LAR and PTPσ receptors are negative regulators of oligodendrogenesis and oligodendrocyte integrity in spinal cord injury

Abstract

Following spinal cord injury (SCI), the population of mature oligodendrocytes undergoes substantial cell death; promoting their preservation and replacement is a viable strategy for preserving axonal integrity and white matter repair in the injured spinal cord. Dramatic upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) is shown to pose an obstacle to endogenous repair processes, and targeting CSPGs improves functional recovery after SCI. However, the cellular and molecular mechanisms underlying the inhibitory effects of CSPGs remain largely undefined. Modulation of CSPGs specific signaling receptors, leukocyte common antigen‐related (LAR), and protein tyrosine phosphatase‐sigma (PTPσ) allows us to uncover the role and mechanisms of CSPGs in regulating oligodendrocytes in SCI. Here, utilizing specific functionally blocking peptides in a clinically relevant model of contusive/compressive SCI in the rat, we demonstrate that inhibition of PTPσ and LAR receptors promotes oligodendrogenesis by endogenous precursor cells, attenuates caspase 3‐mediated cell death in mature oligodendrocytes, and preserves myelin. In parallel in vitro systems, we have unraveled that CSPGs directly induce apoptosis in populations of neural precursor cells and oligodendrocyte progenitor cells and limit their ability for oligodendrocyte differentiation, maturation, and myelination. These negative effects of CSPGs are mediated through the activation of both LAR and PTPσ receptors and the downstream Rho/ROCK pathway. Thus, we have identified a novel inhibitory role for PTPσ and LAR in regulating oligodendrocyte differentiation and apoptosis in the injured adult spinal cord and a new feasible therapeutic strategy for optimizing endogenous cell replacement following SCI.

PTPσ Knockdown in Lampreys Impairs Reticulospinal Axon Regeneration and Neuronal Survival After Spinal Cord Injury

“…Although most studies on PTPσ have focused on neuronintrinsic effects, PTPσ is also expressed in non-neuronal cells. Reports have suggested that CSPGs antagonize neural progenitor and oligodendrocyte precursor cell survival, proliferation, and differentiation, which can be rescued by deleting PTPσ or inhibiting receptor function with peptides (Dyck et al, , 2019Zhong et al, 2019). Notably, PTPσ is also expressed within the immune system among subpopulations of dendritic cells and, in lower levels among T-cells and microglia (Bunin et al, 2015;Ohtake et al, 2017).…”

“…However, other studies using sciatic nerve injury models reported that deletion of LAR or PTPδ, a third LAR-family RPTP member, reduced sensory axon regeneration and worsened outcomes (Xie et al, 2001;Van der Zee et al, 2003). As a further complication, RPTPs have been reported to modulate the immune responses to CNS injury, as well as the survival and differentiation of local oligodendrocyte precursors and neural progenitors (Dyck et al, , 2018(Dyck et al, , 2019Ohtake et al, 2017).…”

The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury

“…The speed of remyelination following SCI is likely affected by injury‐induced changes in the microenvironment, which have been recently reviewed elsewhere (Alizadeh & Karimi‐Abdolrezaee, ; Plemel et al, ; Pu, Stephenson, & Yong, ; Pukos, Goodus, Sahinkaya, & McTigue, ). Notably, remyelination may be slowed by cytotoxicity near the lesion, insufficient tissue oxygenation (Tsai et al, ; Yuen et al, ), or inhibitory factors in the glial scar and myelin debris (Buss & Schwab, ; Church, Milich, Lerch, Popovich, & McTigue, ; Dyck et al, ; Dyck, Kataria, Akbari‐Kelachayeh, Silver, & Karimi‐Abdolrezaee, ; Keough et al, ; Plemel, Manesh, Sparling, & Tetzlaff, ). Accelerated remyelination is sufficient to preserve axons following T‐cell mediated demyelination (Mei et al, ).…”

2‐arachidonoylglycerol reduces chondroitin sulphate proteoglycan production by astrocytes and enhances oligodendrocyte differentiation under inhibitory conditions

“…Following injury, CSPGs are immediately upregulated to limit tissue damage (Silver & Miller, ), yet when CSPG accumulation persists, spontaneous repair mechanisms are inhibited due to the formation of a non‐permissive environment that restricts oligodendrocyte precursor cell (OPC) differentiation (Chang et al, ; Karus et al, ; Lau et al, ; Pendleton et al, ; Siebert & Osterhout, ; Sobel & Ahmed, ). Importantly, CSPG clearance through the digestion of their glycosaminoglycan (GAG) chains, or the blockage of CSPG synthesis and the disruption of CSPG receptors, all provoke remyelination and axon regeneration in culture, as well as in different experimental conditions of demyelination and spinal cord injury (SCI) (Bartus et al, ; Dyck et al, ; Dyck, Kataria, Akbari‐Kelachayeh, Silver, & Karimi‐Abdolrezaee, ; Keough et al, ; Lang et al, ; Lau et al, ; Rolls et al, ; Siebert & Osterhout, ).…”