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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by gradual motor neuron degeneration in the brain and spinal cord leading to paralysis and fatality[1]
In a separate set of the cervical and lumbar spinal cord tissue sections (n = 5/group), initial staining with the human-specific nuclei marker (HuNu) was performed as we described previously[47,48,49]
Of the 64 total G93A superoxide dismutase 1 (SOD1) mice used in the study, five mice (Group 1 – one, Group 3 – three, Group 4 – one) were excluded due to death precipitated by conditions other than disease progression, anesthetic complications during cell or media administrations
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by gradual motor neuron degeneration in the brain and spinal cord leading to paralysis and fatality[1]. ALS is a complex multifactorial disease with numerous intrinsic and extrinsic factors underlying disease pathogenesis (reviewed in refs 15–24) such as glutamate excitotoxicity, mitochondrial dysfunction, oxidative stress, altered glial cell function, impaired axonal transport, protein aggregations, immune reactivity, neurotrophic factor deficits, and neuroinflammation These multiple pathogenic effectors and the diffuse motor neuron degeneration in ALS present a formidable obstacle to treatment development for this disease. BSCB alterations were indicated in SOD1 mutant mice and rats prior to motor neuron degeneration and neuroinflammation[29,30,31], suggesting vascular damage as an early ALS pathological event These vascular pathologies, demonstrating impairment of neurovascular unit components in the brain and spinal cord, are key factors identifying ALS as a neurovascular disease[34]. Transplanted bone marrow-derived CD34+ cells migrate and home into damaged tissue, as shown in treatment of patients with ischemic or degenerative retinal conditions[45] or cardiomyopathy[46] by contributing to revascularization via formation of new blood vessels from existing vascularity in ischemic tissues
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