Schwann cell transplantation and descending propriospinal regeneration after spinal cord injury

Highlights

• Schwann cell (SC) is a promising treatment for spinal cord injury (SCI).

• Propriospinal (PS) axons have powerful intrinsic capacity to regenerate.

• SCs promote extensive propriospinal regeneration.

• This review focuses on optimizing SCs transplantation strategy for PS regeneration.

• This discussion will benefit the clinical trial of SCs transplantation for SCI.

Abstract

After spinal cord injury (SCI), poor ability of damaged axons of the central nervous system (CNS) to regenerate causes very limited functional recovery. Schwann cells (SCs) have been widely explored as promising donors for transplantation to promote axonal regeneration in the CNS including the spinal cord. Compared with other CNS axonal pathways, injured propriospinal tracts display the strongest regenerative response to SC transplantation. Even without providing additional neurotrophic factors, propriospinal axons can grow into the SC environment which is rarely seen in supraspinal tracts. Propriospinal tract has been found to respond to several important neurotrophic factors secreted by SCs. Therefore, the SC is considered to be one of the most promising candidates for cell-based therapies for SCI. Since many reviews have already appeared on topics of SC transplantation in SCI repair, this review will focus particularly on the rationale of SC transplantation in mediating descending propriospinal axonal regeneration as well as optimizing such regeneration by using different combinatorial strategies.

This article is part of a Special Issue entitled SI: Spinal cord injury.

Introduction

After spinal cord injury (SCI), rostrocaudal axonal regeneration is crucial for significant functional recovery; however, neurons of the mature central nervous system (CNS) are believed to have low regenerative ability. In some central axons, an early growth response may be seen, but this response is abortive and generally does not create meaningful connections (Hall and Berry, 1989, Steward et al., 2008, Zeng et al., 1994). The abortive regeneration of CNS axons contributes heavily to the poor recovery observed after SCI. In the early 1980s, the elegant experiments done by Aguayo and colleagues demonstrated that the peripheral nerve (PN) milieu, mainly composed of Schwann cells (SCs), was more favorable for regeneration of injured CNS axons than the CNS environment (Bray et al., 1987, David and Aguayo, 1981, Richardson et al., 1980, Richardson et al., 1982, Richardson et al., 1984). Since then, many therapeutic strategies have been established through transplantation of either a PN segment containing SCs or SCs isolated from the PN (Decherchi and Gauthier, 2000; Houle, 1991; Houle et al., 2006; Iannotti et al., 2003; Levi et al., 2002; Oudega et al., 2001; Xu et al., 1995b, Xu et al., 1997. These experiments strongly support the premise of using SCs for repair after SCI (Wiliams and Bunge, 2012). To date, most regeneration studies after SCI have focused on long supraspinal pathways that project from the brain or brainstem to the spinal cord such as the corticospinal (CST) and rubrospinal (RST) tracts. However, regeneration of these long supraspinal tracts is difficult to achieve (Deng et al., 2013, Guest et al., 1997a, Kanno et al., 2014, Lee et al., 2013, Papastefanaki et al., 2007, Tuszynski et al., 1998, Xu et al., 1995a). On the contrary, although greatly understudied, propriospinal tracts (PSTs) possess greater innate regenerative capacity, and have been shown to strongly respond to PN/SC grafts (Deng et al., 2013, Iannotti et al., 2003, Xu et al., 1995b, Xu et al., 1997). The regenerative response of the PSTs could even result in a significant functional recovery after SCI (Deng et al., 2013). In this review, we will discuss results obtained from both PN and SC transplantation into injured spinal cords. We will discuss some unique characteristics of the PSTs, their responses to SC transplantation, and their limitations.

