Open Access Open Access  Restricted Access Subscription or Fee Access

Are there endogenous stem cells in the spinal cord?

M. Ferrucci, L. Ryskalin, C. L. Busceti, A. Gaglione, F. Biagioni, F. Fornai


Neural progenitor cells (NPC) represent the stem-like niche of the central nervous system that maintains a regenerative potential also in the adult life. Despite NPC in the brain are well documented, the presence of NPC in the spinal cord has been controversial for a long time. This is due to a scarce activity of NPC within spinal cord, which also makes difficult their identification. The present review recapitulates the main experimental studies, which provided evidence for the occurrence of NPC within spinal cord, with a special emphasis on spinal cord injury and amyotrophic lateral sclerosis. By using experimental models, here we analyse the site-specificity, the phenotype and the main triggers of spinal cord NPC. Moreover, data are reported on the effect of specific neurogenic stimuli on these spinal cord NPC in an effort to comprehend the endogenous neurogenic potential of this stem cell niche.

Full Text:



Abbaszadeh H.A., Tiraihi T., Noori-Zadeh A., Delshad A.R., Sadeghizade M., Taheri T. Human ciliary neurotrophic factor-overexpressing stable bone marrow stromal cells in the treatment of a rat model of traumatic spinal cord injury. Cytotherapy, 17: 912-921, 2015.

Abematsu M., Tsujimura K., Yamano M., Saito M., Kohno K., Kohyama J., Namihira M., Komiya S., Nakashima K. Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury. J. Clin. Invest., 120: 3255-3266, 2010.

Adrian E.K. Jr and Walker B.E. Incorporation of thymidine-H3 by cells in normal and injured mouse spinal cord. J. Neuropathol. Exp. Neurol., 21: 597-609, 1962.

Adrian E.K. Jr., Williams M.G. Cell proliferation in injured spinal cord. An electron microscopic study. J. Comp. Neurol., 151: 1-24, 1973.

Arvidsson A., Collin T., Kirik D., Kokaia Z., Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med., 8: 963-970, 2002.

Awad B.I., Carmody M.A., Steinmetz M.P. Potential role of growth factors in the management of spinal cord injury. World Neurosurg., 83: 120-131, 2015.

Bang W.S., Kim K.T., Cho D.C., Kim H.J., Sung J.K. Valproic Acid increases expression of neuronal stem/progenitor cell in spinal cord injury. J. Korean Neurosurg. Soc., 54: 8-13, 2013.

Banker B.Q. The pathology of the motor neuron diseases. pp. 2031-2066. In: Engel A.G., Banker B.Q. (Eds.) Myology. New York, McGraw-Hill, 1986.

Barnabé-Heider F., Göritz C., Sabelström H., Takebayashi H., Pfrieger F.W., Meletis K., Frisén J. Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell, 7: 470-482, 2010.

Batista C.E., Mariano E.D., Marie S.K., Teixeira M.J., Morgalla M., Tatagiba M., Li J., Lepski G. Stem cells in neurology-current perspectives. Arq. Neuropsiquiatr., 72: 457-465, 2014.

Benner E.J., Luciano D., Jo R., Abdi K., Paez-Gonzalez P., Sheng H., Warner D.S., Liu C., Eroglu C., Kuo C.T. Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature, 497: 369-373, 2013.

Bernier P.J., Bedard A., Vinet J., Levesque M., Parent A. Newly generated neurons in the amygdala and adjoining cortex of adult primates. Proc. Natl. Acad. Sci. USA, 99: 11464-11469, 2002.

Bifari F., Decimo I., Chiamulera C., Bersan E., Malpeli G., Johansson J., Lisi V., Bonetti B., Fumagalli G., Pizzolo G., Krampera M. Novel stem/progenitor cells with neuronal differentiation potential reside in the leptomeningeal niche. J. Cell Mol. Med., 13: 3195- 3208, 2009.

Blesch A., Yang H., Weidner N., Hoang A., Otero D. Axonal responses to cellularly delivered NT-4/5 after spinal cord injury. Mol. Cell Neurosci., 27: 190-201, 2004.

Boyce V.S., Mendell L.M. Neurotrophins and spinal circuit function. Front. Neural Circuits., 8: 59, 2014.

Brock J.H., Graham L., Staufenberg E., Collyer E., Koffler J., Tuszynski M.H. Bone Marrow Stromal Cell Intraspinal Transplants Fail to Improve Motor Outcomes in a Severe Model of Spinal Cord Injury. J. Neurotrauma, 33: 1103-1114, 2016.

Bruni J.E. Ependyma of the central canal of the rat spinal cord: A light and transmission electron microscopic study. J. Anat., 152: 55-70, 1987.

Buffo A., Rite I., Tripathi P., Lepier A., Colak D., Horn A.P., Mori T., Götz M. Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain. Proc. Natl. Acad. Sci. USA, 105: 3581-3586, 2008.

Burda J.E., Sofroniew M.V. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron, 81: 229-248, 2014.

Calderó J., Brunet N., Tarabal O., Piedrafita L., Hereu M., Ayala V., Esquerda J.E. Lithium prevents excitotoxic cell death of motoneurons in organotypic slice cultures of spinal cord. Neuroscience, 165: 1353-1369, 2010.

