Gap junction-mediated cell-cell interaction between transplanted mesenchymal stem cells and vascular endothelium in stroke

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)

Increased RNA transcription of energy source transporters in circulating white blood cells of aged mice

Circulating white blood cells (WBC) contribute toward maintenance of cerebral metabolism and brain function. Recently, we showed that during aging, transcription of metabolism related genes, including energy source transports, in the brain significantly decreased at the hippocampus resulting in impaired neurological functions. In this article, we investigated the changes in RNA transcription of metabolism related genes (glucose transporter 1 [Glut1], Glut3, monocarboxylate transporter 4 [MCT4], hypoxia inducible factor 1-α [Hif1-α], prolyl hydroxylase 3 [PHD3] and pyruvate dehydrogenase kinase 1 [PDK1]) in circulating WBC and correlated these with brain function in mice. Contrary to our expectations, most of these metabolism related genes in circulating WBC significantly increased in aged mice, and correlation between their increased RNA transcription and impaired neurological functions was observed. Bone marrow mononuclear transplantation into aged mice decreased metabolism related genes in WBC with accelerated neurogenesis in the hippocampus. In vitro analysis revealed that cell-cell interaction between WBC and endothelial cells via gap junction is impaired with aging, and blockade of the interaction increased their transcription in WBC. Our findings indicate that gross analysis of RNA transcription of metabolism related genes in circulating WBC has the potential to provide significant information relating to impaired cell-cell interaction between WBC and endothelial cells of aged mice. Additionally, this can serve as a tool to evaluate the change of the cell-cell interaction caused by various treatments or diseases

Ischemia-induced neural stem/progenitor cells express pyramidal cell markers

Adult brain-derived neural stem cells have acquired a lot of interest as an endurable neuronal cell source that can be used for central nervous system repair in a wide range of neurological disorders such as ischemic stroke. Recently, we identified injury-induced neural stem/progenitor cells in the poststroke murine cerebral cortex. In this study, we show that, after differentiation in vitro, injury-induced neural stem/progenitor cells express pyramidal cell markers Emx1 and CaMKIIα, as well as mature neuron markers MAP2 and Tuj1. 5-bromo-2-deoxyuridinine-positive neurons in the peristroke cortex also express such pyramidal markers. The presence of newly regenerated pyramidal neurons in the poststroke brain might provide a noninvasive therapeutic strategy for stroke treatment with functional recovery.

Ischemia-Induced Neural Stem/Progenitor Cells in the Pia Mater Following Cortical Infarction

Increasing evidence shows that neural stem/ progenitor cells (NSPCs) can be activated in the nonconventional neurogenic zones such as the cortex following ischemic stroke. However, the precise origin, identity, and subtypes of the ischemia-induced NSPCs (iNSPCs), which can contribute to cortical neurogenesis, is currently still unclear. In our present study, using an adult mouse cortical infarction model, we found that the leptomeninges (pia mater), which is widely distributed within and closely associated with blood vessels as microvascular pericytes/perivascular cells throughout central nervous system (CNS), have NSPC activity in response to ischemia and can generate neurons. These observations indicate that microvascular pericytes residing near blood vessels that are distributed from the leptomeninges to the cortex are potential sources of iNSPCs for neurogenesis following cortical infarction. In addition, our results propose a novel concept that the leptomeninges, which cover the entire brain, have an important role in CNS restoration following brain injury such as stroke