The propriospinal tract (PST) is important in mediating and maintaining a variety of normal spinal functions including reflexes, posture, and locomotion (Cowley et al., 2008, Jankowska, 1992, Kostyuk and Vasilenko, 1979). The neurons within the PST constitute an uninterrupted cell column and their axons project either unilaterally or bilaterally in the rostrocaudal plane and directly affect motoneurons and interneurons in multiple cord segments (Szentagothai, 1964). Anatomically, PSTs are classified as either “short” or “long” PST based on the distances of their axon projections (Cowley et al., 2010). Although argument still exists as to what defines a short or long PN, we consider short PSTs (sPSTs) as those spanning less than six spinal segments, whereas long PSTs (lPSTs) project further than six spinal segments (Flynn et al., 2011). Short propriospinal pathways interconnecting several neighboring segments are located both in the lateral and ventral funiculus (Sterling and Kuypers, 1968), The sPSTs with cell bodies medially located in the grey matter often project contralaterally, while the sPSTs with cell bodies laterally located project ipsilaterally. The sPSTs can project bidirectionally (Burton and Loewy, 1976, Matsushita, 1970, Menetrey et al., 1985, Petko and Antal, 2000). In line with classical studies by Romanes and Sprague who demonstrated a medio-lateral division between motoneurons and their target muscle groups, within the limb enlargements (Romanes, 1951, Sprague, 1948), Kuypers and colleagues proposed a somatotopic organization of sPSTs. The sPSTs originating in neurons within the ventromedial grey matter (lamina VIII and the medial portion of lamina VII), innervate and influence motoneurons supplying axial muscles as their axons terminate within and around medial motoneurons pools. Correspondingly, the soma of sPSTs located in lateral regions (lateral parts of laminae VII) innervate motoneurons supplying more distal limb muscles, as their axons terminate in the vicinity of the lateral motoneuron pools (Molenaar and Kuypers, 1978, Sterling and Kuypers, 1968). lPSTs that are involved in locomotor activity reciprocally connect cervical and lumbar enlargements and are concentrated in the ventral quadrants (Giovanelli Barilari and Kuypers, 1969). The anatomical distinction that can be made with respect to lPST is whether their cell bodies are located rostrally (within the cervical enlargement) and project caudally, or vice-versa. These two populations are termed long descending PST (ldPST) and long ascending PST (laPST), respectively (Giovanelli Barilari and Kuypers, 1969, Matsushita and Ueyama, 1973, Molenaar and Kuypers, 1978). The function of ldPSTs is involved in feed-forward inhibition of supraspinal command and reciprocal connection of cervical and lumbar motor circuits (Alstermark et al., 1991a, Alstermark et al., 1999, Isa et al., 2006). The laPST system was found to play an important role in locomotion by coupling neural activity in cervical and lumbar enlargements (Cote et al., 2012, Miller et al., 1973). Propriospinal neurons receive strong and convergent supraspinal innervations including those from the corticospinal (CST), rubrospinal (RST), reticulospinal (ReST) and vestibulospinal (VST) tracts (Alstermark et al., 1987, Alstermark et al., 1991b, Illert et al., 1977, Kostyuk and Vasilenko, 1978, Nishimura et al., 2009, Robbins et al., 1992, Skinner et al., 1979). Such signal relay has significance in transporting supraspinal command down to the spinal cord not only in normal physiological but also in pathological conditions (Fig. 1).

Several critical literatures concluded that supraspinal axons, which usually fail to regenerate through and beyond the lesion site, form “new” contacts with spared intraspinal or propriospinal circuits projecting past a SCI lesion to lumbar segments. Such supraspinal–propriospinal reorganization formed an anatomical “bridge” allowing transmission of descending signals below the lesion to activate the lumbar locomotor central pattern generator (CPG) (Bareyre et al., 2004, Courtine et al., 2008, Cowley et al., 2008, Vavrek et al., 2006). Such plasticity occurred based on the intact propriospinal system spared following an incomplete SCI. However, for a severe injury such as a complete SCI, axonal regeneration through and beyond the injury is required to achieve meaningful functional recovery. Descending propriospinal axons (dPSTs) are uniquely suited for reestablishing connections across the lesion since they show greater growth responses after SCI than long-tract axons (Deng et al., 2013, Iannotti et al., 2003, Xu et al., 1995b, Zhang et al., 2009). Therefore, the plasticity of CST axons that innervate dPST neurons and subsequent regeneration of dPST axons beyond the lesion site may provide an alternative pathway or “functional relay” for transmission of supraspinal motor command down to the spinal cord to promote motor recovery.