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

Eve, David J.; Steiner, George; Mahendrasah, Ajay; Sanberg, Paul R.; Kurien, Crupa; Thomson, Avery; Borlongan, Cesar V.

doi:10.18632/oncotarget.24360

Cited by 24 publications

(21 citation statements)

References 66 publications

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“…More efficacious repair was determined by the administration of hBM-EPCs versus hBM34+ cells. Similar results on the reduction of mh in the spinal cords of symptomatic ALS mice treated with hBM stem cells were reported in our previous study 53 .…”

Section: Respiratory Dysfunction and Lung Damage In Rodent Models Of supporting

confidence: 91%

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

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration in the brain and spinal cord. Progressive paralysis of the diaphragm and other respiratory muscles leading to respiratory dysfunction and failure is the most common cause of death in ALS patients. Respiratory impairment has also been shown in animal models of ALS. Vascular pathology is another recently recognized hallmark of ALS pathogenesis. Central nervous system (CNS) capillary damage is a shared disease element in ALS rodent models and ALS patients. Microvascular impairment outside of the CNS, such as in the lungs, may occur in ALS, triggering lung damage and affecting breathing function. Stem cell therapy is a promising treatment for ALS. However, this therapeutic strategy has primarily targeted rescue of degenerated motor neurons. We showed functional benefits from intravenous delivery of human bone marrow (hBM) stem cells on restoration of capillary integrity in the CNS of an superoxide dismutase 1 (SOD1) mouse model of ALS. Due to the widespread distribution of transplanted cells via this route, administered cells may enter the lungs and effectively restore microvasculature in this respiratory organ. Here, we provided preliminary evidence of the potential role of microvasculature dysfunction in prompting lung damage and treatment approaches for repair of respiratory function in ALS. Our initial studies showed proof-of-principle that microvascular damage in ALS mice results in lung petechiae at the late stage of disease and that systemic transplantation of mainly hBM-derived endothelial progenitor cells shows potential to promote lung restoration via re-established vascular integrity. Our new understanding of previously underexplored lung competence in this disease may facilitate therapy targeting restoration of respiratory function in ALS.

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Section: Respiratory Dysfunction and Lung Damage In Rodent Models Of supporting

confidence: 91%

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

et al. 2020

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“…Also, in our later study 31 , significantly restored ultrastructural capillary morphology, improved basement membrane integrity, enhanced axonal myelin coherence, and stabilized capillary density in the spinal cords were determined, primarily in ALS mice receiving the high dose of 1 × 10 6 cells. Additionally, significantly decreased microhemorrhages were noted in spinal cords from ALS mice treated with the hBM34 + cells 32 . These results support the benefit of an optimal dose of bone marrow hematopoietic stem cells in repairing the damaged BSCB by delaying disease and preserving motor neuron survival in symptomatic ALS mice.…”

Section: Introductionmentioning

confidence: 90%

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

Garbuzova‐Davis

Kurien

Haller

et al. 2019

Sci Rep

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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.

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“…Yet leaked hemoglobin was detected across both grey and white matter; most severely in the dorsomedial white matter and rarely in the ventral grey matter. Similarly, microhemorrhages in the cervical and lumbar spinal cord of SOD1 mice were found to be quite uniformly distributed across the grey and white matter, without preference for the ventral grey matter [36]. Therefore, although motor neuron damage has been proposed to induce neuroinflammation and BSCB permeability to infiltrating immune cells [21], our data argue against BSCB changes in ALS being initiated by nearby neuronal damage.…”

Section: Discussionmentioning

confidence: 76%

Blood-spinal cord barrier leakage is independent of motor neuron pathology in ALS

Waters

Dieriks

Swanson

et al. 2019

Preprint

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BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. Both lower motor neuron loss and the deposition of phosphorylated TDP-43 inclusions display regional patterning along the spinal cord. The blood-spinal cord barrier (BSCB) ordinarily restricts entry into the spinal cord parenchyma of blood components that are neurotoxic, but in ALS there is evidence for barrier breakdown. Here we sought to examine whether BSCB breakdown, motor neuron loss, and TDP-43 proteinopathy display the same regional patterning across and along the spinal cord.MethodsWe measured cerebrospinal fluid (CSF) hemoglobin in living ALS patients (n=87 controls, n=236 ALS) as a potential biomarker of BSCB and blood-brain barrier leakage. We then immunostained cervical, thoracic, and lumbar post mortem spinal cord tissue (n=5 controls, n=13 ALS) and employed semi-automated imaging and analysis to quantify and map lower motor neuron loss and phosphorylated TDP-43 inclusion load against hemoglobin leakage.ResultsMotor neuron loss and TDP-43 proteinopathy were seen at all three levels of the ALS spinal cord, with most abundant TDP-43 deposition in the ventral grey (lamina IX) of the cervical and lumbar cord. In contrast, hemoglobin leakage was observed along the ALS spinal cord axis but was most severe in the dorsal grey and white matter in the thoracic spinal cord.ConclusionsOur data show that leakage of the blood-spinal cord barrier occurs during life but at end-stage its distribution is independent from the major motor neuron pathology and is unlikely to be a major contributor to pathogenesis in ALS.

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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

Cited by 24 publications

References 66 publications

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

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

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

Blood-spinal cord barrier leakage is independent of motor neuron pathology in ALS

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