Human Bone Marrow Endothelial Progenitor Cell Transplantation into Symptomatic ALS Mice Delays Disease Progression and Increases Motor Neuron Survival by Repairing Blood-Spinal Cord Barrier

Abstract

Convincing evidence demonstrated impairment of the blood-spinal cord barrier (BSCB) in Amyotrophic Lateral Sclerosis (ALS), mainly by endothelial cell (EC) alterations. Replacing damaged ECs by cell transplantation is a potential barrier repair strategy. Recently, we showed that intravenous (iv) administration of human bone marrow CD34 + (hBM34 + ) cells into symptomatic ALS mice benefits BSCB restoration and postpones disease progression. However, delayed effect on motor function and some severely damaged capillaries were noted. We hypothesized that hematopoietic cells from a restricted lineage would be more effective. This study aimed to establish the effects of human bone marrow-derived endothelial progenitor cells (hBMEPCs) systemically transplanted into G93A mice at symptomatic disease stage. Results showed that transplanted hBMEPCs significantly improved behavioral disease outcomes, engrafted widely into capillaries of the gray/white matter spinal cord and brain motor cortex/brainstem, substantially restored capillary ultrastructure, significantly decreased EB extravasation into spinal cord parenchyma, meaningfully re-established perivascular astrocyte end-feet, and enhanced spinal cord motor neuron survival. These results provide novel evidence that transplantation of hBMEPCs effectively repairs the BSCB, potentially preventing entry of detrimental peripheral factors, including immune/inflammatory cells, which contribute to motor neuron dysfunction. Transplanting EC progenitor cells may be a promising strategy for barrier repair therapy in this disease.

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.…”

Extracellular vesicle-based therapy for amyotrophic lateral sclerosis

“…[ 17 26 27 28 ] When hBM-EPCs were delivered intravenously to symptomatic G93A SOD1 mutant mice (an ALS model), the blood-CNS-barrier was significantly restored potentially due to the replacement of damaged ECs with “healthy” transplanted cells. [ 29 ] Barrier functionality in gray matter horns and white matter columns in the spinal cord, as well as in gray and white matter in the cerebral motor cortex/brainstem was substantially ameliorated following extensive hBM-EPC engraftment. [ 29 ] This improvement of barrier structure and function in the SOD1 mutant mice was observed through a significant reduction in capillary permeability and bolstering of perivascular astrocyte end-feet function.…”

“…[ 29 ] Barrier functionality in gray matter horns and white matter columns in the spinal cord, as well as in gray and white matter in the cerebral motor cortex/brainstem was substantially ameliorated following extensive hBM-EPC engraftment. [ 29 ] This improvement of barrier structure and function in the SOD1 mutant mice was observed through a significant reduction in capillary permeability and bolstering of perivascular astrocyte end-feet function. [ 29 ] Therefore, the manifestations of disease in these mice were greatly mitigated via blood-CNS-barrier restoration, resulting in augmented motor neuron viability in the spinal cord.…”

“…[ 29 ] This improvement of barrier structure and function in the SOD1 mutant mice was observed through a significant reduction in capillary permeability and bolstering of perivascular astrocyte end-feet function. [ 29 ] Therefore, the manifestations of disease in these mice were greatly mitigated via blood-CNS-barrier restoration, resulting in augmented motor neuron viability in the spinal cord. [ 29 ]…”

Advancing Stem Cell Therapy for Repair of Damaged Lung Microvasculature in Amyotrophic Lateral Sclerosis

“…To determine that structural and functional lung improvements were related to a cell treatment effect, immunohistochemical staining of residual parts of the lung tissues from ALS mice which received hBM34+ cells and hBM-EPC transplants in our histological study was performed via detection of human anti-von Willibrand factor (hvWF) antigen as we previously described 50 , 52 . At 4 wk post-transplant, there were a few hvWF-positive cells in the lungs of mice treated with hBM34+ cells that displayed epithelial-like morphology and were located near the alveolar sac ( Fig.…”