Schwann Cells Generated from Neonatal Skin-Derived Precursors or Neonatal Peripheral Nerve Improve Functional Recovery after Acute Transplantation into the Partially Injured Cervical Spinal Cord of the Rat

Abstract

The transplantation of Schwann cells (SCs) holds considerable promise as a therapy for spinal cord injury, but the optimal source of these cells and the best timing for intervention remains debatable. Previously, we demonstrated that delayed transplantation of SCs generated from neonatal mouse skin-derived precursors (SKP-SCs) promoted repair and functional recovery in rats with thoracic contusions. Here, we conducted two experiments using neonatal rat cells and an incomplete cervical injury model to examine the efficacy of acute SKP-SC transplantation versus media control (Experiment 1) and versus nerve-derived SC or dermal fibroblast (Fibro) transplantation (Experiment 2). Despite limited graft survival, by 10 weeks after injury, rats that received SCs from either source showed improved functional recovery compared with media-or fibroblast-treated animals. Compared with media treatment, SKP-SC-transplanted rats showed enhanced rubrospinal tract (RST) sparing/plasticity in the gray matter (GM) rostral to injury, particularly in the absence of immunosuppression. The functional benefits of SC transplantations over fibroblast treatment correlated with the enhanced preservation of host tissue, reduced RST atrophy, and/or increased RST sparing/plasticity in the GM. In summary, our results indicate that: (1) early transplantation of neonatal SCs generated from skin or nerve promotes repair and functional recovery after incomplete cervical crush injury; (2) either of these cell types is preferable to Fibros for these purposes; and (3) age-matched SCs from these two sources do not differ in terms of their reparative effects or functional efficacy after transplantation into the injured cervical spinal cord.

Does the preclinical evidence for functional remyelination following myelinating cell engraftment into the injured spinal cord support progression to clinical trials?

“…The hope in transplanting SCs into the spinal cord after SCI is that enhanced remyelination will lead to greater functional recovery. In these final 6 papers that met the latter inclusion criteria, SC grafting alone typically did not change the number of myelinated axons in the spinal cord after injury (Flora et al, 2013; Lavdas et al, 2010; Pearse et al, 2004; Pearse et al, 2007; Sparling et al, 2015; Takami et al, 2002), with the exception of two papers (Pearse et al, 2004; Takami et al, 2002). The source of SCs did not appear to have a consistent effect on overall remyelination.…”

“…Sparling et al (2015) took a different approach to SC transplantation. Unlike other studies in this group that waited one week after injury, they transplanted SCs immediately after C4/5 crush injury of the left dorsal longitudinal fasciculus.…”

“…Three papers from the final 6 showed clear evidence that remyelination by the transplanted cells was occurring (Lavdas et al, 2010; Pearse et al, 2007; Sparling et al, 2015). This is an important distinction as endogenous SCs are also recruited into the spinal cord after injury (Beattie et al, 1997; Perez-Bouza et al, 1998).…”

Adult tissue–derived neural crest-like stem cells: Sources, regulatory networks, and translational potential

“…Similarly, rat‐derived SKP‐SCs aided sensory, motor, and behavioral recovery, and enhanced peripheral nerve regeneration compared with acellular nerve grafts . Finally, SC generated from SKPs were used successfully for the treatment of incomplete cervical SCI …”

Heregulin-1β Promotes the Synergistic Effect Between Allogenic Skin-Derived Precursor Differentiated Schwann Cells (SKP-SC) and Acellular Nerve Allograft (ANA) in Peripheral Nerve Regeneration Through Inhibiting Mir-21

“…The differentiation of stem cells into Schwann cells and neural stem cells were proposed as candidates for transplantation with the potential to replace lost neurons or increase the number of glial support cells, and finally rescue and replenish axotomized neurons (Kitada, 2012;Vroemen et al, 2007). Recently, skin-derived precursors (SKPs), a type of novel multipotent progenitor cell, have been reported in the dermis of both neonatal and adult skin, which are characterized by similar gene expression patterns and functional properties as neural crest-derived cells in the embryonic stage (McKenzie et al, 2006;Sparling et al, 2015). Previous research demonstrated that SKPs can be induced to differentiate into neurons and Schwann cells (SKPSCs) under specific differentiating culture conditions (Fernandes et al, 2004;Zhang et al, 2014), which may be an accessible and efficacious cell source for remarkably promoting peripheral nerve regeneration in 15 mm nerve defects in rats through being seeded into ANA (Seo et al, 2013).…”