Chen G., Huang L.D., Jiang Y.M., Manji H.K. The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J. Neurochem., 72: 1327-1330, 1999.

Chen G., Rajkowska G., Du F., Seraji-Bozorgzad N., Manji H.K. Enhancement of hippocampal neurogenesis by lithium. J. Neurochem., 75: 1729-1734, 2000.

Cheriyan T., Ryan D.J., Weinreb J.H., Cheriyan J., Paul J.C., Lafage V., Kirsch T., Errico T.J. Spinal cord injury models: A review. Spinal Cord, 52: 588-595, 2014.

Chi L., Gan L., Luo C., Lien L., Liu R. Temporal response of neural progenitor cells to disease onset and progression in amyotrophic lateral sclerosis-like transgenic mice. Stem Cells Dev., 16: 579-588, 2007.

Chi L., Ke Y., Luo C., Li B., Gozal D., Kalyanaraman B., Liu R. Motor neuron degeneration promotes neural progenitor cell proliferation, migration, and neurogenesis in the spinal cords of amyotrophic lateral sclerosis mice. Stem Cells, 24: 34-43, 2006.

Chiu C.T., Wang Z., Hunsberger J.G., Chuang D.M. Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharmacol. Rev., 65: 105-142, 2013.

Choi C.I., Lee Y.D., Kim H., Kim S.H., Suh-Kim H., Kim S.S. Neural induction with neurogenin 1 enhances the therapeutic potential of mesenchymal stem cells in an ALS mouse model. Cell Transplant., 22: 855-870, 2013.

Chung H.J., Chung W.H., Lee J.H., Chung D.J., Yang W.J., Lee A.J., Choi C.B., Chang H.S., Kim D.H., Suh H.J., Lee D.H., Hwang S.H., Do S.H., Kim H.Y. Expression of neurotrophic factors in injured spinal cord after transplantation of human-umbilical cord blood stem cells in rats. J. Vet. Sci., 17: 97-102, 2016.

Clelland C.D., Choi M., Romberg C., Clemenson G.D. Jr., Fragniere A., Tyres P., Jessberger S., Saksida L.M., Barker R.A., Gage F.H., Bussey T.J. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science, 325: 210-213, 2009.

Cote D.J., Bredenoord A.L., Smith T.R., Ammirati M., Brennum J., Mendez I., Ammar A.S., Balak N., Bolles G., Esene I.N., Mathiesen T., Broekman M.L. Ethical clinical translation of stem cell interventions for neurologic disease. Neurology, 88: 322-328, 2017.

Crigler L., Robey R.C., Asawachaicharn A., Gaupp D., Phinney D.G. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp. Neurol., 198: 54-64, 2006.

Crochemore C., Virgili M., Bonamassa B., Canistro D., Pena-Altamira E., Paolini M., Contestabile A. Long- term dietary administration of valproic acid does not affect, while retinoic acid decreases, the lifespan of G93A mice, a model for amyotrophic lateral sclerosis. Muscle Nerve, 39: 548-552, 2009.

Dahlstrand L., Collins V.P., Lendahl U. Expression of the class VI intermediate filament nestin in human central nervous system tumors. Cancer Res., 52: 5334-5341, 1992.

Dahlstrand J., Lardelli M., Lendahl U. Nestin mRNA expression correlates with the CNS progenitor cell state in many, but not all, regions of developing CNS. Dev. Brain Res., 84: 109-129, 1995.

Dasari V.R., Spomar D.G., Cady C., Gujrati M., Rao J.S., Dinh D.H. Mesenchymal stem cells from rat bone marrow downregulate caspase-3-mediated apoptotic pathway after spinal cord injury in rats. Neurochem. Res., 32: 2080-2093, 2007.

Dasari V.R., Veeravalli K.K., Dinh D.H. Mesenchymal stem cells for spinal cord injury. World J. Stem Cells, 6: 120-133, 2014.

Dash P.K., Orsi S.A., Zhang M., Grill R.J., Pati S., Zhao J., Moore A.N. Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats. PLoS One, 5: e11383, 2010.

Davies S.J.A., Fitch M.T., Silver J. Regeneration of adult axons in white matter tracts of the central nervous system. Nature, 390: 372-375. 1997.

De Sarno P., Li X., Jope R.S. Regulation of Akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium. Neuropharmacology, 43: 1158-1164, 2002.

Ding Y., Zhang R.Y., He B., Liu Z., Zhang K., Ruan J.W., Ling E.A., Wu J.L., Zeng Y.S. Combination of electroacupuncture and grafted mesenchymal stem cells overexpressing TrkC improves remyelination and function in demyelinated spinal cord of rats. Sci. Rep., 5: 9133, 2015.

Doetsch F., García-Verdugo J.M., Alvarez-Buylla A. Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J. Neurosci., 17: 5046-5061, 1997.

Doetsch F., García-Verdugo J.M., Alvarez-Buylla A. Regeneration of a germinal layer in the adult mammalian brain. Proc. Natl. Acad. Sci. USA., 96: 11619-11624, 1999.

Elliott Donaghue I., Tator C.H., Shoichet M.S. Sustained delivery of bioactive neurotrophin-3 to the injured spinal cord. Biomater. Sci., 3: 65-72, 2015.

