TY - JOUR
T1 - Beneficial effects of transplanted human bone marrow endothelial progenitors on functional and cellular components of blood-spinal cord barrier in ALSMice
AU - Garbuzova-Davis, Svitlana
AU - Boccio, Kayla J.
AU - Llauget, Alexander
AU - Shell, Robert
AU - Hailu, Surafuale
AU - Mustafa, Hilmi
AU - Ehrhart, Jared
AU - Sanberg, Paul R.
AU - Appel, Stanley H.
AU - Borlongan, Cesario V.
N1 - Funding Information:
Received July 24, 2021; accepted August 30, 2021; First published September 3, 2021. The authors declare no competing financial interests. Author contributions: S.G.-D., P.R.S., S.H.A., and C.V.B. designed research; K.J.B., A.L., R.S., S.H., H.M., and J.E. performed research; S.G.-D., K.J.B., A.L., R.S., S.H., and J.E. analyzed data; S.G.-D. and H.M. wrote the paper. This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke Grant 1R01NS090962. Acknowledgements: This manuscript is dedicated to the memory of Robert Shell, B.S., who died on April 24, 2021. Correspondence should be addressed to Svitlana Garbuzova-Davis at [email protected]. https://doi.org/10.1523/ENEURO.0314-21.2021 Copyright © 2021 Garbuzova-Davis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Publisher Copyright:
© 2021 Garbuzova-Davis et al.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Convincing evidence of blood-spinal cord barrier (BSCB) alterations has been demonstrated in amyotrophic lateral sclerosis (ALS) and barrier repair is imperative to prevent motor neuron dysfunction. We showed benefits of human bone marrow-derived CD34+ cells (hBM34+) and endothelial progenitor cells (hBM-EPCs) intravenous transplantation into symptomatic G93A SOD1 mutant mice on barrier reparative processes. These gains likely occurred by replacement of damaged endothelial cells, prolonging motor neuron survival. However, additional investigations are needed to confirm the effects of administered cells on integrity of the microvascular endothelium. The aim of this study was to determine tight junction protein levels, capillary pericyte coverage, microvascular basement membrane, and endothelial filamentous actin (F-actin) status in spinal cord capillaries of G93A SOD1 mutant mice treated with human bone marrow-derived stem cells. Tight junction proteins were detected in the spinal cords of cell-treated versus non-treated mice via Western blotting at four weeks after transplant. Capillary pericyte, basement membrane laminin, and endothelial F-actin magnitudes were determined in cervical/lumbar spinal cord tissues in ALS mice, including controls, by immunohistochemistry and fluorescent staining. Results showed that cell-treated versus media-treated ALS mice substantially increased tight junction protein levels, capillary pericyte coverage, basement membrane laminin immunoexpressions, and endothelial cytoskeletal F-actin fluorescent expressions. The greatest benefits were detected in mice receiving hBM-EPCs versus hBM34+ cells. These study results support treatment with a specific cell type derived from human bone marrow toward BSCB repair in ALS. Thus, hBM-EPCs may be advanced for clinical applications as a cell-specific approach for ALS therapy through restored barrier integrity.
AB - Convincing evidence of blood-spinal cord barrier (BSCB) alterations has been demonstrated in amyotrophic lateral sclerosis (ALS) and barrier repair is imperative to prevent motor neuron dysfunction. We showed benefits of human bone marrow-derived CD34+ cells (hBM34+) and endothelial progenitor cells (hBM-EPCs) intravenous transplantation into symptomatic G93A SOD1 mutant mice on barrier reparative processes. These gains likely occurred by replacement of damaged endothelial cells, prolonging motor neuron survival. However, additional investigations are needed to confirm the effects of administered cells on integrity of the microvascular endothelium. The aim of this study was to determine tight junction protein levels, capillary pericyte coverage, microvascular basement membrane, and endothelial filamentous actin (F-actin) status in spinal cord capillaries of G93A SOD1 mutant mice treated with human bone marrow-derived stem cells. Tight junction proteins were detected in the spinal cords of cell-treated versus non-treated mice via Western blotting at four weeks after transplant. Capillary pericyte, basement membrane laminin, and endothelial F-actin magnitudes were determined in cervical/lumbar spinal cord tissues in ALS mice, including controls, by immunohistochemistry and fluorescent staining. Results showed that cell-treated versus media-treated ALS mice substantially increased tight junction protein levels, capillary pericyte coverage, basement membrane laminin immunoexpressions, and endothelial cytoskeletal F-actin fluorescent expressions. The greatest benefits were detected in mice receiving hBM-EPCs versus hBM34+ cells. These study results support treatment with a specific cell type derived from human bone marrow toward BSCB repair in ALS. Thus, hBM-EPCs may be advanced for clinical applications as a cell-specific approach for ALS therapy through restored barrier integrity.
KW - ALS
KW - Blood-spinal cord barrier
KW - G93A SOD1 mice
KW - Human bone marrow-derived stem cells
KW - Repair
KW - Transplantation
KW - Endothelial Cells
KW - Superoxide Dismutase/genetics
KW - Humans
KW - Mice, Transgenic
KW - Endothelium
KW - Animals
KW - Spinal Cord
KW - Amyotrophic Lateral Sclerosis/therapy
KW - Mice
KW - Bone Marrow
KW - Disease Models, Animal
UR - http://www.scopus.com/inward/record.url?scp=85115624069&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85115624069&partnerID=8YFLogxK
U2 - 10.1523/ENEURO.0314-21.2021
DO - 10.1523/ENEURO.0314-21.2021
M3 - Article
C2 - 34479980
AN - SCOPUS:85115624069
SN - 2373-2822
VL - 8
JO - eNeuro
JF - eNeuro
IS - 5
M1 - ENEURO.0314-21.2021
ER -