Shifting the balance: cell-based therapeutics as modifiers of the amyotrophic lateral sclerosis–specific neuronal microenvironment

Abstract

<jats:p>✓ Recent advances in the laboratory have improved the current understanding of neurobiological mechanisms underlying the initiating events and pathological progression observed in amyotrophic lateral sclerosis (ALS). Whereas initial studies have revealed the late-stage intracellular cascades contributing to neuronal dysfunction and cell death, more recently collected data have begun to elucidate the presence and importance of a “non–cell autonomous” component indicating that affected glial cell subtypes may serve distinct and required roles. Pharmacological interventions for ALS have largely been disappointing likely in part because they have failed to address either the proximate events contributing to neuronal dysfunction and death or the deleterious contributions of non-neuronal cells within the local microenvironment. Alternatively, cell-based therapeutics offer the potential of a multifaceted approach oriented toward the dual ends of protecting remaining viable neurons and attempting to restore neuronal function lost as a manifestation of disease progression. The authors review the evolving knowledge of disease initiation and progression, with specific emphasis on the role of affected glia as crucial contributors to the observed ALS phenotype. This basis is used to underscore the potential roles of cell-based therapeutics as modifiers of the ALS-specific microenvironment.</jats:p>

Multiple Intravenous Administrations of Human Umbilical Cord Blood Cells Benefit in a Mouse Model of ALS

“…Although motor neuron replacement is possible, this treatment strategy should take into account the multifocal motor neuron degeneration and death [6] . The roles of cell-based therapeutics might be more practical “as modifiers of the ALS-specific microenvironment” [7] or serving to “detoxify the local environment around dying motor neurons” [8] , therefore providing protection for motor neurons and retarding disease progression. Neuroinflammation, comprised mainly of astrocyte and microglial activation, is a central feature in ALS, and directly contributes to neuronal death [9] – [11] .…”

Optimization of Immunosuppressive Therapy for Spinal Grafting of Human Spinal Stem Cells in a Rat Model of ALS

“…Recently, cell-based therapies have emerged as potential treatments for sevtion of upper and lower motor neurons and corresponding motor and respiratory dysfunction. Approximately eral neurological disorders including ALS (18,28). For example, Xu et al (34) reported that spinal grafting of 10% of patients have an inherited form of the disease, and of these 20% carry a mutation in the superoxide human spinal stem cells (hSSCs) to the lumbar spinal cord of G93A SOD1 rats delayed the onset and progresdismutase 1 (SOD1) gene.…”

“…Despite the discovery of several putative mechanisms underlying the onset and progression of ALS, there are no therapeutic strategies that successfully modify disease progression or outcome (33). Recently, cell-based therapies have emerged as potential treatments for several neurological disorders including ALS (18,28). For example, Xu et al (34) reported that spinal grafting of human spinal stem cells (hSSCs) to the lumbar spinal cord of G93A SOD1 rats delayed the onset and progression of disease, while also extending the life span by more than 10 days.…”

Repeated courses of granulocyte colony‐stimulating factor in amyotrophic lateral sclerosis: Clinical and biological results from a prospective multicenter study

“…Recently, stem cell transplantation has been proposed as a promising therapeutic strategy in neurological disorders 2, 3. In superoxide dismutase 1 (SOD1) mutant ALS mice, this approach, using bone marrow cells (BMCs), has been found to modify the microenvironment of the nervous system by generating microglia and glial cells,4–6 slowing disease progression and increasing survival 7…”