Gap Junction–Mediated Transport of Metabolites Between Stem Cells and Vascular Endothelial Cells

Abstract

We have previously demonstrated that small molecular transfer, such as glucose, between hematopoietic stem cells (HSCs) or mesenchymal stem cells (MSCs) and vascular endothelial cells via gap junctions constitutes an important mechanism of stem cell therapy. Cell metabolites are high-potential small-molecule candidates that can be transferred to small molecules between stem cells and vascular endothelial cells. Here, we investigated the differences in metabolite levels between stem cells (HSCs and MSCs), vascular endothelial cells, and the levels of circulating non-hematopoietic white blood cells (WBCs). The results showed remarkable differences in metabolite concentrations between cells. Significantly higher concentrations of adenosine triphosphate (ATP), guanosine triphosphate (GTP), total adenylate or guanylate levels, glycolytic intermediates, and amino acids were found in HSCs compared with vascular endothelial cells. In contrast, there was no significant difference in the metabolism of MSCs and vascular endothelial cells. From the results of this study, it became clear that HSCs and MSCs differ in their metabolites. That is, metabolites that transfer between stem cells and vascular endothelial cells differ between HSCs and MSCs. HSCs may donate various metabolites, several glycolytic and tricarboxylic acid cycle metabolites, and amino acids to damaged vascular endothelial cells as energy sources and activate the energy metabolism of vascular endothelial cells. In contrast, MSCs and vascular endothelial cells regulate each other under normal conditions. As the existing MSCs cannot ameliorate the dysregulation during insult, exogenous MSCs administered by cell therapy may help restore normal metabolic function in the vascular endothelial cells by taking up excess energy sources from the lumens of blood vessels. Results of this study suggested that the appropriate timing of cell therapy is different between HSCs and MSCs.

RNA Analysis of Circulating Leukocytes in Patients with Alzheimer’s Disease

“…5 . The concentration of various glycolytic substrates and AMP in cytosol of leukocyte was higher than those of endothelium [ 14 ]. The transfer of glycolytic substrates and AMP from leukocyte to endothelium would reduce O2 consumption with inactivation of Hif1α and AMPKa mediated cascade in leukocyte.…”

“…The therapeutic mechanisms of action of cell therapies, for instance hematopoietic or mesenchymal stem cells, can be mediated by gap junctions [3,4]. Moreover, systemically administered hematopoietic stem cells and circulat- Taking drugs that have a clear effect on the immune system, such as anti-cancer drugs, steroids, and anti-rheumatic drugs 13 Patients with serious complications, or those who have a history of these and are judged by the investigator and the investigator to be ineligible for this study 14 Others who are judged by the principal investigator and the investigator to be ineligible for this study ing blood cells directly interact with hippocampal neuronal stem cells via gap junction after penetrating the blood-brain barrier (manuscript under review). These findings are consistent with our previous report showing that hematopoietic stem cell transplantation increases post-stroke neurogenesis in mice [5].…”

Fueling recovery: The importance of energy coupling between angiogenesis and osteogenesis during fracture healing

“…However, whether this is due to alteration of gene expression or lack of energetic fueling remains to be elucidated. Recently, it has been shown that MSCs and ECs can directly transfer metabolites as energy sources to enhance energy metabolism of other cells ( Ogawa et al, 2022 ). Indeed, NAD+ can be released by MSCs via Cx43 gap junctions, causing positive autocrine effects on BMSC proliferation and migration ( Fruscione et al, 2011 ).…”