursor cells in the developing cerebral cortex. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 33, 4216–4233.Google Scholar
  66. 66.
    Wu, H. M., Zhang, L. F., Ding, P. S., Liu, Y. J., Wu, X., Zhou, J. N. (2014). Microglial activation mediates host neuronal survival induced by neural stem cells. Journal of Cellular and Molecular Medicine.Google Scholar
  67. 67.
    Boulanger, L. M. (2009). Immune proteins in brain development and synaptic plasticity. Neuron, 64, 93–109.PubMedGoogle Scholar
  68. 68.
    Bonfanti, L., & Peretto, P. (2011). Adult neurogenesis in mammals—a theme with many variations. The European Journal of Neuroscience, 34, 930–950.PubMedGoogle Scholar
  69. 69.
    van den Berge, S. A., van Strien, M. E., & Hol, E. M. (2013). Resident adult neural stem cells in Parkinson’s disease–the brain’s own repair system? European Journal of Pharmacology, 719, 117–127.PubMedGoogle Scholar
  70. 70.
    Hickey, W. F. (1999). Leukocyte traffic in the central nervous system: the participants and their roles. Seminars in Immunology, 11, 125–137.PubMedGoogle Scholar
  71. 71.
    Whitney, N. P., Eidem, T. M., Peng, H., Huang, Y., & Zheng, J. C. (2009). Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders. Journal of Neurochemistry, 108, 1343–1359.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Tian, L., Rauvala, H., & Gahmberg, C. G. (2009). Neuronal regulation of immune responses in the central nervous system. Trends in Immunology, 30, 91–99.PubMedGoogle Scholar
  73. 73.
    Northrop, N. A., & Yamamoto, B. K. (2011). Neuroimmune pharmacology from a neuroscience perspective. Journal of Neuroimmune Pharmacology: The Official Journal of the Society on NeuroImmune Pharmacology, 6, 10–19.Google Scholar
  74. 74.
    Gonzalez-Perez, O., Garcia-Verdugo, J. M., Quinones-Hinojosa, A., Luquin, S., Gudino-Cabrera, G., & Gonzalez-Castaneda, R. E. (2012). Neural stem cells in the adult brain: from benchside to clinic. Stem Cells International, 2012, 378356.PubMedCentralPubMedGoogle Scholar
  75. 75.
    Ourednik, J., Ourednik, V., Lynch, W. P., Schachner, M., & Snyder, E. Y. (2002). Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nature Biotechnology, 20, 1103–1110.PubMedGoogle Scholar
  76. 76.
    Pluchino, S., Quattrini, A., Brambilla, E., Gritti, A., Salani, G., Dina, G., et al. (2003). Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature, 422, 688–694.PubMedGoogle Scholar
  77. 77.
    Pluchino, S., Zanotti, L., Rossi, B., Brambilla, E., Ottoboni, L., Salani, G., & Martinello, M. (2005). Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature, 436, 266–271.PubMedGoogle Scholar
  78. 78.
    Martino, G., & Pluchino, S. (2006). The therapeutic potential of neural stem cells. Nature Reviews. Neuroscience, 7, 395–406.PubMedGoogle Scholar
  79. 79.
    Martino, G., Butti, E., & Bacigaluppi, M. (2014). Neurogenesis or non-neurogenesis: that is the question. The Journal of Clinical Investigation, 124, 970–973.PubMedCentralPubMedGoogle Scholar
  80. 80.
    Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Greenberg, N., Cohen, H., et al. (2006). Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nature Neuroscience, 9, 268–275.PubMedGoogle Scholar
  81. 81.
    Yirmiya, R., & Goshen, I. (2011). Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain, Behavior, and Immunity, 25, 181–213.PubMedGoogle Scholar
  82. 82.
    Mishra, S. K., Braun, N., Shukla, V., Füllgrabe, M., Schomerus, C., Korf, H. W., et al. (2006). Extracellular nucleotide signaling in adult neural stem cells: synergism with growth factor-mediated cellular proliferation. Development, 133, 675–684.PubMedGoogle Scholar
  83. 83.
    Trujillo, C. A., Negraes, P. D., Schwindt, T. T., Lameu, C., Carromeu, C., Muotri, A. R., et al. (2012). Kinin-B2 receptor activity determines the differentiation fate of neural stem cells. The Journal of Biological Chemistry, 287, 44046–44061.PubMedCentralPubMedGoogle Scholar
  84. 84.
