Transduced Schwann cells promote axon growth and myelination after spinal cord injury

Abstract

We sought to directly compare growth and myelination of local and supraspinal axons by implanting into the injured spinal cord Schwann cells (SCs) transduced ex vivo with adenoviral (AdV) or lentiviral (LV) vectors encoding a bifunctional neurotrophin molecule (D15A). D15A mimics actions of both neurotrophin-3 and brain-derived neurotrophic factor. Transduced SCs were injected into the injury center 1 week after a moderate thoracic (T8) adult rat spinal cord contusion. D15A expression and bioactivity in vitro; D15A levels in vivo; and graft volume, SC number, implant axon number and cortico-, reticulo-, raphe-, coerulo-spinal and sensory axon growth were determined for both types of vectors employed to transduce SCs. ELISAs revealed that D15A-secreting SC implants contained significantly higher levels of neurotrophin than non-transduced SC and AdV/GFP and LV/GFP SC controls early after implantation. At 6 weeks post-implantation, D15A-secreting SC grafts exhibited 5-fold increases in graft volume, SC number and myelinated axon counts and a 3-fold increase in myelinated to unmyelinated (ensheathed) axon ratios. The total number of axons within grafts of LV/GFP/D15A SCs was estimated to be over 70,000. Also 5-HT, DbetaH, and CGRP axon length was increased up to 5-fold within D15A grafts. In sum, despite qualitative differences using the two vectors, increased neurotrophin secretion by the implanted D15A SCs led to the presence of a significantly increased number of axons in the contusion site. These results demonstrate the therapeutic potential for utilizing neurotrophin-transduced SCs to repair the injured spinal cord.

Human Schwann Cells Retain Essential Phenotype Characteristics After Immortalization

“…Indeed, SCs have been shown to promote axonal regeneration and remyelinate regrowing axons in various experimental paradigms of CNS and PNS injury [3,[25][26][27]. These studies support the idea that in humans, after nerve injury, autologous SCs could be obtained from healthy nerves, expanded ex vivo, and retransplanted at the sites of injury [28,29].…”

Effect of Low-Intensity Pulsed Ultrasound on Nerve Repair

“…Additionally, some studies using genetically modified Schwann cells to overexpress the NT-3 gene have examined the role of NT-3 in the neuron survival and axonal regeneration/remyelination (Zhang, Zeng et al 2007;Pettingill, Minter et al 2008). It has been reported that Schwann cells transduced ex vivo with adenoviral (AdV) or lentiviral www.intechopen.com (LV) vectors encoding a functional NT-3 molecule led to the presence of a significantly increased number of axons in the contusion site (Golden, Pearse et al 2007). The results of Yamauchi (Yamauchi, Miyamoto et al 2005) et al showed that NT-3 activation of TrkC stimulates Schwann cell migration through two parallel signaling units, Ras/Tiam1/Rac1 and Dbs/Cdc.…”

Peripheral Nerve Grafts Support Regeneration after Spinal Cord Injury

“…Here, we will discuss some basic technical aspects of using a PNG to promote regeneration, the application of PNGs to a variety of injury conditions (including a delayed grafting [chronic injury] approach), the use of PNGs in a combinatorial treatment strategy, and the translation of peripheral nerve (PN) grafting to large animal models of spinal cord injury (SCI). This review focuses on results obtained from grafting peripheral nerve segments into the injured spinal cord, but it would be remiss not to mention that alternative approaches using components of peripheral nerves (e.g., purified Schwann cells in implantable guidance channels [11][12][13][14][15][16][17][18][19][20][21], or the re-routing of a peripheral nerve from its target muscle to enter the spinal cord distal to an injury [22][23][24]) have demonstrated considerable success in establishing connectivity across a lesion site. Notably, the number of Electronic supplementary material The online version of this article (doi:10.1007/s13311-011-0024-6) contains supplementary material, which is available to authorized users.…”