Eng L.F., Yu A.C.H., Lee Y.L. Astrocytic response to injury. Pp. 353-365. In: Yu A.C.H., Hertz L., Norenberg M.D., Sykovl E., and Waxman S.G. (Eds.) Progress in Brain Research. Elsevier, New York, 1992.

Esmaeili A., Pakravan G., Ghaedi K., Noorbakhshia M. Alteration in messenger RNA neurotrophin 4 and tyrosine kinase receptors B expression levels following spinal cord injury. J. Neurosurg. Sci., [Epub ahead of print], 2014.

Faulkner J.R., Herrmann J.E., Woo M.J., Tansey K.E., Doan N.B., Sofroniew M.V. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J. Neurosci., 24: 2143-2155, 2004.

Fornai F., Longone P., Cafaro L., Kastsiuchenka O., Ferrucci M., Manca M.L., Lazzeri G., Spalloni A., Bellio N., Lenzi P., Modugno N., Siciliano G., Isidoro C., Murri L., Ruggieri S., Paparelli A. Lithium delays progression of amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA, 105: 2052-2057, 2008a.

Fornai F., Longone P., Ferrucci M., Lenzi P., Isidoro C., Ruggieri S., Paparelli A. Autophagy and amyotrophic lateral sclerosis: The multiple roles of lithium. Autophagy, 4: 527-530, 2008b.

Fornai F., Ferrucci M., Lenzi P., Falleni A., Biagioni F., Flaibani M., Siciliano G., Giannessi F., Paparelli A. Plastic changes in the spinal cord in motor neuron disease. Biomed. Res. Int., 2014: 670756, 2014.

Frisén J., Johansson C.B., Török C., Risling M., Lendahl U. Rapid, widespread, and longlasting induction of nestin contributes to the generation of glial scar tissue after CNS injury. J. Cell Biol., 131: 453-464, 1995.

Galan L., Gomez-Pinedo U., Vela-Souto A., Guerrero- Sola A., Barcia J.A., Gutierrez A.R., Martinez- Martinez A., Jiménez M.S., García-Verdugo J.M., Matias-Guiu J. Subventricular zone in motor neuron disease with frontotemporal dementia. Neurosci. Lett., 499: 9-13, 2011.

Gheusi G., Lledo P.M. (2014). Adult neurogenesis in the olfactory system shapes odor memory and perception. Prog. Brain Res., 208: 157-175, 2014.

Go H.S., Kim K.C., Choi C.S., Jeon S.J., Kwon K.J., Han S.H., Lee J., Cheong J.H., Ryu J.H., Kim C.H., Ko K.H., Shin C.Y. Prenatal exposure to valproic acid increases the neural progenitor cell pool and induces macrocephaly in rat brain via a mechanism involving the GSK-3β/β-catenin pathway. Neuropharmacology, 63: 1028-1041, 2012.

Goldman S.A., Luskin M.B. Strategies utilized by migrating neurons of the postnatal vertebrate forebrain. Trends Neurosci., 21: 107-114, 1998.

Göritz C., Dias D.O., Tomilin N., Barbacid M., Shupliakov O., Frisén J. A pericyte origin of spinal cord scar tissue. Science, 333: 238-242, 2011.

Gowing G., Shelley B., Staggenborg K., Hurley A., Avalos P., Victoroff J., Latter J., Garcia L., Svendsen C.N. Glial cell line-derived neurotrophic factor- secreting human neural progenitors show long-term survival, maturation into astrocytes, and no tumor formation following transplantation into the spinal cord of immunocompromised rats. Neuroreport., 25: 367-372, 2014.

Guan Y.J., Wang X., Wang H.Y., Kawagishi K., Ryu H., Huo C.F., Shimony E.M., Kristal B.S., Kuhn H.G., Friedlander R.M. Increased stem cell proliferation in the spinal cord of adult amyotrophic lateral sclerosis transgenic mice. J. Neurochem., 102: 1125-1138, 2007.

Gurney M.E., Pu H., Chiu A.Y., Dal Canto M.C., Polchow C.Y., Alexander D.D., Caliendo J., Hentati A., Kwon Y.W., Deng H.X., et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science, 264: 1772- 1775, 1994. Erratum in: Science, 269: 149, 1995.

Hamilton L.K., Truong M.K.V., Bednarczyk M.R., Aumont A., Fernandes K.J.L. Cellular organization of the central canal ependymal zone, a niche of latent neural stem cells in the adult mammalian spinal cord. Neuroscience, 164: 1044-1056, 2009.

Harvey A.R., Lovett S.J., Majda B.T., Yoon J.H., Wheeler L.P., Hodgetts S.I. Neurotrophic factors for spinal cord repair: Which, where, how and when to apply, and for what period of time? Brain Res., 1619: 36-71, 2015.

Hatten M.E., Liem R.K.H., Shelanski M.L., Mason C.A. Astroglia in CNS injury. Glia, 4: 233-243, 1991.

Hawryluk G.W., Mothe A., Wang J., Wang S., Tator C., Fehlings M.G. An in vivo characterization of trophic factor production following neural precursor cell or bone marrow stromal cell transplantation for spinal cord injury. Stem Cells Dev., 21: 2222-2238, 2012.

