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    • The following are the supplementary data

    2018-11-08

    The following are the supplementary data related to this article.
    Contribution statement O.K., J.J.K. and Y.K. participated in designing the experiments, execution of described works, statistical analysis, interpretation of data and writing the manuscript. H.-S.K., M.H., O.E., C.L., C.V. and T.T. contributed to the execution of the experiments or writing the manuscript. S.H. provided statistical consultation and bioinformatic support. I.S. participated in the interpretation of data and writing the manuscript.
    Acknowledgments We thank the UCLA Clinical Microarray Core Facility for microarray analysis. We also acknowledge the UCLA Broad Stem Cell Institute for providing us with human embryonic stem cell cultures. This work was supported by an NIH award from NIAAA (R01AA21301), CIRM Basic Biology Award II (RB02-1562), and UCLA School of Dentistry Faculty Seed Grant Award to Y.K. and T32 training grant awards from NIDCR to O.K. and J.J.K. (T32DE07269).
    Introduction The ependymal region of the adult spinal cord in mammals harbors a pool of stem and progenitor Prosaptide TX14(A) (SPCs) readily activated and recruited by spinal damage (Weiss et al., 1996; Hugnot and Franzen, 2011). Even though their adult neurogenesis has not been observed (Sabourin et al., 2009; Hugnot and Franzen, 2011), the neural stem cells present in the adult spinal cord are recruited and proliferate after spinal cord injury (Yamamoto et al., 2001b), producing scar-forming astrocytes and myelinating oligodendrocytes (Meletis et al., 2008). The manipulation of endogenous spinal stem cells after injury could represent one valid alternative to stem cell transplantation, since it is noninvasive and avoids the need for immune suppression (Meletis et al., 2008). Spinal stem cells are difficult to identify due to their heterogeneity and lack of specific expressional markers, since the ones currently used significantly overlap with those of mature astrocytes (McDonough and Martínez-Cerdeño, 2012). Furthermore, there is no specific marker to discriminate between quiescent and activated ependymal spinal cells, or to monitor migratory ependymal cells. Moreover, the signaling pathways and genes controlling the spinal SPC fate in normal and pathological conditions, remain largely unknown (Hugnot and Franzen, 2011). Brain transcription factors that regulate formation and proliferation of neural SPCs depend on the Sox family of genes, in particular Sox2 (Liu et al., 2013). Genomic and proteomic technologies have recently identified Wnt/beta-catenin, Notch, sonic hedgehog and growth factor networks as major signaling pathways involved in maintenance, self-renewal, proliferation and neurogenesis of the neural SPCs, and have demonstrated cross-talk between key molecules of these pathways and their modulations by transcription factors, miRNA and histone modifications (Yun et al., 2010). At variance with the wealth of brain data, transcription factors controlling spinal cord stem cells remain incompletely understood as they have been studied with in vitro primary cultures, showing common expression of various homeodomain-type (Pax6, Pax7, Nkx2.2, and Prox1) and basic helix-loop-helix (bHLH)-type (Ngn2, Mash1, NeuroD1, and Olig2) regulatory factors in adult and embryonic rat spinal neural progenitors (Yamamoto et al., 2001a,b). In the course of our studies with biomarkers of neuronal damage (Kuzhandaivel et al., 2011) we serendipitously discovered intense immunostaining of ependymal cells for the Activating transcription factor 3 (ATF3): this observation led us to explore its expression in control or damage-induced protocols. ATF3 belongs to the mammalian ATF/cAMP responsive element-binding (CREB) protein family of the Basic Leucine Zipper (bZIP) transcription factors (Hashimoto et al., 2002) that generate a wide range of either repressors or activators of transcription (Thompson et al., 2009). ATF3 is thought to be an immediate early gene, a stress inducible gene and an adaptive response gene, which, when activated by various stimuli, can control cell cycle and cell death machinery (Hunt et al., 2012). ATF3 promotes proliferation, motility and invasiveness of certain cancer cell lines (Wang et al., 2008; Thompson et al., 2009). ATF3 expression is normally very low in central neurons and glia, but it is markedly upregulated in response to injury and closely linked to survival and regeneration of peripheral axons (Hunt et al., 2012). Both cytoplasmic and nuclear ATF3 immunostaining has been reported with variations related to cell type, species, and injury state when it becomes prevalently nuclear (Hunt et al., 2012). ATF3 is supposed to have a role in neurite growth and regeneration (Moore and Goldberg, 2011) and it has been identified as a regulator of neuronal survival against excitotoxic and ischemic brain damage (Zhang et al., 2011). ATF3 knockout exacerbates inflammation and brain injury after transient focal cerebral ischemia (Wang et al., 2012). ATF3 has no known role in neuronal development of the intact nervous system, neither has its expression been reported in SPCs. The present study is the first report of ATF3 as a reliable marker of activated neuroprogenitor cells in the rat spinal cord.