CXCR4 signaling regulates remyelination by endogenous oligodendrocyte progenitor cells in a viral model of demyelination

Abstract

Following intracranial infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV), susceptible mice will develop widespread myelin destruction that results in pathological and clinical outcomes similar to those seen in humans with the demyelinating disease Multiple Sclerosis (MS). Partial remyelination and clinical recovery occurs during the chronic phase following control of viral replication yet the signaling mechanisms regulating these events remain enigmatic. Here we report the kinetics of proliferation and maturation of oligodendrocyte progenitor cells (OPCs) within the spinal cord following JHMV-induced demyelination and that CXCR4 signaling contributes to the maturation state of OPCs. Following treatment with AMD3100, a specific inhibitor of CXCR4, mice recovering from widespread demyelination exhibit a significant (P < 0.01) increase in the number of OPCs and fewer (P < 0.05) mature oligodendrocytes compared with HBSS-treated animals. These results suggest that CXCR4 signaling is required for OPCs to mature and contribute to remyelination in response to JHMV-induced demyelination. To assess if this effect is reversible and has potential therapeutic benefit, we pulsed mice with AMD3100 and then allowed them to recover. This treatment strategy resulted in increased numbers of mature oligodendrocytes, enhanced remyelination, and improved clinical outcome. These findings highlight the possibility to manipulate OPCs in order to increase the pool of remyelination-competent cells that can participate in recovery.

Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction

“…Previous studies have demonstrated neuroprotective effects of CXCL12/CXCR4 in regulating the antiapoptotic kinase Akt (60) and various cell cycle proteins, whose aberrant expression in postmitotic neurons leads to cell death (2-4). This signaling pair also decreases excitotoxicity by regulating the subunit composition of extrasynaptic NMDA receptors (5) and promotes tissue repair by regulating differentiation and migration of progenitor cells in models of multiple sclerosis (7,61) and ischemia (8,62). Additionally, CXCL12 has been shown to block a reduction in hippocampal dendritic spines caused by the neurotoxin amyloid β (63), although this study did not report any changes in spine density in the absence of amyloid β.…”

Targeting CXCR7/ACKR3 as a therapeutic strategy to promote remyelination in the adult central nervous system

“…In a viral model of demyelination, CXCR4 signaling was indispensable for OPC proliferation and enhanced remyelination (Carbajal et al, 2011). Furthermore, AMD3100 treatment Statistical analysis.…”

How stem cells speak with host immune cells in inflammatory brain diseases

“…The activation of the CXCR4/SDF-1α signaling pathway on NPCs and MSCs increases their migratory capacity, survival, and remyelinating capacity, both in vitro on slice cultures (Corti et al, 2005;Imitola et al, 2004b), as well as in vivo upon focal transplantation into rodents with experimental cerebral ischemia (Robin et al, 2006;Wang et al, 2008), and JHMV-induced demyelination (Carbajal et al, 2010(Carbajal et al, , 2011. In human NPCs, integrins α2, α6, and β preferentially mediate the homing toward the vasculature, whereas the CXCR4/ SDF-1α signaling pathway regulates homing through the brain parenchyma (Carbajal et al, 2010;Mueller et al, 2006;van der Meulen et al, 2009).…”