Hefferan M.P., Galik J., Kakinohana O., Sekerkova G., Santucci C., Marsala S., Navarro R., Hruska-Plochan M., Johe K., Feldman E., Cleveland D.W., Marsala M. Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation. PLoS One, 7: e42614, 2012.

Horky L.L., Galimi F., Gage F.H., Horner P.J. Fate of Endogenous Stem/Progenitor Cells Following Spinal Cord Injury. J. Comp. Neurol., 498: 525-538, 2006.

Horner P.J., Power A.E., Kempermann G., Kuhn H.G., Palmer T.D., Winkler J., Thal L.J., Gage F.H. Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord. J. Neurosci., 20, 2218-2228, 2000.

Hsieh J., Nakashima K., Kuwabara T., Mejia E., Gage F.H. Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc. Natl. Acad. Sci. USA, 101: 16659-16664, 2004.

Huang H., Chen L., Wang H., Xiu B., Li B., Wang R., Zhang J., Zhang F., Gu Z., Li Y., Song Y., Hao W., Pang S., Sun J. Influence of patients’ age on functional recovery after transplantation of olfactory ensheathing cells into injured spinal cord injury. Chinese Medical Journal, 116: 1488-1491, 2003.

Hugnot J.P., Franzen R. The spinal cord ependymal region: a stem cell niche in the caudal central nervous system. Front. Biosci. (Landmark Ed), 16: 1044-1059, 2011.

Isele N.B., Lee H.S., Landshamer S., Straube A., Padovan C.S., Plesnila N., Culmsee C. Bone marrow stromal cells mediate protection through stimulation of PI3-K/ Akt and MAPK signaling in neurons. Neurochem. Int., 50: 243-250, 2007.

Iizuka H., Yamamoto H., Iwasaki Y., Yamamoto T., Konno H. Evolution of tissue damage in compressive spinal cord injury in rats. J. Neurosurg., 66: 595-603, 1987.

Johansson C.B., Momma S., Clarke D.L., Risling M., Lendahl U., Frisén J. Identification of a neural stem cell in the adult mammalian central nervous system. Cell, 96: 25-34, 1999.

Jung G.A., Yoon J.Y., Moon B.S., Yang D.H., Kim H.Y., Lee S.H., Bryja V., Arenas E., Choi K.Y. Valproic acid induces differentiation and inhibition of proliferation in neural progenitor cells via the beta-catenin-Ras- ERK-p21Cip/WAF1 pathway. BMC Cell Biol., 9: 66, 2008.

Kang K.N., Lee J.Y., Kim da Y., Lee B.N., Ahn H.H., Lee B., Khang G., Park S.R., Min B.H., Kim J.H., Lee H.B., Kim M.S. Regeneration of completely transected spinal cord using scaffold of poly(D,L-lactide-co- glycolide)/small intestinal submucosa seeded with rat bone marrow stem cells. Tissue Eng. Part. A, 17: 2143-2152, 2011.

Karamouzian S., Nematollahi-Mahani S.N., Nakhaee N., Eskandary H. Clinical safety and primary efficacy of bone marrow mesenchymal cell transplantation in subacute spinal cord injured patients. Clinical Neurology and Neurosurgery, 114: 935-939, 2012.

Kelamangalath L., Tang X., Bezik K., Sterling N., Son Y.J., Smith G.M. Neurotrophin selectivity in organizing topographic regeneration of nociceptive afferents. Exp. Neurol., 271: 262-278, 2015.

Kim J.S., Chang M.Y., Yu I.T., Kim J.H., Lee S.H., Lee Y.S., Son H. Lithium selectively increases neuronal differentiation of hippocampal neural progenitor cells both in vitro and in vivo. J. Neurochem., 89: 324-336, 2004.

Kim S.U., Lee H.J., Kim Y.B. Neural stem cell- based treatment for neurodegenerative diseases. Neuropathology, 33: 491-504, 2013.

Kitamura K., Iwanami A., Nakamura M., Yamane J., Watanabe K., Suzuki Y., Miyazawa D., Shibata S., Funakoshi H., Miyatake S., Coffin R.S., Nakamura T., Toyama Y., Okano H. Hepatocyte growth factor promotes endogenous repair and functional recovery after spinal cord injury. J. Neurosci. Res., 85: 2332- 2342, 2007.

Knippenberg S., Nadine T., Dengler R., Brinker T., Petri S. Intracerebroventricular injection of encapsulated human mesenchymal cells producing glucagon-like peptide 1 prolongs survival in a mouse model of ALS. PLoS One, 7: e36857, 2012.

Kohyama J., Kojima T., Takatsuka E., Yamashita T., Namiki J., Hsieh J., Gage F.H., Namihira M., Okano H., Sawamoto K., Nakashima K. Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain. Proc. Natl. Acad. Sci. USA, 105: 18012-18017, 2008.

Kulenkampff H., Krbek F. Morphological studies on the glia and ependyma of the spinal cord of mice. Z. Anat. Entwicklungsgesch., 121: 65-78, 1959.

Kumar M., Csaba Z., Peineau S., Srivastava R., Rasika S., Mani S., Gressens P., El Ghouzzi V. Endogenous cerebellar neurogenesis in adult mice with progressive ataxia. Ann. Clin. Transl. Neurol., 1: 968-981, 2014.

