Patching Up the Permeability: The Role of Stem Cells in Lessening Neurovascular Damage in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a debilitating disease with poor prognosis. The pathophysiology of ALS is commonly debated, with theories involving inflammation, glutamate excitotoxity, oxidative stress, mitochondria malfunction, neurofilament accumulation, inadequate nutrients or growth factors, and changes in glial support predominating. These underlying pathological mechanisms, however, act together to weaken the blood brain barrier and blood spinal cord barrier, collectively considered as the blood central nervous system barrier (BCNSB). Altering the impermeability of the BCNSB impairs the neurovascular unit, or interdependent relationship between the brain and advances the concept that ALS is has a significant neurovascular component contributing to its degenerative presentation. This unique categorization of ALS opens a variety of treatment options targeting the reestablishment of BCNSB integrity. This review will critically assess the evidence implicating the significant neurovascular components of ALS pathophysiology, while also offering an in-depth discussion regarding the use of stem cells to repair these pathological changes within the neurovascular unit.

Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity

“…In experimental ALS models, transplantation of human bone marrow-derived (hBM) mesenchymal stroma cells and endothelial progenitor cells has been shown to promote repair and stabilization of the CNS microvascular wall, which includes an increase in pericyte coverage and leads to improved motor neuron survival and motor function (extensively reviewed in [ 89 , 158 ]). Experimental application of hBM mesenchymal stroma, endothelial or muscle progenitor cells further increased VEGF expression, suggesting to combine the advantages of cell-based and exerkine approaches (reviewed in [ 158 ]). Intriguingly, endothelial progenitor cells additionally release beneficial EVs, to strengthen and repair the microvascular wall in experimental ALS [ 159 ].…”

“…Despite increasingly convincing preclinical evidence for the potential of cell-based therapies for NVU function and microvascular repair, clinical trials using hBM-derived cells in ALS patients have focused on monitoring the (downstream) rescue of degenerating motor neurons (reviewed in [ 158 ]). Hence, the clinical role of hBM-induced (upstream) microcirculatory recovery as a potential mediator of motor neuron survival has not yet been elucidated.…”

“…From the perspective of motor cortex vascular supply, a recently initiated phase I clinical trial (CNS10-NPC-GDNF Delivered to the Motor Cortex for ALS—Full Text View— , accessed on 7 March 2023) is of particular relevance. Here, cell-based therapy is used, in which neural progenitor cells producing VEGF are directly transplanted into the motor cortex of ALS patients [ 158 , 160 ]. Thus, therapy probably acts on the local microvasculature, which would provide the opportunity to monitor in situ the relationship between intervention, vascular supply, motor neuron degeneration and motor function with cutting-edge MRI sequences, as described above.…”

Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity

“…Despite convincing preclinical evidence for the great potential of cell-based therapies for NVU function and microvascular repair, clinical trials using hBM-derived cells in ALS patients have focused on monitoring the (downstream) rescue of degenerating motor neurons (reviewed in [158]). Hence, the clinical role of hBM-induced (upstream) microcirculatory recovery as a potential mediator of motor neuron survival has not yet been elucidated.…”

“…From the perspective of motor cortex vascular supply, a recently initiated phase I clinical trial (CNS10-NPC-GDNF Delivered to the Motor Cortex for ALS -Full Text View -Clinical-Trials.gov) is of particular relevance. Here, cell-based therapy is used, in which neural progenitor cells producing VEGF are directly transplanted into the motor cortex of ALS patients [158,160]. Thus, therapy probably acts on the local microvasculature, which would provide the opportunity to monitor in situ the relationship between intervention, vascular supply, motor neuron degeneration, and motor function with cutting-edge MRI sequences, as described above.…”