Endothelial and Astrocytic Support by Human Bone Marrow Stem Cell Grafts into Symptomatic ALS Mice towards Blood-Spinal Cord Barrier Repair

Abstract

Vascular pathology, including blood-CNS barrier (B-CNS-B) damage via endothelial cell (EC) degeneration, is a recently recognized hallmark of Amyotrophic Lateral Sclerosis (ALS) pathogenesis. B-CNS-B repair may be a new therapeutic approach for ALS. This study aimed to determine effects of transplanted unmodified human bone marrow CD34+ (hBM34+) cells into symptomatic G93A mice towards blood-spinal cord barrier (BSCB) repair. Thirteen weeks old G93A mice intravenously received one of three different doses of hBM34+ cells. Cell-treated, media-treated, and control mice were euthanized at 17 weeks of age. Immunohistochemical (anti-human vWF, CD45, GFAP, and Iba-1) and motor neuron histological analyses were performed in cervical and lumbar spinal cords. EB levels in spinal cord parenchyma determined capillary permeability. Transplanted hBM34+ cells improved behavioral disease outcomes and enhanced motor neuron survival, mainly in high-cell-dose mice. Transplanted cells differentiated into ECs and engrafted within numerous capillaries. Reduced astrogliosis, microgliosis, and enhanced perivascular end-feet astrocytes were also determined in spinal cords, mostly in high-cell-dose mice. These mice also showed significantly decreased parenchymal EB levels. EC differentiation, capillary engraftment, reduced capillary permeability, and re-established perivascular end-feet astrocytes in symptomatic ALS mice may represent BSCB repair processes, supporting hBM34+ cell transplantation as a future therapeutic strategy for ALS patients.

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

“…It is also notable that growing evidence suggests that endothelial cells are also affected in this disease, which in turn may cause progressive BBB alterations leading to infiltration of peripheral blood monocytes/macrophages. This has been confirmed in recent work by Garbuzova-Davis et al (2017 , 2019 ) as restoration of capillary integrity by delivery of human bone marrow stem cells reduced BBB permeability and delayed progression of disease in SOD1 mutant mice. Although the role and contribution of peripheral monocytes/macrophages in ALS-induced neurodegeneration remains elusive, these cells do have an important role in regulation of peripheral immunity.…”

Reduction of microhemorrhages in the spinal cord of symptomatic ALS mice after intravenous human bone marrow stem cell transplantation accompanies repair of the blood-spinal cord barrier

“…Since BSCB dysfunction is a potential contributor to ALS pathogenesis, restoration of BSCB integrity could be an important target in treatment development for ALS. We have recently shown that unmodified human bone marrow CD34 + (hBM34 + ) stem cells intravenously transplanted into symptomatic ALS mice dose-dependently differentiate into endothelial cells and engraft into the capillary walls in the cervical and lumbar spinal cords at 4 weeks post-transplantation [ 38 ]. Moreover, mice treated with the highest cell dose demonstrated improvements in behavioral disease outcomes and motor neuron survival in addition to reductions of macro- and microgliosis, maintenance of perivascular end-feet astrocytes, and reduction of capillary permeability.…”

Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs

“…Novel treatment: developing new target and testing of multidrug therapy, stem cells grafting, growth factor therapy, antisense therapies, mitochondrial replacement therapy. [54][55][56][57][58] ( Dr. William Thomas Beaver is credited with drafting the initial regulations defining "adequate and controlled" clinical studies. Over the time, clinical trials have evolved into a standardized procedure, focusing on scientific assessment of efficacy and guarding the patient safety.…”