Neural Stem Cell-Based Regenerative Approaches for the Treatment of Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory, and demyelinating disorder of the central nervous system (CNS), which ultimately leads to axonal loss and permanent neurological disability. Current treatments for MS are largely comprised of medications that are either immunomodulatory or immunosuppressive and are aimed at reducing the frequency and intensity of relapses. Neural stem cells (NSCs) in the adult brain can differentiate into oligodendrocytes in a context-specific manner and are shown to be involved in the remyelination in these patients. NSCs may exert their beneficial effects not only through oligodendrocyte replacement but also by providing trophic support and immunomodulation, a phenomenon now known as "therapeutic plasticity." In this review, we first provided an update on the current knowledge regarding MS pathogenesis and the role of immune cells, microglia, and oligodendrocytes in MS disease progression. Next, we reviewed the current progress on research aimed toward stimulating endogenous NSC proliferation and differentiation to oligodendrocytes in vivo and in animal models of demyelination. In addition, we explored the neuroprotective and immunomodulatory effects of transplanted exogenous NSCs on T cell activation, microglial activation, and endogenous remyelination and their effects on the pathological process and prognosis in animal models of MS. Finally, we examined various protocols to generate genetically engineered NSCs as a potential therapy for MS. Overall, this review highlights the studies involving the immunomodulatory, neurotrophic, and regenerative effects of NSCs and novel methods aiming at stimulating the potential of NSCs for the treatment of MS.

Keywords: Microglia; Multiple sclerosis; Neural progenitor cell; Neural stem cell; Oligodendrocyte.

Figure 1. NSC survival, differentiation, and immunomodulation are shaped by NSC-microglia cross talk

Microglial derived signals determine NSC survival and differentiation in EAE. Conversely, NSC derived signals cause immunomodulation in microglia via paracrine factors and signaling pathways. Resting microglia stimulated by IL-4 in vitro, promotes Insulin-like growth factor-1 (IGF-1) mediated oligodendrogenesis from adult NPCs in mice [120]. On the other hand, microglia-derived tumor necrosis factor-alpha (TNF-α) induced the expression of the BH3 (Bcl-2 homology domain-3) in NPCs by an NF-k B (nuclear factor- kB)-dependent mechanism and, increases NPC apoptosis by a mitochondrial pathway [121]. Soluble factors released from mouse microglial cells direct the migration of NPCs in vitro and in vivo [117]. In the EAE brain, microglia produce stromal cell-derived factor-1 (SDF-1), monocyte chemo-attractant protein-1 (MCP-1) and hepatocyte growth factor (HGF), responsible for the inflammation-induced attraction of transplanted NPCs into white matter lesions [118]. In an allogeneic co-culture model, both human NPCs and microglia showed increased survival and proliferation, and the release of transforming growth factor-β (TGF-β) was also upregulated. NSCs can induce a significant up-regulation of the surface molecules CX3CR1 on microglia which is associated with a neuroprotective phenotype, and triggering receptor expressed on myeloid cells-2 (TREM2) [119, 122, 123, 124].

Figure 2. Functions of adult NSCs in healthy and EAE (MS) brain

NSCs in the adult mammalian brain have been shown to give rise to rapidly dividing neural progenitor cells (NPCs) to produce neurons, astrocytes, and oligodendrocytes, and functionally contribute to (although modest) cognition and repair processes after injury. In EAE, NSCs have been shown to exert their beneficial effects through a) immunomodulation b) by cell replacement [153], c) by providing trophic support, d) by stimulation of endogenous remyelination [166, 167, 168]. Transplanted NPCs can stimulate endogenous remyelination by inducing the proliferation and terminal differentiation of host OPCs, likely via CXCL12/CXCR4 autocrine signaling post inflammation [87]. NSCs inhibit MOG and MBP specific CD4+T cell activation, proliferation, increased number of FOXP3+ Tregs cells [145, 150, 158, 160]. Intraspinally transplanted NPCs in postnatal mice can differentiate into mature oligodendrocytes and functionally incorporate throughout the demyelinated white matter tracts in JHMV-infected demyelination model [97]. NSCs can transform microglia from a harmful to a neuroprotective phenotype by significantly increasing the expression of molecules associated with a neuroprotective phenotype in adult mouse brain [119, 122, 123, 124]. Transplanted NSCs can indirectly suppress astrocyte gliosis in EAE.