hCNS SCns migration was extensive

hCNS-SCns sodium butyrate was extensive, detected by 1 week following transplantation, and altered by the injured microenvironment. Injury induced transplanted hCNS-SCns to remain closer to the SCI epicenter, which has been reported in other cases of CNS trauma and degeneration (Connor et al., 2011; Leong and Turnley, 2011). As in the case of cell survival, inflammatory chemokines and cytokines can regulate NSC migration (Connor et al., 2011). Alternatively, CSPGs could also play a role in hCNS-SCns migration/localization (Kearns et al., 2003; Ikegami et al., 2005; Karimi-Abdolrezaee et al., 2010, 2012). Surprisingly, we found that hCNS-SCns migrated in an evenly distributed manner over even longer distances in the uninjured compared with the injured microenvironment. NSC migration in adult, intact CNS is typically inhibited by regulators (e.g., netrin-1) outside of specialized sites (e.g., the rostral migratory stream) (Petit et al., 2007). Taken together, these data suggest the potential for transplanted hCNS-SCns to overcome migratory repulsion, allowing for greater surveillance of the transplantation niche. Molecular dissection of these interactions could permit manipulation of the injured spinal cord or transplanted NSCs to allow for even greater migration and repair. Our data demonstrate that proliferation and migration occurred in waves from the site of transplantation in the uninjured spinal cord (Figure 1B, paradigm 2), as opposed to predominantly near the lesion epicenter in the injured spinal cord (Figure 1B, paradigm 1). This suggests that injury shifted the dynamics of hCNS-SCns migration and proliferation from one paradigm to another. Many factors, including FGF, Wnts, BMPs, and Shh, are altered following SCI and could mediate this effect, given their established roles in NSC proliferation in the CNS (Ulloa and Briscoe, 2007; Sabo et al., 2009; Fernández-Martos et al., 2011). We also found that SCI altered the localization of specific hCNS-SCns fates along the axis of the spinal cord. hCNS-SCns retained a more immature, OLIG2+ phenotype in the uninjured spinal cord and migrated in a long and even distribution (Figure 6), whereas this population was found predominantly in the region 1–2 mm from the lesion epicenter in the injured spinal cord. This suggests that hCNS-SCns in the injured spinal cord were recruited to perilesional sites based on region- and niche-specific cues. Finally, our OLIG2 and APC/CC1 data demonstrated that hCNS-SCns acquired a more mature oligodendrocyte phenotype in injured spinal cord by 98 dpt. These data suggest that transplanted hCNS-SCns responded not only to localization cues but also to maturation cues specific to the injured spinal cord. Although the mechanisms of oligodendrocyte maturation remain incompletely understood, multiple regulators, such as axonally expressed ligands, secreted molecules, and neuronal activity, have been identified (Emery, 2010a) and all may be present in the injured spinal cord microenvironment. The uninjured spinal cord may lack these signals, presenting a fundamentally different niche resulting in restricted maturation. In summary, these findings could have profound significance for the field of regenerative medicine, as they suggest the capacity of multipotent cells to respond dynamically to the microenvironment in a niche-specific manner.
Experimental Procedures
Acknowledgments
Introduction In renewable tissues such as the hematopoietic system, skin, and intestine, multipotent stem cells serve as a reservoir of cells that are called upon to maintain tissue homeostasis and function (Blanpain and Fuchs, 2006; Tesori et al., 2013; Toma et al., 2001; Barker et al., 2008; Weissman, 2000). These stem cells have been implicated as precursors to cancer, presumably due to their long-term persistence and high self-renewing capabilities (Barker et al., 2009; Bonnet and Dick, 1997). However, in other tissues such as the mammary gland, lineage-restricted progenitor cells, as opposed to multipotent stem cells, are responsible for tissue maintenance and homeostasis (Van Keymeulen et al., 2011). When called upon for tissue regeneration, as is the case upon transplantation or injury, these lineage-committed progenitor cells unlock primitive stem cell programs that are not normally required for tissue development or tissue homeostasis (Blanpain et al., 2004; Doupé et al., 2012; Kordon and Smith, 1998; Shackleton et al., 2006; Stingl et al., 2006; van Amerongen et al., 2012; Van Keymeulen et al., 2011). By doing so, these cells acquire properties that make them amenable to cancer initiation (Pacheco-Pinedo et al., 2011; Proia et al., 2011; Schwitalla et al., 2013; Youssef et al., 2010, 2012). However, the molecular mechanism by which committed progenitor cells access latent stem cell programs is not well understood.