Abstract
Peripheral nerve injuries arising from trauma or disease can lead to sensory and motor deficits and neuropathic pain. Despite the purported ability of the peripheral nerve to self-repair, lifelong disability is common. New molecular and cellular insights have begun to reveal why the peripheral nerve has limited repair capacity. The peripheral nerve is primarily comprised of axons and Schwann cells, the supporting glial cells that produce myelin to facilitate the rapid conduction of electrical impulses. Schwann cells are required for successful nerve regeneration; they partially “de-differentiate” in response to injury, re-initiating the expression of developmental genes that support nerve repair. However, Schwann cell dysfunction, which occurs in chronic nerve injury, disease, and aging, limits their capacity to support endogenous repair, worsening patient outcomes. Cell replacement-based therapeutic approaches using exogenous Schwann cells could be curative, but not all Schwann cells have a “repair” phenotype, defined as the ability to promote axonal growth, maintain a proliferative phenotype, and remyelinate axons. Two cell replacement strategies are being championed for peripheral nerve repair: prospective isolation of “repair” Schwann cells for autologous cell transplants, which is hampered by supply challenges, and directed differentiation of pluripotent stem cells or lineage conversion of accessible somatic cells to induced Schwann cells, with the potential of “unlimited” supply. All approaches require a solid understanding of the molecular mechanisms guiding Schwann cell development and the repair phenotype, which we review herein. Together these studies provide essential context for current efforts to design glial cell-based therapies for peripheral nerve regeneration.
Highlights
Introduction to Cellular ReprogrammingAn alternative approach to generate Schwann cells for repair is cellular reprogramming, which converts accessible sources of terminally differentiated somatic cells to a Schwann cell fate (Lujan and Wernig, 2013)
More information is required if we are to fully exploit the power of glial cell replacement therapies, either by devising new strategies for the prospective isolation of endogenous ‘‘repair’’ Schwann cells or by engineering an exogenous source of these cells using lineage conversion strategies, as described later. Another important consideration is that Schwann cells derived from the skin, adult nerve, and embryo all differ in their proliferative, myelination, and repair capacity (Krause et al, 2014; Kumar et al, 2016), but whether these differences lie in population heterogeneity, or inherent differences in their myelinating and repair potential, is not known (Arthur-Farraj et al, 2012, 2017; Jessen and Mirsky, 2019b; Toma et al, 2020)
Schwann cells originate from migratory neural crest cells (NCCs) that emerge at the intersection between the neural and non-neural ectoderm and undergo an epithelialto-mesenchymal transition before following distinct migratory paths, with pathway selection influencing final cell fates (Le Douarin and Dupin, 2003; Le Douarin et al, 2004; SaukaSpengler and Bronner-Fraser, 2008; Stuhlmiller and GarcíaCastro, 2012)
Summary
Myelin, which is comprised of layers of tightly compacted cell membranes, is laid down in internodal segments, which are interspersed with myelin-sparse regions known as nodes of Ranvier (Figure 1; Rasband and Peles, 2015). More information is required if we are to fully exploit the power of glial cell replacement therapies, either by devising new strategies for the prospective isolation of endogenous ‘‘repair’’ Schwann cells or by engineering an exogenous source of these cells using lineage conversion strategies, as described later Another important consideration is that Schwann cells derived from the skin, adult nerve, and embryo all differ in their proliferative, myelination, and repair capacity (Krause et al, 2014; Kumar et al, 2016), but whether these differences lie in population heterogeneity (i.e., different frequencies of Schwann cells with reparative potential within each population), or inherent differences in their myelinating and repair potential, is not known (Arthur-Farraj et al, 2012, 2017; Jessen and Mirsky, 2019b; Toma et al, 2020). Other possibilities include future analyses of Schwann cell surface proteomes to identify novel markers that may be used to identify and prospectively isolate repair Schwann cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