Kwon B.K., Streijger F., Hill C.E., Anderson A.J., Bacon M., Beattie M.S., Blesch A., Bradbury E.J., Brown A., Bresnahan J.C., Case C.C., Colburn R.W., David S., Fawcett J.W., Ferguson A.R., Fischer I., Floyd C.L., Gensel J.C., Houle J.D., Jakeman L.B., Jeffery N.D., Jones L.A., Kleitman N., Kocsis J., Lu P., Magnuson D.S., Marsala M., Moore S.W., Mothe A.J., Oudega M., Plant G.W., Rabchevsky A.S., Schwab J.M., Silver J., Steward O., Xu X.M., Guest J.D., Tetzlaff W. Large animal and primate models of spinal cord injury for the testing of novel therapies. Exp. Neurol., 269: 154-168, 2015.

Lacroix S., Hamilton L.K., Vaugeois A., Beaudoin S., Breault-Dugas C., Pineau I., Lévesque S.A., Grégoire C.A., Fernandes K.J.L. Central canal ependymal cells proliferate extensively in response to traumatic spinal cord injury but not demyelinating lesions. PLoS One, 9: e85916, 2014.

Leblond C.P., Walker B.E. Renewal of cell populations. Physiol. Rev., 36: 255-276, 1956.

Lepore A.C., O’Donnell J., Kim A.S., Williams T., Tuteja A., Rao M.S., Kelley L.L., Campanelli J.T., Maragakis N.J. Human glial-restricted progenitor transplantation into cervical spinal cord of the SOD1 mouse model of ALS. PLoS One, 6: e25968, 2011.

Li X., Bijur G.N., Jope R.S. Glycogen synthase kinase 3β, mood stabilizers, and neuroprotection. Bipolar Disord., 4: 137-144, 2002.

Li R., Strykowski R., Meyer M., Mulcrone P., Krakora D., Suzuki M. Male-specific differences in proliferation, neurogenesis, and sensitivity to oxidative stress in neural progenitor cells derived from a rat model of ALS. PLoS One, 7: e48581, 2012.

Lima C., Pratas-Vital J., Escada P., Hasse-Ferreira A., Capucho C., Peduzzi J.D. Olfactory mucosa autografts in human spinal cord injury: a pilot clinical study. J. Spinal Cord Med., 29: 191-203, 2006.

Lima C., Escada P., Pratas-Vital J., Branco C., Arcangeli C.A., Lazzeri G., Maia C.A., Capucho C., Hasse- Ferreira A., Peduzzi J.D. Olfactory mucosal autografts and rehabilitation for chronic traumatic spinal cord injury. Neurorehabil. Neural Repair., 24: 10-22, 2010.

Liu Z., Martin L.J. The adult neural stem and progenitor cell niche is altered in amyotrophic lateral sclerosis mouse brain. J. Comp. Neurol., 497: 468-488, 2006.

Lois C., Alvarez-Buylla A. Long-distance neuronal migration in the adult mammalian brain. Science, 264: 1145-1148, 1994.

Loseva E., Yuan T.F., Karnup S. Neurogliogenesis in the mature olfactory system: a possible protective role against infection and toxic dust. Brain Res. Rev., 59: 374-387, 2009.

Lu P., Jones L.L., Snyder E.Y., Tuszynski M.H. Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp. Neurol., 181: 115-129, 2003.

Lu P., Jones L.L., Tuszynski M.H. Axon regeneration through scars and into sites of chronic spinal cord injury. Exp. Neurol., 203: 8-21, 2007.

Luskin M.B. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron, 11: 173-189, 1993.

Ma X., Hamadeh M.J., Christie B.R., Foster J.A., Tarnopolsky M.A. Impact of treadmill running and sex on hippocampal neurogenesis in the mouse model of amyotrophic lateral sclerosis. PLoS One, 7: e36048, 2012.

Madathil S.K., Saatman K.E. IGF-1/IGF-R Signaling in Traumatic Brain Injury: Impact on Cell Survival, Neurogenesis, and Behavioral Outcome. Chapter 7. In: Kobeissy F.H. (Ed.) Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL), CRC Press, 2015.

Magnus T., Carmen J., Deleon J., Xue H., Pardo A.C., Lepore A.C., Mattson M.P., Rao M.S., Maragakis N.J. Adult glial precursor proliferation in mutant SOD1G93A mice. Glia, 56: 200-208, 2008.

Marcuzzo S., Kapetis D., Mantegazza R., Baggi F., Bonanno S., Barzago C., Cavalcante P., Kerlero de Rosbo N., Bernasconi P. Altered miRNA expression is associated with neuronal fate in G93A-SOD1 ependymal stem progenitor cells. Exp. Neurol., 253: 91-101, 2014.

Martínez H.R., Molina-Lopez J.F., González-Garza M.T., Moreno-Cuevas J.E., Caro-Osorio E., Gil-Valadez A., Gutierrez-Jimenez E., Zazueta-Fierro O.E., Meza J.A., Couret-Alcaraz P., Hernandez-Torre M. Stem

cell transplantation in amyotrophic lateral sclerosis patients: methodological approach, safety, and feasibility. Cell Transplant., 21: 1899-1907, 2012.

Meletis K., Barnabé-Heider F., Carlén M., Evergren E., Tomilin N., Shupliakov O., Frisén J. Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biol., 6: e182, 2008.

