Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3-5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective. In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1^G93A mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi-differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed.

Keywords: Adipose derived stem cells; Amyotrophic lateral sclerosis; Neurodegeneration; Stem cell transplantation.

Fig. 1

Molecular mechanisms in the pathology of amyotrophic lateral sclerosis. a Schematic representation of healthy spinal cord motor neuron. b Schematic representation of ALS affected spinal cord motor neuron: 1) Astrocytes are not able to support neuronal functions and impaired glutamate clearance leads to neuronal excitotoxicity; 2) Defects in protein degradation pathways and disturbances in RNA processing result in protein aggregate formation, RNA toxicity and mitochondrial dysfunction; 3) The secretion of pro-inflammatory cytokines by predominant M1 activated microglia contributes to the development of an inflammatory milieu; 4) Failure of axonal architecture and transport functions, together with the alteration of the physiological role of oligodendrocytes results in 5) synaptic failure, denervation and finally, muscle atrophy

Fig. 2

Isolation process to obtain ADSCs from human lipoaspirate. Fresh lipoaspirate is extensively washed in PBS to remove blood and contaminants. The adipose tissue is then enzymatically digested and the stromal vascular fraction (SVF) is obtained by filtration and centrifugation. Culture of the SVF in standard plastic tissue culture flasks results in the selection and expansion of the adipose stem cell population

Fig. 3

Potential mechanisms of mesenchymal stem cell efficacy in neurodegeneration. Transplanted MSCs may provide therapeutic responses through paracrine effects and cell-to-cell contacts with resident neural cells. The capacity of MSCs to secrete cytokines, growth factors and exosomes could potentially induce and support regeneration processes, including angiogenesis, synaptogenesis, axonal re-myelination and neurogenesis. Because of their immunomodulatory properties, MSCs could attenuate inflammatory responses in the central nervous system by inhibiting maturation and migration of dendritic cells, suppression of lymphocyte activation and proliferation, and by reducing gliosis. Moreover, MSCs possess anti-apoptotic properties, and may limit excitotoxicity by modulating astrocyte functions

Fig. 4

Delivery strategies for the transplantation of MSCs in ALS. a Intrathecal delivery of MSCs into the spinal cord CSF; b Systemic delivery of MSCs; c Local delivery of MSCs directly into the spinal cord parenchyma. For each delivery route, advantages and disadvantages are summarized