TMRC - Transborder Medical Research Center

Publication

Published:
Published in Nature Feb 22 2023

Chemically defined cytokine-free expansion of human haematopoietic stem cells

Researchers from the University of Tsukuba develop a system for effectively growing large numbers of blood stem cells outside of the human body

Tsukuba, Japan—Hematopoietic stem cells (HSCs) are important immature blood cells in bone marrow that can be triggered to develop into any blood cell type. HSC transplants can be used to treat conditions where bone marrow is damaged and no longer able to produce healthy blood cells, but the widespread and safe use of HSCs is limited by barriers to cell growth and expansion in the lab (i.e. ex vivo). Now, a team led by researchers at the University of Tsukuba has established a novel culture system that supports long term ex vivo expansion of HSCs… Read More –> University of Tsukuba Research News Press Release

→ Nature 【DOI】 10.1038/s41586-023-05739-9
Chemically defined cytokine-free expansion of human haematopoietic stem cells.

→ Research Outline (PDF In Japanese language)

Publication

Published:
Published Feb 14 2023

Transcription factor c-Maf deletion improves streptozotocin-induced diabetic nephropathy by directly regulating Sglt2 and Glut2

(Note: Text has been auto translated from Japanese language.)

Chronic kidney disease is often caused by lifestyle-related diseases such as diabetes and hypertension. It is estimated to affect one in eight adults in Japan (approximately 13.3 million people). Chronic kidney disease progresses with few initial symptoms, and severe kidney dysfunction also significantly increases the risk of developing cardiovascular diseases such as myocardial infarction, stroke and arteriosclerosis; therefore, it is necessary to diagnose the disease at an earlier stage and start prevention and treatment prior to more severe conditions. However, there is currently no fundamental cure for advanced chronic kidney disease.

Research has previously discovered that the transcription factor (a protein that regulates gene expression) c-Maf regulates the expression of various membrane transporter proteins in the proximal tubules, which in addition to its therapeutic effect on diabetes, is also involved in renal damage and cardiovascular disease. c-Maf is also known to be involved in the regulation of organ development and immune cell function during embryonic development, but its function in adults is not well understood.

This study discovered that whole-body deletion of c-Maf in adult mice models of diabetes and associated renal damage ameliorated hyperglycemia and renal damage caused by diabetes and reduced oxidative stress in the kidney, is one of the main causes of renal damage. In other words, controlling timing of c-Maf expression could improve diabetes and chronic kidney disease, suggesting that targeting c-Maf could lead to the development of novel therapies for diabetes and chronic kidney disease.

→ JCI Insight DOI 10.1172/jci.insight.163306
"Transcription factor c-Maf deletion improves streptozotocin-induced diabetic nephropathy by directly regulating Sglt2 and Glut2."

→ Research Outline (PDF In Japanese language)

Publication

Published:
9 Dec 2022

Molecular signals within excitatory neurons regulate sleep

Elucidating the mechanism that determines the quantity and quality of sleep.

Sleep is necessary for everyone, but why sleep is needed at all is a mystery to this day. The research team focused on an enzyme (SIK3) which is key to solving this mystery. This enzyme regulates the chain of reactions in the brain involved in sleep, forming a molecular signal which regulates the quality and quantity of sleep. However, it was not known what kind of molecules and chains of molecules SIK3 forms for sleep regulation, or through which cells it is determined. In this study, the details of the chain (molecular signal) and the genes regulated by this molecular signal were clarified for the first time ever internationally.

We also found that the quality of sleep is regulated by excitatory neurons in the cortex and the quantity is regulated by excitatory neurons in the hypothalamus. We have also succeeded in further validating this molecular signal by using viral vectors to alter the quantity and quality of sleep in an acquired manner.

Sleep is essential for physical and mental health. Sleep disorders increase the risk of mental disorders, diabetes, heart disease, and dementia such as Alzheimer's disease, and decrease brain performance during the day. It is said that many people in Japan have sleep debt (mental and physical disorders associated with sleep deprivation). Through understanding the mechanisms that control the quantity and quality of sleep, it is expected to contribute to the development of new methods of sleep control and treatments for sleep disorders.

→ Journal Publication A - Nature 【DOI】 10.1038/s41586-022-05450-1
Kinase signalling in excitatory neurons regulates sleep quantity and depth.

→ Journal Publication B - Nature 【DOI】 10.1038/s41586-022-05510-6
A signaling pathway for transcriptional regulation of sleep amount in mice.

→ Research Outline (PDF In Japanese language)

Notice of Award

Published:
Dec 02 2022

2022 Chemo-Sero Therapeutic Research Institute Grant

Professor Mamiko Sakata-Yanagimoto (坂田-柳元　麻実子), who heads up the Advanced Hemato Oncology Laboratory in the TMRC Integrated Research Division, was selected for the Japan 2022 Chemo-Sero Therapeutic Research Institute Grant. The funding will go to support her lab's important research elucidating the pathogenesis of age pre-related malignant lymphoma.

