Increased RNA Transcription of Energy Source Transporters in Circulating White Blood Cells of Aged Mice.

Yukiko Takeuchi,Yuko Ogawa,Carsten Claussen,Yuka Okinaka,Sheraz Gul,Akie Kikuchi-Taura,Yosky Kataoka,Akihiko Taguchi,Orie Saino,Rie Akamatsu,Mitsuyo Maeda,Johannes Boltze

doi:10.3389/fnagi.2022.759159

Abstract

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.

Highlights

Circulating white blood cells (WBC) have been shown to contribute to the maintenance of cerebral circulation, metabolism, development, neurogenesis and brain function (Taguchi et al, 2004a, 2008; Filiano et al, 2017; Smith et al, 2018; Pasciuto et al, 2020; Runtsch et al, 2020)
We have demonstrated that RNA transcription of metabolism related genes in circulating WBC, including glucose transporter 1 (Glut1), glucose transporter 3 (Glut3), monocarboxylate transporter 4 (MCT4), prolyl hydroxylase 3 (PHD3), and pyruvate dehydrogenase kinase 1 (PDK1), are significantly increased during aging
Our findings indicate that the level of RNA transcription of metabolism related genes in circulating WBC can be potentially utilized as markers for decreased cell-cell interaction between circulating WBC and endothelial cells during aging

Summary

Introduction

Circulating white blood cells (WBC) have been shown to contribute to the maintenance of cerebral circulation, metabolism, development, neurogenesis and brain function (Taguchi et al, 2004a, 2008; Filiano et al, 2017; Smith et al, 2018; Pasciuto et al, 2020; Runtsch et al, 2020). We showed that intravenously injected BM-MNC supplies an energy source, such as glucose, to endothelial cells via gap junction and activates injured endothelial cells by induction of hypoxia inducible factor 1-α (Hif1-α), which is one of the major activators of metabolism related genes (Kim et al, 2006), in a cerebral ischemia model (Kikuchi-Taura et al, 2020). We have shown that intravenously transplanted mesenchymal stem cells remove the energy source from endothelial cells via gap junction, and suppress their excessive activation in a cerebral ischemia model (Kikuchi-Taura et al, 2021). These findings indicate that circulating cells have a significant effect on the regulation of cerebral circulation, metabolism, and function via gap junction. These findings are consistent with our previous findings that patients with decreased number of circulating hematopoietic stem cells, which express Connexin (Pfenniger et al, 2013) and contain significant amount of glycolysis substrates due to anaerobic metabolism (Takubo et al, 2013), showed impaired cerebral circulation and function (Taguchi et al, 2004a, 2008)

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