Stem Cell Therapies for Progressive Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal degeneration. MS patients typically present with a relapsing-remitting (RR) disease course, manifesting as sporadic attacks of neurological symptoms including ataxia, fatigue, and sensory impairment. While there are several effective disease-modifying therapies able to address the inflammatory relapses associated with RRMS, most patients will inevitably advance to a progressive disease course marked by a gradual and irreversible accrual of disabilities. Therapeutic intervention in progressive MS (PMS) suffers from a lack of well-characterized biological targets and, hence, a dearth of successful drugs. The few medications approved for the treatment of PMS are typically limited in their efficacy to active forms of the disease, have little impact on slowing degeneration, and fail to promote repair. In looking to address these unmet needs, the multifactorial therapeutic benefits of stem cell therapies are particularly compelling. Ostensibly providing neurotrophic support, immunomodulation and cell replacement, stem cell transplantation holds substantial promise in combatting the complex pathology of chronic neuroinflammation. Herein, we explore the current state of preclinical and clinical evidence supporting the use of stem cells in treating PMS and we discuss prospective hurdles impeding their translation into revolutionary regenerative medicines.

Keywords: clinical trial; mesenchymal stem cell; neural stem cell; progressive multiple sclerosis; regenerative neuroimmunology; stem cell therapy.

FIGURE 1

Pathology of progressive multiple sclerosis. Subpial lesions are typically found in PMS which are characterized by lymphocyte accumulation in the meninges. Activated T and B cells can secrete inflammatory cytokines causing microglia and astrocyte activation and ensuing demyelination of the cortex. Smoldering lesions are characterized by the degeneration of demyelinated neurons and surrounding microglial rim. Demyelinated axons have been found to have mitochondrial (mt) damage caused by ROS/RNS secretion from activated microglia. ROS/RNS can also oxidize myelin debris to generate oxidized phosphatidylcholines (OxPCs), which are toxic to neurons. Few oligodendrocyte progenitor cells (OPCs) are seen in these lesions, with no remyelination.

FIGURE 2

Mechanisms of action for non-hematopoietic stem cells. Following transplantation, non-hematopoietic stem cells can exert their therapeutic effects by: (1) replacing damaged CNS cells; (2) offering neurotrophic support to CNS cells via paracrine and juxtracrine signaling; (3) affecting immunomodulatory functions on both the innate and adaptative immune systems via paracrine and juxtracrine signaling, or via direct cell-to-cell contacts; and (4) engaging in metabolic signaling with cells within their niche. Representative examples of key players in each mechanism are illustrated. BDNF, brain-derived neurotrophic factor; CNTF, ciliary neurotrophic factor; GDNF, glial cell–derived neurotrophic factor; NGF, nerve growth factor; NT-3, neurotrophin-3; TSP1-2, thrombospondins 1 and 2; VEGF, vascular endothelial growth factor.