Bone Marrow Mononuclear Cells Activate Angiogenesis via Gap Junction–Mediated Cell-Cell Interaction

Abstract

Background and Purpose— Bone marrow mononuclear cells (BM-MNCs) are a rich source of hematopoietic stem cells and have been widely used in experimental therapies for patients with ischemic diseases. Activation of angiogenesis is believed to be one of major BM-MNC mode of actions, but the essential mechanism by which BM-MNCs activate angiogenesis have hitherto been elusive. The objective of this study is to reveal the mechanism how BM-MNCs activate angiogenesis. Methods— We have evaluated the effect of direct cell-cell interaction between BM-MNC and endothelial cell on uptake of VEGF (vascular endothelial growth factor) into endothelial cells in vitro. Cerebral ischemia model was used to evaluate the effects of direct cell-cell interaction with transplanted BM-MNC on endothelial cell at ischemic tissue. Results— The uptake of VEGF into endothelial cells was increased by BM-MNC, while being inhibited by blockading the gap junction. Low-molecular-weight substance was transferred from BM-MNC into endothelial cells via gap junctions in vivo, followed by increased expression of hypoxia-inducible factor-1α and suppression of autophagy in endothelial cells. The concentration of glucose in BM-MNC cytoplasm was significantly higher than in endothelial cells, and transfer of glucose homologue from BM-MNC to endothelial cells was observed. Conclusions— Our findings demonstrated cell-cell interaction via gap junction is the prominent pathway for activation of angiogenesis at endothelial cells after ischemia and provided novel paradigm that energy source supply by stem cell to injured cell is one of the therapeutic mechanisms of cell-based therapy. Visual Overview— An online visual overview is available for this article.

Intravenous Bone Marrow Mononuclear Cells Transplantation in Aged Mice Increases Transcription of Glucose Transporter 1 and Na+/K+-ATPase at Hippocampus Followed by Restored Neurological Functions

“…BCECF-AM was converted to BCECF (2 ,7 -bis-(2-carboxyethyl)-5-(6)-carboxyfluorescein) at cytoplasm, and BCECF-loaded BM-MNCs were washed twice with PBS before injection. 1 × 10 5 BCECF-loaded BM-MNCs in 100 µl PBS was injected to aged mice (80 weeks old, N = 2), and the transfer of BCECF from transplanted BM-MNCs to cerebral endothelium was evaluated by immunohistochemistry as described previously (Kikuchi-Taura et al, 2020). Briefly, at 10 min after cell injection, mice were anesthetized with sodium pentobarbital.…”

“…We had shown that transfer of low molecular weight substance from transplanted BM-MNCs to cerebral endothelial cells is the prominent pathway in the activation of endothelial cells by BM-MNC transplantation after cerebral ischemia (Kikuchi-Taura et al, 2020). To evaluate the transfer of low molecular weight substance from transplanted BM-MNCs to cerebral endothelial cells in aged mice, BCECF-loaded BM-MNCs were injected, and mice were sacrificed at 10 min after injection.…”

“…Recently, we had shown that transfer of low molecular weight substance, including glucose, from transplanted BM-MNCs to cerebral endothelial cells, is the prominent pathway in the activation of endothelial cells by BM-MNC transplantation after cerebral ischemia, and the transfer of low molecular weight substance suppresses autophagy in injured endothelia cells (Kikuchi-Taura et al, 2020). In this article, transfer of low molecular weight substance from transplanted BM-MNCs to cerebral endothelial cells was observed in non-stroke aged mice within 10 min after BM-MNC transplantation.…”

“…Furthermore, we have demonstrated that BM-MNC transplantation after stroke activates Hif-1α in endothelial cells via gap junction mediated cell-cell interaction followed by activation of angiogenesis and suppression of autophagy in murine model. Additionally, there is the transfer of low molecular weight substances from transplanted BM-MNCs to cerebral endothelial cells through gap junction, which is the major therapeutic mechanism of BM-MNC transplantation (Kikuchi-Taura et al, 2020). However, the link between BM-MNC transplantation and activation of cerebral metabolism was unclear.…”

Aging of the Vascular System and Neural Diseases

“…Also, bone marrow mononuclear cells (BM-MNC) have been shown to activate the repopulation or regeneration of neovascularization in ischemic tissue (Tateishi-Yuyama et al, 2002 ; Taguchi et al, 2003 ). Furthermore, a recent study has demonstrated that transplanted BM-MNCs activate angiogenesis through gap junction-mediated, direct cell-to-cell interactions between BM-MNC and ECs, followed by activation of HIF-1α, and suppression of autophagy in the ECs of ischemic brain tissue (Kikuchi-Taura et al, 2020 ). These studies suggest that stem cell-based therapies, which have utilized MSCs, ASCs, and BM-MNCs, have great potential for neovascularization in neural diseases.…”