Unveiling the fate and potential neuroprotective role of neural stem/progenitor cells in multiple sclerosis

Abstract

Chronic pathological conditions often induce persistent systemic inflammation, contributing to neuroinflammatory diseases like Multiple Sclerosis (MS). MS is known for its autoimmune-mediated damage to myelin, axonal injury, and neuronal loss which drive disability accumulation and disease progression, often manifesting as cognitive impairments. Understanding the involvement of neural stem cells (NSCs) and neural progenitor cells (NPCs) in the remediation of MS through adult neurogenesis (ANG) and gliogenesis-the generation of new neurons and glial cells, respectively is of great importance. Hence, these phenomena, respectively, termed ANG and gliogenesis, involve significant structural and functional changes in neural networks. Thus, the proper integration of these newly generated cells into existing circuits is not only key to understanding the CNS's development but also its remodeling in adulthood and recovery from diseases such as MS. Understanding how MS influences the fate of NSCs/NPCs and their possible neuroprotective role, provides insights into potential therapeutic interventions to alleviate the impact of MS on cognitive function and disease progression. This review explores MS, its pathogenesis, clinical manifestations, and its association with ANG and gliogenesis. It highlights the impact of altered NSCs and NPCs' fate during MS and delves into the potential benefits of its modifications. It also evaluates treatment regimens that influence the fate of NSCS/NPCs to counteract the pathology subsequently.

Keywords: adult neurogenesis; demyelination; immune system dysfunction; multiple sclerosis; neural progenitor cells; novel therapies; oligodendrogenesis; stem cells.

Figure 1

The chief role of diverse immune cells in the pathogenesis of MS. Activated T-cells (both CD4⁺ and CD8⁺ T-cells), B-cells, and Natural Killer (NK) cells originating in the periphery cross the blood–brain barrier (BBB) and enter the central nervous system (CNS). Within the CNS, these cells undergo reactivation and release cytokines as part of their effector functions. CD4+ T-cells are reactivated when MHC-II molecules on APCs or macrophages (macro) specifically present peptide anti-gens to their surface receptors and differentiate into either Th1 or Th17 phenotypes. B-cells play an active role in the progression of MS by potentially triggering the activation of Th1 cells to produce IFN-γ and TNF-α or Th17 cells to produce IL-17a, IL-17f, IL-21, IL-22, IL-23, and GM-CSF (granulocyte-macrophage colony-stimulating factor). Moreover, B cells co-express the pro-inflammatory cytokines GM-CSF, IL-6, and TNF-α leading to the activation and recruitment of macrophages/microglial cells and astrocytes. B-cells are further differentiated into plasma cells (plasmablasts), producing autoantibodies against myelin proteins. NK cells release IFN-γ creating a pro-inflammatory environment. This integrated neuro-inflammatory network plays an essential role in demyelination and neuronal destruction as well as oligodendrocyte (OLDC) necrosis/apoptosis in MS.

Figure 2

The fates of NSCs/NPCs in the SVZ in normal conditions compared to MS. Quiescent neural stem cells (NSCs or RGLs) undergo proliferation to become neural progenitor cells (NPS or C cells). These NPCs in turn, differentiate into neuroblasts, referred to as Type A cells. Following this stage, these cells migrate along the rostral migratory stream (RMS) to reach the olfactory bulb (OB). Once in the OB, they subsequently migrate radially and undergo their differentiation into first immature then mature fully developed neurons, which contribute to the OB circuitry. In MS, NPCs do not progress in their natural path instead they give rise to astrocytes and OPCs, which turn into OLDCs. Whereas, migrating neuroblasts might leave the migratory stream down the RMS and go to the demyelinated lesions to attempt repair.

Figure 3

The fates of NSCs/NPCs in the hippocampus in normal conditions compared to MS. Within the SGZ niche, there is a sequence of cellular transitions. This begins with quiescent neural stem cells, which progress to activated neural stem cells (NSCs). Subsequently, they differentiate into type 1 radial glia cells (RGLs), followed by early-stage type 2a cells and type 2b cells, collectively known as neural progenitor cells (NPCs). These cells then enter a differentiation phase, leading to the generation of late-stage type 3 neuroblasts and, subsequently, immature granule neurons. The latter then mature into granule neurons. The development from quiescent neural stem cells to mature granule neurons in the adult SGZ involves several well-defined stages (as indicated). These newly generated neurons then migrate to the granule cell layer to integrate into the existing hippocampal circuitry. In MS, CD8+ T cells secrete Granzyme B (GrB) which affects NPCs (Type 2a and 2b cells) and inhibits their further differentiation. These NPCs also deviate from the correct path and generate astroglia instead of neurons. Finally, in some MS types, the NSCs might stay quiescent and not enter the ANG stages as reflected by the arrow pointing to the NSCs themselves.

Figure 4

The fates of NSCs/NPCs in the spinal cord in normal conditions compared to MS. Ependymal cells proliferate and generate NSCs, which migrate along lamina IV to the superficial dorsal horn layers. During their journey, they differentiate into immature neurons becoming later mature neurons at their arrival. NSCs could also produce either astrocytes or OPCs which give rise to OLDCs. In MS, NSCs are unable to generate astrocytes and OPCs. In the case of OPC generation, they are unable to differentiate into OLCS, as indicated by the blue arrows interrupting the process.