The roles of neuronal and glial precursors in overcoming chondroitin sulfate proteoglycan inhibition

Abstract

The extension of axons through the major inhibitory component of the glial scar, chondroitin sulfate proteoglycans (CSPG), remains a key obstacle for regeneration following spinal cord injury (SCI). We have previously shown that transplants composed of neuronal and glial restricted precursors (NRP and GRP respectively) promote regeneration and connectivity in the injured spinal cord (Bonner et al., 2010; 2011), however, little is known about the properties of these precursors at a cellular level. We now report that NRP-derived neurons, in contrast to dorsal root ganglion (DRG) neurons, have the ability to extend axons and cross over from a permissive substratum (laminin) onto inhibitory CSPG in vitro. Growth cones of neurons derived from NRP, compared to DRG, exhibit significantly lower levels of the CSPG receptors protein tyrosine phosphatase sigma (PTPσ) and leukocyte common antigen-related phosphatase (LAR). GRP-conditioned medium prepared from the same cell densities did not affect the response of primary sensory neurons to CSPG confirming that the ability of NRP-derived neurons to cross onto CSPG is determined intrinsically. However, GRP-conditioned medium collected from high density cultures increased the probability of DRG axons to cross from LN onto CSPG and increased the length of DRG axons extending on CSPG. Collectively, these results suggest that (1) neurons derived from NRPs are intrinsically insensitive to CSPGs due to low levels of receptor expression, and (2) high levels of factors secreted by GRP can reduce the inhibitory effects of CSPG and promote axonal growth. These observations provide mechanistic insights into the specific roles of NRPs and GRPs in promoting regeneration and repair following SCI.

Protein tyrosine phosphatase–σ regulates hematopoietic stem cell–repopulating capacity

“…ure 1A). Since PTPσ has been implicated in regulating the regeneration of neural stem cells (16,17), we hypothesized that PTPσ might also regulate HSC function. Ptprs expression was increased significantly in HSCs compared with more mature hematopoietic cell populations ( Figure 1A).…”

NG2+ Progenitors Derived From Embryonic Stem Cells Penetrate Glial Scar and Promote Axonal Outgrowth Into White Matter After Spinal Cord Injury

“…These important findings may not contradict our hypothesis, because it is not possible to differentiate following from scaffolding in postmortem tissue from single time points after injury. Alternatively, the intrinsic nature of embryonic derived axons may represent immaturity with growth across chondroitin sulfate proteoglycans [53], suggestive of axonal elongation without regard to receptor based inhibition, for example, leukocyte common antigen-related phosphatase [54].…”

Chondroitin sulfate functionalized mesostructured silica nanoparticles as biocompatible carriers for drug delivery

“…It is a copolymer of D-glucuronic acid and sulfated N-acetyl-D-galactosamine in C4 or C6 and belongs to the group of glycosaminoglycans (GAGs), which are primarily located on the surface of cells or in the extracellular matrix. 25,26 ChS can be degraded by anaerobic bacteria, namely Bacteroides thetaiotaomicron and Bacteroides ovatus, which are residents of the large intestine. This character suggests that ChS is potentially a good candidate for usage as a drug carrier.…”