Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

Abstract

The transplantation of neural stem/precursor cells (NSPCs) is a promising therapeutic strategy for many neurodegenerative disorders including spinal cord injury (SCI) because it provides for neural replacement or trophic support. This strategy is now being extended to the treatment of chronic SCI patients. However, understanding of biological properties of chronically transplanted NSPCs and their surrounding environments is limited. Here, we performed temporal analysis of injured spinal cords and demonstrated their multiphasic cellular and molecular responses. In particular, chronically injured spinal cords were growth factorenriched environments, whereas acutely injured spinal cords were enriched by neurotrophic and inflammatory factors. To determine how these environmental differences affect engrafted cells, NSPCs transplanted into acutely, subacutely, and chronically injured spinal cords were selectively isolated by flow cytometry, and their whole transcriptomes were compared by RNA sequencing. This analysis revealed that NSPCs produced many regenerative/ neurotrophic molecules irrespective of transplantation timing, and these activities were prominent in chronically transplanted NSPCs. Furthermore, chronically injured spinal cords permitted engrafted NSPCs to differentiate into neurons/oligodendrocytes and provided more neurogenic environment for NSPCs than other environments. Despite these results demonstrate that transplanted NSPCs have adequate capacity in generating neurons/oligodendrocytes and producing therapeutic molecules in chronic SCI microenvironments, they did not improve locomotor function. Our results indicate that failure in chronic transplantation is not due to the lack of therapeutic activities of engrafted NSPCs but the refractory state of chronically injured spinal cords. Environmental modulation, rather modification of transplanting cells, will be significant for successful translation of stem cell-based therapies into chronic SCI patients.

Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury

“…Importantly, additional work is required to pinpoint the exact neuroanatomical mechanisms behind this recovery. Given the time course, it is likely that transplant-derived trophic support and ChABC-induced ECM changes aid in the survival/regeneration of endogenous cells[49], even in the chronic phase of injury[50]. The extent to which each of these mechanisms contributes to the overall recovery profile requires further investigation.…”

Transplantation dose alters the dynamics of human neural stem cell engraftment, proliferation and migration after spinal cord injury

“…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 cells (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.…”

SDF-1 overexpression by mesenchymal stem cells enhances GAP-43-positive axonal growth following spinal cord injury

“…Studies examining the expression of key molecules, post-SCI, such as GFAP, CSPGs, or IBA-1, have suggested a return towards baseline from an elevated status around 30-days post-injury (Gwak, Kang, Unabia, & Hulsebosch, 2012;Jones, Margolis, & Tuszynski, 2003;Kumamaru et al, 2013;Lau et al, 2012). This stabilization of the injury environment at earlier time points, postinjury, may explain the inability to detect differences between groups at 7-weeks post-injury.…”