→ "Kaketsuken" Press Release (PDF In Japanese language)
→ TMRC Integrated Research Division - Advanced Hemato Oncology Lab

Publication

Published:
Dec 01 2022

The adhesion G-protein-coupled receptor Gpr116 is essential to maintain the skeletal muscle stem cell pool.

Highlights:
• Quiescent muscle stem cells express the adhesion G-protein-coupled receptor Gpr116
• Gpr116-deficient muscle stem cells are incapable of maintaining quiescence
• The GPR116 Stachel agonist peptide prevents MuSC activation
• GPR116 signaling is mediated in part by nuclear activity of β-arrestin1

Skeletal muscle is populated with a reservoir of quiescent muscle stem cells (MuSCs), which regenerate the tissue after injury. Here, we show that the adhesion G-protein-coupled receptor Gpr116 is essential for long-term maintenance of the MuSC pool. Quiescent MuSCs express high levels of Gpr116, which is rapidly downregulated upon MuSC activation. MuSCs deficient for Gpr116 exhibit progressive depletion over time and are defective in self-renewal. Adhesion G-protein-coupled receptors contain an agonistic peptide sequence, called the “Stachel” sequence, within their long N-terminal ectodomains. Stimulation of MuSCs with the GPR116 Stachel peptide delays MuSC activation and differentiation. Stachel peptide stimulation of GPR116 leads to strong interaction with β-arrestins. Stimulation of GPR116 increases the nuclear localization of β-arrestin1, where it interacts with cAMP response element binding protein to regulate gene expression. Altogether, we propose a model by which GPR116 maintains the MuSC pool via nuclear functions of β-arrestin1.

→ Cell Reports
Volume 41, ISSUE 7, 111645, November 15, 2022
https://doi.org/10.1016/j.celrep.2022.111645

→ Research Outline (PDF In Japanese language)

Event

Published:
Posted 10 November 2022

Digital Medicine Strategy Division - Fourth Seminar Session

Transborder Medical Research Center

Digital Medicine Strategy Division

Online Zoom Event, November 30th, 2022 (Wednesday),
18:00 - 19:00
(Please Note: Seminar will be presented in Japanese language only)

→ Seminar Poster Download (Available in Japanese Language only.)

Notice of Award

Published:
Oct 10, 2022

Professor Sakata-Yanagimoto received Japan Cancer Association (JCA) Mauvernay Award.

Professor Sakata-Yanagimoto of TMRC and Department of Hematology at University of Tsukuba, received the 2022 Japan Cancer Association (JCA) Mauvernay Award within the “Translational Research” catergory. Professor Sakata-Yanagimoto was recognized for her exceptional research related to “Translational research targeting intractable lymphomas.”

The Japanese Cancer Association and Debiopharm jointly established the JCA-Mauvernay Award to recognize the cutting edge oncology research and to encourage Japanese researchers to make their work available to other parts of the world.”

Award Information → (Japan Cancer Association (JCA) - External Website)

Notice

Published:
Oct 10, 2022

Professor Takahashi and Professor Hirokawa of TMRC have been selected to participate in the AMED-BINDS project.

“The “Basic Project for Supporting Life Science and Drug Discovery Research” is a project based on a wide range of life science-related research in Japan, with the aim of linking outstanding research results to practical research and development, such as drug discovery research. ” Read More → (BINDS Website - Available in Japanese Language Only)

Publication

Published:
30 Sept 2022

Development of an analytical method to estimate gene expression by cell-cell interaction

CCPLS reveals cell-type-specific spatial dependence of transcriptomes in single cells.

Our bodies are composed of a wide variety of cells, which interact with each other to ensure that developmental processes proceed properly and that homeostasis is maintained in tissues and organs. When this cell-cell interaction is disrupted, it can lead to disease.

On the other hand, it is known that there are genes whose expression varies from cell to cell, even within the same cell type. Many of these genes are involved in cellular functions and thus affect the function of the entire cell population and the development of disease. Although it was known in some cases that cell-cell interactions are associated with such cell-to-cell variation in gene expression, the full picture was not clear because there was no comprehensive method to examine the effects of multiple cell types on gene expression.

In this study, we developed CCPLS, an information analysis method that uses one-cell spatial transcriptome data, which simultaneously measures cell function and spatial coordinates, to estimate the effects of neighboring cells on each other's gene expression. This method estimates the relationship between the types of neighboring cell types and the resulting gene expression when focusing on a certain cell type. Evaluation experiments using simulated data have shown that CCPLS can estimate cell-cell interactions with high accuracy. In addition, specific cell-cell interactions could be extracted from examples of application to real data in the brain and colon, demonstrating the effectiveness of this method.