Transplantation of glial-committed progenitor cells into a viral model of multiple sclerosis induces remyelination in the absence of an attenuated inflammatory response

Abstract

Transplantation of remyelination-competent cells represents a promising strategy for the treatment of demyelinating diseases. As the environment dictates the success or failure of remyelination, it is critical to understand the role that the immune system plays in transplant-mediated remyelination. In this study, we evaluated the severity of neuroinflammation following transplantation of glial-committed progenitor cells into the spinal cords of mice chronically infected with mouse hepatitis virus (MHV), a model in which T cells and macrophages are critical in amplifying the severity of demyelination. Transplantation was performed following viral persistence in which inflammation and demyelination are established and clinical disease is evident. Mice were sacrificed 10 and 21 days following progenitor cell transplantation and the effect on neuroinflammation evaluated. Treatment did not alter accumulation of T cells or macrophages within the CNS as compared to control mice. Moreover, progenitor cell implantation did not affect local cytokine/chemokine gene expression in the CNS. Finally, remyelination associated with transplantation did not result in an imbalance of T(H)1-associated cytokine production by virus-specific T cells. These studies demonstrate that progenitor cell-mediated remyelination is not the result of modulating the composition of the cellular infiltrate nor cytokine expression by virus-specific T cells and suggest that remyelination may not depend on amelioration of the inflammatory response or alteration of cytokine secretion by virus-specific T cells.

Olig1 function is required for remyelination potential of transplanted neural progenitor cells in a model of viral-induced demyelination

“…Quantification of demyelination in experimental mice indicated a similar level of myelin damage in recipients of either WT or Olig1−/− NPCs compared to vehicle control (Figure 2B). Importantly, these findings are consistent with earlier results and indicate that transplantation of NPCs neither exacerbate nor ameliorate JHMV-induced immunopathology and this was associated with no attenuation in neuroinflammation (Hardison, et al, 2006, Totoiu, et al, 2004). …”

“…Surgically engrafted NPCs preferentially migrate and accumulate within areas of white matter damage in JHMV-infected mice (Hardison, et al, 2006, Totoiu, et al, 2004). Moreover, we have determined that migration is mediated through CXCR4 expressed on transplanted NPCs responding to CXCL12 that is expressed within demyelinating lesions (Carbajal, et al, 2010).…”

“…Our laboratory has recently demonstrated that transplantation of syngeneic mouse NPCs into mice persistently infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) is well tolerated and is associated with axonal sparing accompanied by extensive remyelination while not significantly dampening either neuroinflammation or T cell responses (Hardison, et al, 2006, Totoiu, et al, 2004). Evident from this work is i) the ability of engrafted cells to migrate to regions of demyelination by responding to the chemokine ligand CXCL12 (Carbajal, et al, 2010) and ii) preferential differentiation of transplanted NPCs into oligodendrocyte progenitor cells (OPCs) ((Carbajal, et al, 2010, Totoiu, et al, 2004).…”

ICV‐transplanted human glial precursor cells are short‐lived yet exert immunomodulatory effects in mice with EAE

“…Stem cells are immature cells that differentiate into multiple lineages and provide promising treatment strategies for several neurodegenerative diseases, including MS (Payne et al, 2008). In the animal model of MS, transplanted cells were shown to have the following positive effects on the pathogenesis of MS: (1) generation of oligodendrocytes (Pluchino et al, 2003) with capacity for remyelination (Hardison et al, 2006); (2) inhibition of T cell proliferation in the peripheral lymphoid organs (Einstein et al, 2007); (3) alteration of antigen-presenting cells (Pluchino et al, 2009); and (4) generation of anti-inflammatory cells to restore immune system balance (Takahashi et al, 2007). Although many multipotent stem cells have been developed and their functionality have been documented in vitro and/or in vivo , little is known about which cells are optimally suited for the treatment of MS.…”

Mouse hepatitis virus infection of the CNS: a model for defense, disease, and repair

“…We have previously determined that intraspinal transplantation of OPCs into the mice persistently infected with MHV resulted in extensive migration of transplanted cells, robust remyelination, axonal sparing, and behavioral improvement (121). Moreover, implantation of OPCs did not modulate the severity of inflammation, indicating that remyelination can occur in a pathogenic environment (122). These results show that transplant-mediated remyelination is possible following intraspinal transplantation into an environment of ongoing pathogenesis resembling MS. We believe that the transplanted progenitor cells are likely using specific chemokine receptors to allow for positional migration into areas of demyelination and are directly responsible for the remyelination of demyelinated axons (Figure 4).…”