    Schulze-Topphoff, U., Prat, A., Bader, M., Zipp, F., & Aktas, O. (2008). Roles of the kallikrein/kinin system in the adaptive immune system. International Immunopharmacology, 8, 155–160.PubMedGoogle Scholar
  85. 85.
    Thornton, E., Ziebell, J. M., Leonard, A. V., & Vink, R. (2010). Kinin receptor antagonists as potential neuroprotective agents in central nervous system injury. Molecules, 15, 6598–6618.PubMedGoogle Scholar
  86. 86.
    Noda, M., Sasaki, K., Ifuku, M., & Wada, K. (2007a). Multifunctional effects of bradykinin on glial cells in relation to potential anti-inflammatory effects. Neurochemistry International, 51, 185–191.PubMedGoogle Scholar
  87. 87.
    Noda, M., Kariura, Y., Pannasch, U., Nishikawa, K., Wang, L., Seike, T., et al. (2007b). Neuroprotective role of bradykinin because of the attenuation of pro-inflammatory cytokine release from activated microglia. Journal of Neurochemistry, 101, 397–410.PubMedGoogle Scholar
  88. 88.
    Sarit, B. S., Lajos, G., Abraham, D., Ron, A., & Sigal, F. B. (2012). Inhibitory role of kinins on microglial nitric oxide and tumor necrosis factor-a production. Peptides, 35, 172–181.PubMedGoogle Scholar
  89. 89.
    Ferrari, D., Gulinelli, S., Salvestrini, V., Lucchetti, G., Zini, R., Manfredini, R., et al. (2011). Purinergic stimulation of human mesenchymal stem cells potentiates their chemotactic response to CXCL12 and increases the homing capacity and production of proinflammatory cytokines. Experimental Hematology, 39, 360–374.PubMedGoogle Scholar
  90. 90.
    Boccazzi, M., Rolando, C., Abbracchio, M. P., Buffo, A., & Ceruti, S. (2014). Purines regulate adult brain subventricular zone cell functions: contribution of reactive astrocytes. Glia, 62, 428–439.PubMedGoogle Scholar
  91. 91.
    Wong, G., Goldshmit, Y., & Turnley, A. M. (2004). Interferon-gamma but not TNF alpha promotes neuronal differentiation and neurite outgrowth of murine adult neural stem cells. Experimental Neurology, 187, 171–177.PubMedGoogle Scholar
  92. 92.
    Zheng, M., Liu, J., Ruan, Z., Tian, S., Ma, Y., Zhu, J., & Li, G. (2013). Intrahippocampal injection of Ab1-42 inhibits neurogenesis and down-regulates IFN-g and NF-kB expression in hippocampus of adult mouse brain. Amyloid: The International Journal of Experimental and Clinical Investigation: The Official Journal of the International Society of Amyloidosis, 20, 13–20.Google Scholar
  93. 93.
    Hirsch, M., Knight, J., Tobita, M., Soltys, J., Panitch, H., & Mao-Draayer, Y. (2009). The effect of interferon-beta on mouse neural progenitor cell survival and differentiation. Biochemical and Biophysical Research Communications, 388, 181–186.PubMedGoogle Scholar
  94. 94.
    Cuadrado, E., Jansen, M. H., Anink, J., De Filippis, L., Vescovi, A. L., Watts, C., et al. (2013). Chronic exposure of astrocytes to interferon-a reveals molecular changes related to Aicardi-Goutieres syndrome. Brain: A Journal of Neurology, 136, 245–258.Google Scholar
  95. 95.
    Ryan, S. M., O’Keeffe, G. W., O’Connor, C., Keeshan, K., & Nolan, Y. M. (2013). Negative regulation of TLX by IL-1β correlates with an inhibition of adult hippocampal neural precursor cell proliferation. Brain, Behavior, and Immunity, 33, 7–13.PubMedGoogle Scholar
  96. 96.
    Green, H. F., Treacy, E., Keohane, A. K., Sullivan, A. M., O’Keeffe, G. W., & Nolan, Y. M. (2012). A role for interleukin-1β in determining the lineage fate of embryonic rat hippocampal neural precursor cells. Molecular and Cellular Neurosciences, 49, 311–321.PubMedGoogle Scholar
  97. 97.
