Many MS treatments are geared towards reducing neuroinflammation with ultimate goal of attenuating progression of disease (Rizvi and Agius, 2004
). However, these treatments often do not address the neurodegenerative phase of disease i.e.
demyelination and axonal loss. Indeed, remyelination can occur spontaneously in the adult human brain as evidenced by shadow plaques, in which large regions of white matter undergo remyelination with characteristically thin myelin sheaths (Halfpenny et al., 2002
). However remyelination does not occur uniformly within a lesion or across many lesions. Two major events have been proposed to explain the failure of remyelination in MS: (i) difficulties in recruiting oligodendrocyte progenitor cells (OPCs) to areas of active demyelination and (ii) inhibition in differentiation of OPCs into myelin-competent oligodendrocytes capable of promoting remyelination (Franklin, 2002
). In each of these two possibilities, signaling by growth factors, cytokines/chemokines, and extracellular matrix molecules expressed during neuroinflammation are thought to contribute to an environment restrictive to remyelination by endogenous oligodendrocytes.
Stem cells and neural precursors represent attractive sources for the generation of remyelination-competent cells, as they can be readily amplified and differentiated to the oligodendrocyte lineage (Ben-Hur et al., 1998
; Brustle et al., 1999b
). Studies in animal models have proven invaluable for identifying new methods for inducing remyelination in animals with established demyelination. Transplant of rodent embryonic stem cells into myelin-deficient shiverer mice resulted in cellular migration in the spinal cord, differentiation into oligodendrocytes and astrocytes, and myelination of axons (Brustle et al., 1999a
). Similarly, transplant of human embryonic stem cell (hESC) derived oligodendrocyte progenitor cells into myelin-deficient shiverer mice resulted in oligodendrocyte differentiation and remyelination (Nistor et al., 2005
). Animal models of demyelination have also reported reduced demyelination following transplantation of stem cells. For example, transplantation of stem cells into animal models of acute demyelination resulted in remyelination (Cao et al., 2002
). Injection of adult neuronal precursors into mice with EAE induced recovery from disease and a significant decrease in the level of demyelination (Pluchino et al., 2003
; Pluchino et al., 2005
). Similarly, transplantation of stromal bone marrow cells into demyelinated rat spinal cord yielded remyelination (Akiyama et al., 2002
Transplantation of human OPCs (hOPCs) generated from hESCs into spinal cord injured rats results in successful engraftment associated with cell survival and functional recovery (Keirstead et al., 2005
). In addition, studies have also supported that neural progenitor cells inherently are not immunogenic as they do not elicit an immune response and resist destruction as allografts over relatively short periods of time (Hori et al., 2003
; Hori et al., 2007
; Modo et al., 2002
). Moreover, xenogeneic transplantation of hNSCs derived from hESCs resulted in suppression of the host immune response (Akesson et al., 2009
) and these observations have been supported in additional studies involving transplantation of hNSCs into non-human primate models of demyelination (Pluchino et al., 2009a
). Nonetheless, not all studies support that stem cells or their derivatives are immunosuppressive and/or resist rejection following transplantation. This was recognized by studies over 20 years ago that demonstrated that transplantation of allogeneic neural cells into the CNS of recipient mice resulted in immune cell infiltration and rejection (Mason et al., 1986
; Nicholas et al., 1987a
; Nicholas et al., 1987b
). Transplantation of allogeneic mixed glial cell cultures resulted in remyelination failure and graft rejection by one month in rats with demyelinating lesions induced by spinal cord injection of ethidium bromide (Tepavcevic and Blakemore, 2006
). More recently, elegant tracking methodologies employed by Swijnenburg et al. (Swijnenburg et al., 2008
) demonstrated hESCs are rapidly rejected following injection into immune-competent mice. Indeed, we have also determined that hOPCs derived from hESCs transplanted into MHV-infected mice do not survive and only focal remyelination occurs that is most likely mediated by endogenous OPCs (Hatch et al., 2009
). Grinnemo et al. (Grinnemo et al., 2006
) showed that hESCs expressed HLA class I and II genes and elicited robust infiltration of T cells and macrophages that surrounded hESCs soon after transplantation. Collectively, these findings emphasize the potential clinical hurdles facing transplantation of stem cells for therapeutic use. Even though stem cells reportedly express low levels of MHC antigens, even single differences between donor ESC and recipient minor histocompatibility antigens may facilitate graft rejection (Robertson et al., 2007
). Therefore, it is critical to investigate novel strategies to induce sustained “life-long” tolerance to ensure long-term survival of stem cells.
This brief review will summarize recent studies from our group that have investigated the therapeutic potential of both mouse and human stem cells to promote repair following transplantation into the CNS of mice persistently infected with MHV. Focus points will include a comparison of the therapeutic benefits of cell replacement therapies using these two distinct stem cell populations and discussion about the potential role for chemokines in contributing to the positional migration of these cells following engraftment.