In accordance with our previous observations Salazar et

In accordance with our previous observations (Salazar et al., 2010), hCSN-SCns transplanted at the early-chronic stage of SCI exhibited migration away from the injury epicenter, as well as a preferential rostral localization in migration and proliferation. These data may suggest that extrinsic factors in the microenvironment influence the spatiotemporal dynamics of donor cell engraftment. Cell death induced neuroinflammation causes local upregulation of cytokines and chemokines, such as IL-8, SDF-1a, TNF-a as well as extracellular matrix proteins such as chondroitin sulfate proteoglygans (CSPGs) and integrins, which are crucial for guiding precursor migration and repair process (Leone et al., 2005; Connor et al., 2011; Brizzi et al., 2012; Dyck and Karimi-Abdolrezaee, 2015; Fawcett, 2015; North et al., 2015). In parallel, SCI results in a time-dependent regulation of the expression of trophic and regulatory factors such as ciliary neurotrophic factor (CNTF), FGF2, and glial growth factor 2 (GGF2), which can stimulate proliferation of endogenous precursor buy Celecoxib (Zai et al., 2005; Kumamaru et al., 2013). Interestingly, the highest FGF2 and GGF2 levels, and greatest chronic cell death, after SCI have been reported rostral to the epicenter (Shuman et al., 1997; Warden et al., 2001; Zai et al., 2005), perhaps suggesting that other ongoing injury dynamics could derive selective donor cell recruitment in a spatially dependent manner. Interestingly, increasing transplantation dose increased the number of donor cells localized in the caudal niche at 16 WPT, perhaps suggesting that donor cell density may in turn modulate SCI microenvironment by producing factors that stimulate migration of their sister cells, resulting in an increase in the distribution of donor cells throughout the tissue. Alternatively, as perhaps suggested by the plateau observed in hCNS-SCns engraftment, the number of integration sites adjacent to the injury and transplantation locus could have a limit, resulting in increased migration to distal regions once these closer sites are filled.
Conclusions The following are the supplementary data related to this article.
Acknowledgments We want to thank technical staff at Christopher and Dana Reeve Foundation Core (CDRF core), especially Rebecca Nishi, M.S., Hongli-Liu, M.D., Chelsea Pagan, B.S, Christina de Armond, B.S, and Elizabeth Hoffman, B.S, for their help with animal surgeries. We also thank Colleen Worne, B.S., and Eileen Do, B.S., for technical assistance. This study was supported in part by the National Institutes of Health (Grant U01NS079420) to A.J.A. and B.J.C.; the Christopher Reeve Foundation (AAC-2005) to A.J.A.; and by the CIRM Postdoctoral Training Grant (TG2-01152) to K.M.P.
Introduction Embryonic pluripotent stem cells are isolated from the inner cell mass of developing primordial embryo. These pluripotent stem cells have the ability to generate all cell types in the body. During tissue damage, resident stem and progenitor cells can be activated to repair and regenerate the damaged tissue. Transplantation of progenitor cells derived from pluripotent stem cells is a promising therapeutic option towards treating genetic, infectious and other degenerative disorders. Transplanted cells at the site of injury encounter the inflammatory niche comprised of cellular and soluble factors, including interferons (IFNs). The engrafting cells respond to these stimuli by proliferation, differentiation or cell death. These cell types could also be exposed to infectious agents, such as pathogenic viruses and bacteria. In vitro experiments have shown that embryonic pluripotent stem cells can respond to type I (IFN-α and IFN-β) and II (IFN-γ) interferons that mediate the first line of defense against invading pathogens and generating specific immunity (Whyatt et al., 1993; Drukker et al., 2002; Hong and Carmichael, 2013). These observations are critical for understanding the innate immune function of pluripotent stem as well as progenitor cells and tissue rejection during cell therapy application.