    Nakanishi, M., Niidome, T., Matsuda, S., Akaike, A., Kihara, T., & Sugimoto, H. (2007). Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells. The European Journal of Neuroscience, 25, 649–658.PubMedGoogle Scholar
  98. 98.
    Erta, M., Quintana, A., & Hidalgo, J. (2012). Interleukin-6, a major cytokine in the central nervous system. International Journal of Biological Sciences, 8, 1254–1266.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Liu, Y. P., Lin, H. I., & Tzeng, S. F. (2005). Tumor necrosis factor-alpha and interleukin-18 modulate neuronal cell fate in embryonic neural progenitor culture. Brain Research, 1054, 152–158.PubMedGoogle Scholar
  100. 100.
    Perez-Asensio, F. J., Perpiñá, U., Planas, A. M., & Pozas, E. (2013). Interleukin-10 regulates progenitor differentiation and modulates neurogenesis in adult brain. Journal of Cell Science, 126, 4208–4219.PubMedGoogle Scholar
  101. 101.
    Zhu, Y., Matsumoto, T., Mikami, S., Nagasawa, T., & Murakami, F. (2009). SDF1/CXCR4 signalling regulates two distinct processes of precerebellar neuronal migration and its depletion leads to abnormal pontine nuclei formation. Development, 136, 1919–1928.PubMedGoogle Scholar
  102. 102.
    Schwartz, C. M., Tavakoli, T., Jamias, C., Park, S. S., Maudsley, S., Martin, B., et al. (2012). Stromal factors SDF1α, sFRP1, and VEGFD induce dopaminergic neuron differentiation of human pluripotent stem cells. Journal of Neuroscience Research, 90, 1367–1381.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Yang, S., Edman, L. C., Sánchez-Alcañiz, J. A., Fritz, N., Bonilla, S., Hecht, J., et al. (2013). Cxcl12/Cxcr4 signaling controls the migration and process orientation of A9-A10 dopaminergic neurons. Development, 140, 4554–4564.PubMedGoogle Scholar
  104. 104.
    Iosif, R. E., Ekdahl, C. T., Ahlenius, H., Pronk, C. J., Bonde, S., Kokaia, Z., et al. (2006). Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 26, 9703–9712.Google Scholar
  105. 105.
    Ji, R., Tian, S., Lu, H. J., Lu, Q., Zheng, Y., Wang, X., et al. (2013). TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation. The Journal of Immunology: Official Journal of the American Association of Immunologists, 191, 6165–6177.Google Scholar
  106. 106.
    Wu, R., Tang, Y., Zang, W., Wang, Y., Li, M., Du, Y., et al. (2014). MicroRNA-128 regulates the differentiation of rat bone mesenchymal stem cells into neuron-like cells by Wnt signaling. Molecular and Cellular Biochemistry, 387, 151–158.PubMedGoogle Scholar
  107. 107.
    Zhang, X., Nan, Y., Wang, H., Chen, J., Wang, N., Xie, J., et al. (2013). Model microgravity enhances endothelium differentiation of mesenchymal stem cells. Die Naturwissenschaften, 100, 125–133.PubMedGoogle Scholar
  108. 108.
    Chen, P. M., Yen, M. L., Liu, K. J., Sytwu, H. K., & Yen, B. L. (2011). Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells. Journal of Biomedical Science, 18, 49.PubMedCentralPubMedGoogle Scholar
  109. 109.
    De Miguel, M. P., Fuentes-Julián, S., Blázquez-Martínez, A., Pascual, C. Y., Aller, M. A., Arias, J., & Arnalich-Montiel, F. (2012). Immunosuppressive properties of mesenchymal stem cells: advances and applications. Current Molecular Medicine, 12, 574–591.PubMedGoogle Scholar
  110. 110.
    Dazzi, F., & Krampera, M. (2011). Mesenchymal stem cells and autoimmune diseases. Best Practice & Research. Clinical Haematology, 24, 49–57.Google Scholar
  111. 111.
    Cuerquis, J., Romieu-Mourez, R., François, M., Routy, J. P., Young, Y. K., Zhao, J., & Eliopoulos, N. (2014). Human mesenchymal stromal cells transiently increase cytokine production by activated T cells before suppressing T-cell proliferation: effect of interferon-γ and tumor necrosis factor-α stimulation. Cytotherapy, 16, 191–202.PubMedGoogle Scholar
  112. 112.