Messier B., Leblond C.P. Cell proliferation and migration as revealed by radioautography after injection of thymidine-H3 into male rats and mice. Am. J. Anat., 106: 247-285, 1960.

Messier B., Leblond C.P., Smart I. Presence of DNA synthesis and mitosis in the brain of young adult mice. Exp. Cell Res., 14: 224-226, 1958.

Morshead C.M., Reynolds B.A., Craig C.G., McBurney M.W., Staines W.A., Morassutti D., Weiss S., van der Kooy D. Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron, 13: 1071-1082, 1994.

Nakagomi T., Molnár Z., Nakano-Doi A., Taguchi A., Saino O., Kubo S., Clausen M., Yoshikawa H., Nakagomi N., Matsuyama T. Ischemia-induced neural stem/progenitor cells in the pia mater following cortical infarction. Stem Cells Dev., 20: 2037-2051, 2011.

Nakagomi T., Molnár Z., Taguchi A., Nakano-Doi A., Lu S., Kasahara Y., Nakagomi N., Matsuyama T. Leptomeningeal-derived doublecortin-expressing cells in poststroke brain. Stem Cells Dev., 21: 2350-2354, 2012.

Nakagomi T., Nakano-Doi A., Matsuyama T. Leptomeninges: a novel stem cell niche harboring ischemia-induced neural progenitors. Histol. Histopathol., 30: 391-399, 2015.

Nicaise C., Mitrecic D., Falnikar A., Lepore A.C. Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury. World J. Stem Cells, 7: 380-398, 2015.

Ninomiya S., Esumi S., Ohta K., Fukuda T., Ito T., Imayoshi I., Kageyama R., Ikeda T., Itohara S., Tamamaki N. Amygdala kindling induces nestin expression in the leptomeninges of the neocortex. Neurosci. Res., 75: 121-129, 2013.

Nizzardo M., Simone C., Rizzo F., Ruggieri M., Salani S., Riboldi G., Faravelli I., Zanetta C., Bresolin N., Comi G.P., Corti S. Minimally invasive transplantation of iPSC-derived ALDHhiSSCloVLA41 neural stem cells effectively improves the phenotype of an amyotrophic lateral sclerosis model. Hum. Mol. Genet., 23: 342- 354, 2014.

Novikova L.N., Brohlin M., Kingham P.J., Novikov L.N., Wiberg M. Neuroprotective and growth-promoting effects of bone marrow stromal cells after cervical spinal cord injury in adult rats. Cytotherapy, 13: 873-887, 2011.

Oh K.W., Moon C., Kim H.Y., Oh S.I., Park J., Lee J.H., Chang I.Y., Kim K.S., Kim S.H. Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. Stem Cells Transl. Med., 4: 590-597, 2015.

Ohori Y., Yamamoto S., Nagao M., Sugimori M., Yamamoto N., Nakamura K., Nakafuku M. Growth factor treatment and genetic manipulation stimulate neurogenesis and oligodendrogenesis by endogenous neural progenitors in the injured adult spinal cord. J. Neurosci., 26: 11948-11960, 2006.

Ohta M., Suzuki Y., Noda T., Ejiri Y., Dezawa M., Kataoka K., Chou H., Ishikawa N., Matsumoto N., Iwashita Y., Mizuta E., Kuno S., Ide C. Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation. Exp. Neurol., 187: 266-278, 2004.

Oliveira S.L.B., Pillat M.M., Cheffer A., Lameu C., Schwindt T.T., Ulrich H. Functions of neurotrophins and growth factors in neurogenesis and brain repair. Cytometry A, 83: 76-89. 98, 2013.

Osaka M., Honmou O., Murakami T., Nonaka T., Houkin K., Hamada H., Kocsis J.D. Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome. Brain Res., 1343: 226-235, 2010.

Pajer K., Nemes C., Berzsenyi S., Kovács K.A., Pirity M.K., Pajenda G., Nógrádi A., Dinnyés A. Grafted murine induced pluripotent stem cells prevent death of injured rat motoneurons otherwise destined to die. Exp. Neurol., 269: 188-201, 2015.

Parent J.M., Vexler Z.S., Gong C., Derugin N., Ferriero D.M. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann. Neurol., 52: 802- 813, 2002.

Pasquali L., Busceti C.L., Fulceri F., Paparelli A., Fornai F. Intracellular pathways underlying the effects of lithium. Behav. Pharmacol., 21: 473-492, 2010.

Pierce A.A., Xu A.W. De novo neurogenesis in adult hypothalamus as a compensatory mechanism to regulate energy balance. J. Neurosci., 30: 723-730, 2010.

Priest C.A., Manley N.C., Denham J., Wirth E.D. 3rd, Lebkowski J.S. Preclinical safety of human embryonic stem cell-derived oligodendrocyte progenitors supporting clinical trials in spinal cord injury. Regen. Med., 10: 939-958, 2015.

Qiu X.C., Jin H., Zhang R.Y., Ding Y., Zeng X., Lai B.Q., Ling E.A., Wu J.L., Zeng Y.S. Donor mesenchymal stem cell-derived neural-like cells transdifferentiate into myelin-forming cells and promote axon regeneration in rat spinal cord transection. Stem Cell Res. Ther., 6: 105, 2015.

