Long-term survival, axonal growth-promotion, and myelination of Schwann cells grafted into contused spinal cord in adult rats

Abstract

Schwann cells (SCs) have been considered to be one of the most promising cell types for transplantation to treat spinal cord injury (SCI) due to their unique growth-promoting properties. Despite the extensive use as donor cells for transplantation in SCI models, the fate of SCs is controversial due in part to the lack of a reliable marker for tracing the grafted SCs. To precisely assess the fate and temporal profile of transplanted SCs, we isolated purified SCs from sciatic nerves of adult transgenic rats overexpressing GFP (SCs-GFP). SCs-GFP were directly injected into the epicenter of a moderate contusive SCI at the mid-thoracic level at 1 wk post-injury. The number of SCs-GFP or SCs-GFP labeled with Bromodeoxyuridine (BrdU) was quantified at 5 min, 1 d, and 1, 2, 4, 12 and 24 wk after cell injection. Basso, Beattie, and Bresnahan (BBB) locomotor rating scale, footfall error, thermal withdrawal latency, and footprint analysis were performed before and after the SCs-GFP transplantation. After transplantation, SCs-GFP quickly filled the lesion cavity. A remarkable survival of grafted SCs-GFP up to 24 wk post-grafting was observed with clearly identified SC individuals. SCs-GFP proliferated after injection, peaked at 2 wk (26% of total SCs-GFP), decreased thereafter, and ceased at 12 wk post-grafting. Although grafted SCs-GFP were mainly confined within the border of surrounding host tissue, they migrated along the central canal for up to 5.0 mm at 4 wk post-grafting. Within the lesion site, grafted SCs-GFP myelinated regenerated axons and expressed protein zero (P0) and myelin basic protein (MBP). Within the SCs-GFP grafts, new blood vessels were formed. Except for a significant decrease of angle of rotation in the footprint analysis, we did not observe significant behavioral improvements in BBB locomotor rating scale, thermal withdrawal latency, or footfall errors, compared to the control animals that received no SCs-GFP. We conclude that SCs-GFP can survive remarkably well, proliferate, migrate along the central canal, and myelinate regenerated axons when being grafted into a clinically-relevant contusive SCI in adult rats. Combinatorial strategies, however, are essential to achieve a more meaningful functional regeneration of which SCs may play a significant role.

Biphasic bisperoxovanadium administration and Schwann cell transplantation for repair after cervical contusive spinal cord injury

“…6). In a recent report, we showed that SCs isolated from this transgenic GFP-expressing SD rat strain showed proliferative and considerable survival potential as assessed through 1 year post-transplantation in a contusive SCI lesion produced in SD rats (Wang and Xu, 2014). As SD rats are outbred rats, this recent study involved long-term administration of the immunosuppressant cyclosporin A to repress potential rejection of the SC graft by the rats.…”

“…Prior to surgery, animals were randomly assigned to five groups: 1) Sham (n = 6), 2) Saline-treated only (Veh, n = 6), 3) bpV(pic) treated (n = 6), 4) GFP-SCs (n = 7), 5) bpV(pic) + GFP-SCs (n = 9). The experimental groups were established based on findings reported in previous publications testing the effects of bpV and SCs alone (Walker et al, 2012; Wang and Xu, 2014). In these experiments, the injury only groups and the injury plus saline group showed no difference.…”

Therapeutical Strategies for Spinal Cord Injury and a Promising Autologous Astrocyte-Based Therapy Using Efficient Reprogramming Techniques

“…These stem cells include NSCs, embryonic stem cells, induced potential stem cells (iPSCs), mesenchymal stem cells, fibroblast-derived stem cells, and transdifferentiated stem cells, which have been demonstrated to enhance partial axonal regeneration and even axon's ability to connect and communicate with other neurons, resulting in restoration [58][59][60][61][62]. Among the grafts, the fetal tissue, peripheral nerves, OECs, and Schwann cells can make the lesion area more conducive to regeneration by producing growth factors, cell adhesion molecules, and extracellular matrix components or recruitment of neurotrophins and construction of biobridges to guide axonal extension across the hostile post-injury spinal cord environment for axonal regeneration [61,62].…”

In vitro evaluation of PLLA/PBS sponges as a promisingbiodegradable scaffold for neural tissue engineering

“…There are also studies showing that the usage of Schwann cells in central nervous system injuries enhanced the regeneration process, and this effect was suspected to be provided by the secreted neurotrophins from the Schwann cells. According to Wang and Xu (2014), injection of Schwann cells directly into the lesion site at the midthoracic level in adult rats promoted myelination of regenerating axons. The transplanted cells survived until week 24 and migrated along the central canal.…”