Burns Impair Blood-Brain Barrier and Mesenchymal Stem Cells Can Reverse the Process in Mice

Abstract

Neurological syndromes are observed in numerous patients who suffer burns, which add to the economic burden of societies and families. Recent studies have implied that bloodbrain barrier (BBB) dysfunction is the key factor that induces these central nervous system (CNS) syndromes in peripheral traumatic disease, e.g., surgery and burns. However, the effect of burns on BBB and the underlying mechanism remains, largely, to be determined. The present study aimed to investigate the effect of burns on BBB and the potential of umbilical cord-derived mesenchymal stem cells (UC-MSCs), which have strong antiinflammatory and repairing ability, to protect the integrity of BBB. BBB permeability was evaluated using dextran tracer (immunohistochemistry imaging and spectrophotometric quantification) and western blot, interleukin (IL)-6, and IL-1b levels in blood and brain were measured by enzyme-linked immunosorbent assay. Furthermore, transmission electron microscopy (TEM) was used to detect transcellular vesicular transport (transcytosis) in BBB. We found that burns increased mouse BBB permeability to both 10-kDa and 70-kDa dextran. IL-6 and IL-1b levels increased in peripheral blood and CNS after burns. In addition, burns decreased the level of tight junction proteins (TJs), including claudin-5, occludin, and ZO-1, which indicated increased BBB permeability due to paracellular pathway. Moreover, increased vesicular density after burns suggested increased transcytosis in brain microvascular endothelial cells. Finally, administering UC-MSCs at 1 h after burns effectively reversed these adverse effects and protected the integrity of BBB. These results suggest that burns increase BBB permeability through both paracellular pathway and transcytosis, the potential mechanism of which might be through increasing IL-6 and IL-1b levels and decreasing Mfsd2a level, and appropriate treatment with UC-MSCs can reverse these effects and protect the integrity of BBB after burns.

Treating Metastatic Brain Cancers With Stem Cells

“…As BBB breakdown is exacerbated by decreased angiogenesis and vasculogenesis, promotion of blood vessel growth through bone marrow-derived endothelial progenitor cells (EPCs) may rescue the BBB’s function and attenuate developing brain metastases of melanoma. This hypothesis represents a significant advance over current data on the therapy and pathology of brain cancers ( Kaneko et al, 2015 ; Yang J. et al, 2020 ).…”

“…Angiogenesis, vasculogenesis, and BBB genesis are all distinct phenomena, but are physiologically linked. In cerebrovascular development, blood vessel generation is directed by vasculogenesis and angiogenesis, which are discrete mechanisms ( Lee et al, 2009 ; Yang J. et al, 2020 ). During development, vasculogenesis generates the primary vascular plexus, which is further developed into a highly intricate vascular network by angiogenesis ( Yang J. et al, 2020 ).…”

“…In cerebrovascular development, blood vessel generation is directed by vasculogenesis and angiogenesis, which are discrete mechanisms ( Lee et al, 2009 ; Yang J. et al, 2020 ). During development, vasculogenesis generates the primary vascular plexus, which is further developed into a highly intricate vascular network by angiogenesis ( Yang J. et al, 2020 ). Vasculogenesis functions to generate new blood vessels but does so by inducing differentiation of endothelial cell precursors (angioblasts) into mature endothelial cells ( Liman and Endres, 2012 ).…”

“…After an ischemic stroke, angiogenesis is initiated in the peri-infarct areas, which has been associated with improved stroke rehabilitation in preclinical models ( Nih et al, 2018 ; Rust et al, 2019 ; Rust, 2020 ). Specifically, hypoxia induces endothelial cell damage, triggering the secretion of angiogenic factors, which promotes endothelial cell proliferation for the creation of new blood vessels ( Schreiber et al, 2013 ; Yang et al, 2018 , Yang J. et al, 2020 ). In response to inflammation, mesenchymal stromal cells (MSCs) promote angiogenic and trophic factors that repair and remodel the BBB ( Zhang et al, 2020 ).…”

“…After angiogenesis completes the formation of the primary vascular network, barriergenesis occurs where cerebral vessels mature into the BBB. This process is specifically mediated by mural cells and the formation of the extracellular matrix (ECM) ( Lee et al, 2009 ; Al Ahmad et al, 2011 ; Yang J. et al, 2020 ). As the cerebrovasculature develops, the vessels interact with neurons and glial cells to compose the neurovascular unit (NVU).…”