Reynolds B.A., Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian nervous system. Science, 255: 1707-1710, 1992.

Reynolds B.A., Weiss S. Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic precursor is a stem cell. Dev. Biol., 175: 1-13, 1996.

Reynolds B.A., Rietze R.L. Neural stem cells and neurospheres — re-evaluating the relationship. Nat. Methods, 2: 333-336, 2005.

Rivlin A.S., Tator C.H. Regional spinal cord blood flow in rats after severe cord trauma. J. Neurosurg., 49: 844-853, 1978.

Rosen D.R., Siddique T., Patterson D., Figlewicz D.A., Sapp P., Hentati A., Donaldson D., Goto J., O’Regan J.P., Deng H.X., Rahmanim Z., Krizus A., McKenna- Yasek D., Cayabyab A., Gaston S.M., Berger R., Tanzi R.E., Halperin J.J., Herzfeldt B., Van den Bergh R., Hung W.Y., Bird T., Deng G., Mulder D.W., Smyth C., Laing N.G., Soriano E., Pericak-Vance M.A., Haines J., Rouleau G.A., Rouleau G.A., Gusella J.S. Horvitz H.R., Brown R.H Jr. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 362: 59-62, 1993. Erratum in: Nature, 364: 362, 1993.

Rowland L.P., Shneider N.A. Amyotrophic lateral sclerosis. N. Engl. J. Med., 344: 1688-1700, 2001.

Sabapathy V., Tharion G., Kumar S. Cell Therapy Augments Functional Recovery Subsequent to Spinal Cord Injury under Experimental Conditions. Stem Cells Int., 2015: 132172, 2015.

Sabelström H., Stenudd M., Réu P., Dias D.O., Elfineh M., Zdunek S., Damberg P., Göritz C., Frisén J. Resident neural stem cells restrict tissue damage and neuronal loss after spinal cord injury in mice. Science, 342: 637-640, 2013.

Saha B., Peron S., Murray K., Jaber M., Gaillard A. Cortical lesion stimulates adult subventricular zone neural progenitor cell proliferation and migration to the site of injury. Stem Cell Res., 11: 965-977, 2013.

Sakakibara A., Aoki E., Hashizume Y., Mori N., Nakayama A. Distribution of nestin and other stem cell-related molecules in developing and diseased human spinal cord. Pathol. Int., 57: 358-368, 2007.

Schizas N., Andersson B., Hilborn J., Hailer N.P. Interleukin-1 receptor antagonist promotes survival of ventral horn neurons and suppresses microglial activation in mouse spinal cord slice cultures. J. Neurosci. Res., 92: 1457-1465, 2014.

Schroeder J., Kueper J., Leon K., Liebergall M. Stem cells for spine surgery. World J. Stem Cells, 7: 186- 194, 2015.

Schwab M.E., Kapfhammer J.P., Bandtlow C.E. Inhibitors of neurite growth. Annu. Rev. Neurosci., 16: 565-595, 1993.

Sharma H.S., Muresanu D.F., Sharma A. Novel therapeutic strategies using nanodrug delivery, stem cells and combination therapy for CNS trauma and neurodegenerative disorders. Expert. Rev. Neurother., 13: 1085-1088, 2013.

Shihabuddin L.S., Ray J., Gage F.H. FGF-2 is sufficient to isolate progenitors found in the adult mammalian spinal cord. Exp. Neurol., 148: 577-586, 1997.

Silani V., Calzarossa C., Cova L., Ticozzi N. Stem cells in amyotrophic lateral sclerosis: motor neuron protection or replacement? CNS Neurol. Disord. Drug Targets, 9: 314-324, 2010.

Silva R., Mesquita A.R., Bessa J., Sousa J.C., Sotiropoulos I., Leao P., Almeida O.F., Sousa N. Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate: the role of glycogen-synthase- kinase-3beta. Neuroscience, 152: 656-669, 2008.

Silva N.A., Sousa N., Reis R.L., Salgado A.J. From basics to clinical: a comprehensive review on spinal cord injury. Prog. Neurobiol., 114: 25-57, 2014.

Silver J., Miller J.H. Regeneration beyond the glial scar. Nat. Rev. Neurosci., 5: 146-156, 2004.

Srivastava A.K., Gross S.K., Almad A.A., Bulte C.A., Maragakis N.J., Bulte J.W. Serial in vivo imaging of transplanted allogeneic neural stem cell survival in a mouse model of amyotrophic lateral sclerosis. Exp. Neurol., 289: 96-102, 2017.

Stambolic V., Ruel L., Woodgett J.R. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol., 6: 1664-1668, 1996.

Su H., Chu T.H., Wu W. Lithium enhances proliferation and neuronal differentiation of neural progenitor cells in vitro and after transplantation into the adult rat spinal cord. Exp. Neurol., 206: 296-307, 2007.

Sugai F., Yamamoto Y., Miyaguchi K., Zhou Z., Sumi H., Hamasaki T., Goto M., Sakoda S. Benefit of valproic acid in suppressing disease progression of ALS model mice. Eur. J. Neurosci., 20: 3179-3183, 2004.

Sykova E., Homola A., Mazanec R., Lachmann H., Konrádová S.L., Kobylka P., Pádr R., Neuwirth J., Komrska V., Vávra V., Stulík J., Bojar M. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant., 15: 675-687, 2006.

