A Systematic Review of Cellular Transplantation Therapies for Spinal Cord Injury

Abstract

Cell transplantation therapies have become a major focus in pre-clinical research as a promising strategy for the treatment of spinal cord injury (SCI). In this article, we systematically review the available pre-clinical literature on the most commonly used cell types in order to assess the body of evidence that may support their translation to human SCI patients. These cell types include Schwann cells, olfactory ensheathing glial cells, embryonic and adult neural stem=progenitor cells, fate-restricted neural=glial precursor cells, and bone-marrow stromal cells. Studies were included for review only if they described the transplantation of the cell substrate into an in-vivo model of traumatic SCI, induced either bluntly or sharply. Using these inclusion criteria, 162 studies were identified and reviewed in detail, emphasizing their behavioral effects (although not limiting the scope of the discussion to behavioral effects alone). Significant differences between cells of the same ''type'' exist based on the species and age of donor, as well as culture conditions and mode of delivery. Many of these studies used cell transplantations in combination with other strategies. The systematic review makes it very apparent that cells derived from rodent sources have been the most extensively studied, while only 19 studies reported the transplantation of human cells, nine of which utilized bone-marrow stromal cells. Similarly, the vast majority of studies have been conducted in rodent models of injury, and few studies have investigated cell transplantation in larger mammals or primates. With respect to the timing of intervention, nearly all of the studies reviewed were conducted with transplantations occurring subacutely and acutely, while chronic treatments were rare and often failed to yield functional benefits.

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

“…To identify the cellular and molecular properties of NSPCs transplanted into chronically injured spinal cords, we combined flow-cytometric isolation and RNA-Seq. We found that NSPCs transplanted into chronically injured spinal cords have a sufficient capacity to produce therapeutic molecules and differentiate into neurons/oligodendrocytes [14]. However, chronic transplantation of NSPCs did not improve locomotor function after SCI.…”

“…The success of stem cell-based strategies is strongly influenced by the timing of transplantation following SCI [14,15], which may be attributable to the changing environment of the injured spinal cord and the adaptation capacity of engrafted cells. Many researchers focused on elucidating pathophysiological processes during the acute and subacute phases of SCI [11,14], but the microenvironment of chronic SCI (more than 42 days after SCI) is still poorly understood.…”

“…Many researchers focused on elucidating pathophysiological processes during the acute and subacute phases of SCI [11,14], but the microenvironment of chronic SCI (more than 42 days after SCI) is still poorly understood. Therefore, we first examined the time course of the change in the number of inflammatory cells until 3 months after SCI using flow cytometry.…”

“…Based on considerable experimental evidences, clinical trials for SCI have been performed or initiated [5,6,10], and stem cell-based therapies using NSPCs are now being translated to patients with chronic SCI [6,11,12]. However, while emerging evidence supports the therapeutic potential of NSPC transplantation for the acute and subacute phases of SCI [4,5,13], few studies have investigated NSPC transplantation for the chronic phase of SCI [14] and its therapeutic efficacy for chronic SCI thus remains controversial [3,14,15].…”

“…In this study, NSPCs were transplanted at 3 months after incomplete contusion injury as chronic phase of SCI [14]. To identify the cellular and molecular properties of NSPCs transplanted into chronically injured spinal cords, we combined flow-cytometric isolation and RNA-Seq.…”