Sciatic Nerve Regeneration by Cocultured Schwann Cells and Stem Cells on Microporous Nerve Conduits

Abstract

Cell transplantation is a useful therapy for treating peripheral nerve injuries. The clinical use of Schwann cells (SCs), however, is limited because of their limited availability. An emerging solution to promote nerve regeneration is to apply injured nerves with stem cells derived from various tissues. In this study, different types of allogeneic cells including SCs, adipose-derived adult stem cells (ASCs), dental pulp stem cells (DPSCs), and the combination of SCs with ASCs or DPSCs were seeded on nerve conduits to test their efficacy in repairing a 15-mm-long critical gap defect of rat sciatic nerve. The regeneration capacity and functional recovery were evaluated by the histological staining, electrophysiology, walking track, and functional gait analysis after 8 weeks of implantation. An in vitro study was also performed to verify if the combination of cells led to syner-gistic neurotrophic effects (NGF, BDNF, and GDNF). Experimental rats receiving conduits seeded with a combination of SCs and ASCs had the greatest functional recovery, as evaluated by the walking track, functional gait, nerve conduction velocity (NCV), and histological analysis. Conduits seeded with cells were always superior to the blank conduits without cells. Regarding NCV and the number of blood vessels, conduits seeded with SCs and DPSCs exhibited better values than those seeded with DPSCs only. Results from the in vitro study confirmed the synergistic NGF production from the coculture of SCs and ASCs. It was concluded that coculture of SCs with ASCs or DPSCs in a conduit promoted peripheral nerve regeneration over a critical gap defect.

Stimulating the Neurotrophic and Angiogenic Properties of Human Adipose-Derived Stem Cells Enhances Nerve Repair

“…We showed that Schwann cell-like differentiated ASC could enhance motor neuron regeneration and improve evoked electrical potentials in the gastrocnemius muscle [26] and also at early stages of regeneration, we observed a down-regulation of apoptotic markers in the DRG which was suggestive of a pro-survival effect [29]. Undifferentiated rat ASC have also been shown to enhance peripheral nerve repair [28,30], and they may act synergistically with Schwann cells to secrete growth factors such as NGF [25]. Alternatively, the stem cells can be neurally induced to release enhanced levels of BDNF, which is necessary for their nerve stimulatory effects [27].…”

“…Transplantation of rat ASC in nerve conduits promotes nerve regeneration, enhances nerve conduction velocities, and reduces muscle atrophy and sensory neuron cell death after sciatic nerve injury [25][26][27][28][29][30]. To date, only a few reports show these results can be replicated using human ASC.…”

Adipose-Derived Stem Cells for Nerve Repair: Hype or Reality?

“…Unfortunately, in those studies a direct comparison with differentiated cells was not made. An alternative approach has been to use undifferentiated stem cells transplanted in coculture with Schwann cells, which gives better functional and morphological results than using ADSCs alone [Dai et al, 2013]. Another route to clinical translation might be to bypass the use of living cells and instead isolate exosomes/microvesicles from the cells.…”

“…The cytokine CXCL5 is produced abundantly by ADSCs and is responsible for promoting neurite outgrowth from rat major pelvic ganglia and stimulating signaling cascades in Schwann cells [Zhang et al, 2011]. Coculture of Schwann cells and ADSCs synergistically upregulates the expression of NGF, BDNF and glial cellderived neurotropic factor (GDNF) [Dai et al, 2013]. Both undifferentiated stem cells and those treated with stimulating factors can induce neurite outgrowth, but only the later type can form myelin in vitro [Wei et al, 2010].…”

Expression of Nrf2 Promotes Schwann Cell-Mediated Sciatic Nerve Recovery in Diabetic Peripheral Neuropathy

“…Dai et al . tested the efficacy of different types of allogeneic cells including SCs, ASCs, dental pulp stem cells (DPSCs), and the combination of SCs with ASCs or DPSCs seeded on nerve conduits to repair rat sciatic nerves [13]. A combination of SCs and ASCs or DPCs resulted in the greatest functional recovery, as evaluated by walking track, functional gait, nerve conduction velocity, and histological analysis.…”