Gap Junction-Mediated Cell-Cell Interaction Between Transplanted Mesenchymal Stem Cells and Vascular Endothelium in Stroke

Abstract

We have shown previously that transplanted bone marrow mononuclear cells (BM-MNC), which are a cell fraction rich in hematopoietic stem cells, can activate cerebral endothelial cells via gap junction-mediated cell-cell interaction. In the present study, we investigated such cell-cell interaction between mesenchymal stem cells (MSC) and cerebral endothelial cells. In contrast to BM-MNC, for MSC we observed suppression of vascular endothelial growth factor uptake into endothelial cells and transfer of glucose from endothelial cells to MSC in vitro. The transfer of such a small molecule from MSC to vascular endothelium was subsequently confirmed in vivo and was followed by suppressed activation of macrophage/microglia in stroke mice. The suppressive effect was absent by blockade of gap junction at MSC. Furthermore, gap junction-mediated cell-cell interaction was observed between circulating white blood cells and MSC. Our findings indicate that gap junction-mediated cell-cell interaction is one of the major pathways for MSC-mediated suppression of inflammation in the brain following stroke and provides a novel strategy to maintain the blood-brain barrier in injured brain. Furthermore, our current results have the potential to provide a novel insight for other ongoing clinical trials that make use of MSC transplantation aiming to suppress excess inflammation, as well as other diseases such as COVID-19 (coronavirus disease 2019).

Mesenchymal Stem/Stromal Cell Therapy in Blood–Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects

“…Moreover, blocking the gap junction channel of MSCs reversed the VEGF uptake of BMVECs in vitro and in vivo. These results revealed cell-cell interaction between MSC and BMVECs through gap junction [36]. Previous studies have shown that VEGF stimulates angiogenesis and increases BBB permeability, promoting inflammatory responses following stroke [129,130].…”

“…The morphological enclosing of the entire cerebral microvascular system, by the terminal feet of astrocytes and their interactions with BMVECs through extracellular vesicles, determines the BBB properties [51][52][53]. In addition, astrocytes contribute to the stability of TJs through VEGF-mediated signal transduction [27,36], and regulating tissue inhibitors of metalloproteinases (TIMPs) [54].…”

“…Concomitantly, MSCs and circulating lymphocytes/monocytes also established a direct interaction via gap junction. In brief, gap junction-mediated MSC-recipient cell interaction serves as a potential therapy to warrant BBB steadiness after ischemic brain injury involving suppression of VEGF uptake and inflammatory responses [36].…”

“…Numerous subclinical investigations indicated the amelioration of endothelial permeability after MSC treatment with the highly complex relationship of cellular components of BBB and intercellular junctions [27,[35][36][37]. Understandably, BBB preservation postischemia is receiving significant attention from investigators, promising to explore novel therapeutic targets.…”

Editorial: Protein–Protein Interactions: Drug Discovery for the Future

“…With the resurgence of phenotypic assays in drug discovery, the observations in these systems are often complex as recently shown by cell-cell interactions in stroke models ( Kikuchi-Taura et al, 2020 ; Takeuchi et al, 2020 ; Kikuchi-Taura et al, 2021 ) and understanding the nature of the PPIs using novel technologies will allow the scientific community to better understand and unveil therapeutically relevant aspects of such PPIs to treat a variety of human diseases.…”