Teixeira F.G., Carvalho M.M., Sousa N., Salgado A.J. Mesenchymal stem cells secretome: a new paradigm for central nervous system regeneration? Cell Mol. Life Sci., 70: 3871-3882, 2013.

Teng Y.D., Benn S.C., Kalkanis S.N., Shefner J.M., Onario R.C., Cheng B., Lachyankar M.B., Marconi M., Li J., Yu D., Han I., Maragakis N.J., Llado J., Erkmen K., Redmond D.E., Sidman R.L., Przedborski S., Rothstein J.D., Brown R.H., Snyder E.Y. Multimodal actions of neural stem cells in a mouse model of ALS: A meta-analysis. Sci. Transl. Med., 4: 165ra164, 2012.

Thomsen G.M., Gowing G., Svendsen S., Svendsen C.N. The past, present and future of stem cell clinical trials for ALS. Exp. Neurol., 262: 127-137, 2014.

Tsumuraya T., Ohtaki H., Song D., Sato A., Watanabe J., Hiraizumi Y., Nakamachi T., Xu Z., Dohi K., Hashimoto H., Atsumi T., Shioda S. Human mesenchymal stem/stromal cells suppress spinal inflammation in mice with contribution of pituitary adenylate cyclase-activating polypeptide (PACAP). J. Neuroinflammation, 12: 35, 2015.

Tripathi R.B., McTigue D.M. Chronically increased ciliary neurotrophic factor and fibroblast growth factor-2 expression after spinal contusion in rats. J. Comp. Neurol., 510: 129-144, 2008.

Wang Y., Li J., Kong P., Zhao S., Yang H., Chen C., Yan J. Enhanced expression of neurotrophic factors in the injured spinal cord through vaccination with myelin basic protein-derived peptide pulsed dendritic cells. Spine (Phila Pa 1976), 40: 95-101, 2015a.

Wang Y.T., Lu X.M., Zhu F., Huang P., Yu Y., Long Z.Y., Wu Y.M. Ameliorative Effects of p75NTR-ED- Fc on Axonal Regeneration and Functional Recovery in Spinal Cord-Injured Rats. Mol. Neurobiol., 52: 1821-1834, 2015b.

Weishaupt N., Mason A.L., Hurd C., May Z., Zmyslowski D.C., Galleguillos D., Sipione S., Fouad K. Vector- induced NT-3 expression in rats promotes collateral growth of injured corticospinal tract axons far rostral to a spinal cord injury. Neuroscience, 272: 65-75, 2014.

Xu L., Mahairaki V., Koliatsos V.E. Host induction by transplanted neural stem cells in the spinal cord: further evidence for an adult spinal cord neurogenic niche. Regen. Med., 7: 785-797, 2012.

Xu L., Shen P., Hazel T., Johe K., Koliatsos V.E. Dual transplantation of human neural stem cells into cervical and lumbar cord ameliorates motor neuron disease in SOD1 transgenic rats. Neurosci. Lett., 494: 222-226, 2011.

Xu L., Yan J., Chen D., Welsh A.M., Hazel T., Johe K., Hatfield G., Koliastos V.E. Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats. Transplantation, 82: 865-875, 2006.

Yu I.T., Park J.Y., Kim S.H., Lee J.S., Kim Y.S., Son H. Valproic acid promotes neuronal differentiation by induction of proneural factors in association with H4 acetylation. Neuropharmacology, 56: 473-480, 2009.

Yuan T.F. Smell with new neurons. Cell Tissue Res., 340: 211-214, 2010.

Yuan T.F., Liang Y.X., So K.F. Occurrence of new neurons in the piriform cortex. Front. Neuroanat., 8: 167, 2015.

Zeng X., Zeng Y.S., Ma Y.H., Lu L.Y., Du B.L., Zhang W., Li Y., Chan W.Y. Bone marrow mesenchymal stem cells in a threedimensional gelatin sponge scaffold attenuate inflammation, promote angiogenesis, and reduce cavity formation in experimental spinal cord injury. Cell Transplant., 20: 1881-1899, 2011.

Zhang Z., Guth L. Experimental spinal cord injury: Wallerian degeneration in the dorsal column is followed by revascularization, glial proliferation, and nerve regeneration. Exp. Neurol., 147: 159-171, 1997.

Zhang Z., Guth L. Revascularization, wound healing and nerve regeneration in lesion caused by Wallerian degeneration after spinal cord injury. FASEB J., 10: A130, 1996.

Zhao C., Deng W., Gage F.H. Mechanisms and functional implications of adult neurogenesis. Cell, 132: 645-660, 2008.

Zhou Y., Lu Y., Fang X., Zhang J., Li J., Li S., Deng X., Yu Y., Xu R. An astrocyte regenerative response from vimentin-containing cells in the spinal cord of amyotrophic lateral sclerosis’s disease-like transgenic (G93A SOD1) mice. Neurodegener. Dis., 15: 1-12, 2015.

Zhu T., Tang Q., Gao H., Shen Y., Chen L., Zhu J. Current status of cell-mediated regenerative therapies for human spinal cord injury. Neurosci. Bull., 30: 671- 682, 2014.



  • There are currently no refbacks.