    Schurgers, E., Kelchtermans, H., Mitera, T., Geboes, L., & Matthys, P. (2010). Discrepancy between the in vitro and in vivo effects of murine mesenchymal stem cells on T-cell proliferation and collagen-induced arthritis. Arthritis Research & Therapy, 12, R31.Google Scholar
  113. 113.
    Beyth, S., Borovsky, Z., Mevorach, D., Liebergall, M., Gazit, Z., Aslan, H., et al. (2005). Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood, 105, 2214–2219.PubMedGoogle Scholar
  114. 114.
    Bai, L., Lennon, D. P., Eaton, V., Maier, K., Caplan, A. I., Miller, S. D., & Miller, R. H. (2009). Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia, 57, 1192–1203.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Duijvestein, M., Wildenberg, M. E., Welling, M. M., Hennink, S., Molendijk, I., van Zuylen, L., et al. (2011). Pretreatment with interferon-γ enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis. Stem Cells, 29, 1549–1558.PubMedGoogle Scholar
  116. 116.
    Xiao, J., Zhang, C., Zhang, Y., Zhang, X., Zhao, J., Liang, J., et al. (2012). Transplantation of adipose-derived mesenchymal stem cells into a murine model of passive chronic immune thrombocytopenia. Transfusion, 52, 2551–2558.PubMedGoogle Scholar
  117. 117.
    Zappia, E., Casazza, S., Pedemonte, E., Benvenuto, F., Bonanni, I., Gerdoni, E., et al. (2005). Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood, 106, 1755–1761.PubMedGoogle Scholar
  118. 118.
    Gerdoni, E., Gallo, B., Casazza, S., Musio, S., Bonanni, I., & Pedemonte, E. (2007). Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Annals of Neurology, 61, 219–227.PubMedGoogle Scholar
  119. 119.
    Benvenuto, F., Ferrari, S., Gerdoni, E., Gualandi, F., Frassoni, F., Pistoia, V., et al. (2007). Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem Cells, 25, 1753–1760.PubMedGoogle Scholar
  120. 120.
    Zhou, Y., Day, A., Haykal, S., Keating, A., & Waddell, T. K. (2013). Mesenchymal stromal cells augment CD4+ and CD8+ T-cell proliferation through a CCL2 pathway. Cytotherapy, 15, 1195–1207.PubMedGoogle Scholar
  121. 121.
    Liotta, F., Angeli, R., Cosmi, L., Filì, L., Manuelli, C., Frosali, F., et al. (2008). Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells, 26, 279–289.PubMedGoogle Scholar
  122. 122.
    Thakur, R. S., Tousif, S., Awasthi, V., Sanyal, A., Atul, P. K., Punia, P., & Das, J. (2013). Mesenchymal stem cells play an important role in host protective immune responses against malaria by modulating regulatory T cells. European Journal of Immunology, 43, 2070–2077.PubMedGoogle Scholar
  123. 123.
    Sun, J., Zhou, W., Ma, D., & Yang, Y. (2010). Endothelial cells promote neural stem cell proliferation and differentiation associated with VEGF activated Notch and Pten signaling. Developmental Dynamics: An Official Publication of the American Association of Anatomists, 239, 2345–2353.Google Scholar
  124. 124.
    Chen, J., Zhang, Z. G., Li, Y., Wang, L., Xu, Y. X., Gautam, S. C., et al. (2003). Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circulation Research, 92, 692–699.PubMedGoogle Scholar
  125. 125.
    Taguchi, A., Soma, T., Tanaka, H., Kanda, T., Nishimura, H., Yoshikawa, H., et al. (2004). Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. The Journal of Clinical Investigation, 114, 330–338.PubMedCentralPubMedGoogle Scholar
  126. 126.
    Melief, S. M., Zwaginga, J. J., Fibbe, W. E., & Roelofs, H. (2013). Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Translational Medicine, 2, 455–463.PubMedCentralPubMedGoogle Scholar
  127. 127.
    Waterman, R. S., Tomchuck, S. L., Henkle, S. L., & Betancourt, A. M. (2010). A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PLoS One, 5, e10088.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Departamento de Bioquímica, Instituto de QuímicaUniversidade de São PauloSão PauloBrazil
  2. 2.Heart Center Leipzig, Department of Pediatric Cardiology, Cardiac CentreUniversity of LeipzigLeipzigGermany
  3. 3.Translational Centre for Regenerative Medicine (TRM)University of LeipzigLeipzigGermany

Personalised recommendations