News and Publications


Publication

Published:
29 June 2021

Nuclear factor E2-related factor 2 (NRF2) deficiency accelerates fast fibre type transition in soleus muscle during space flight


Microgravity induces skeletal muscle atrophy, particularly in the soleus muscle, which is predominantly composed of slow-twitch myofibre (type I) and is sensitive to disuse. Muscle atrophy is commonly known to be associated with increased production of reactive oxygen species. However, the role of NRF2, a master regulator of antioxidative response, in skeletal muscle plasticity during microgravity-induced atrophy, is not known. To investigate the role of NRF2 in skeletal muscle within a microgravity environment, wild-type and Nrf2-knockout (KO) mice were housed in the International Space Station for 31 days. Gene expression and histological analyses demonstrated that, under microgravity conditions, the transition of type I (oxidative) muscle fibres to type IIa (glycolytic) was accelerated in Nrf2-KO mice without affecting skeletal muscle mass. Therefore, our results suggest that NRF2 affects myofibre type transition during space flight.

Communications Biology     volume 4, Article number: 787 (2021)
DOI 10.1038/s42003-021-02334-4
Nuclear factor E2-related factor 2 (NRF2) deficiency accelerates fast fibre type transition in soleus muscle during space flight.

Research Outline (PDF In Japanese language)

Publication

Published:
25 May 2021

Overexpression of Gata4, Mef2c, and Tbx5 Generates Induced Cardiomyocytes Via Direct Reprogramming and Rare Fusion in the Heart


(Note: Text has been auto translated from Japanese language.)
Cardiomyocytes that make up the heart have poor regenerative capacity and heart transplantation is the only radical treatment when cardiac function is significantly reduced. However, due to issues such as a shortage of donors, it is challenging to provide sufficient treatment. Regenerative medicine using pluripotent stem cells such as ES cells and iPS cells is attracting attention as an alternative method to heart transplantation, but it also leads to possibility of tumor formation, function issues and low tissue engraftment rate. The complexity and high cost of this approach is also a challenge to negate.


To date, this research group has developed a "myocardial direct reprogramming method" that induces cardiomyocytes directly from cardiac fibroblasts without using stem cells. This is another method that can help solve these issues. However, the myocardial cells produced by introducing a myocardial reprogramming gene into cardiac fibroblasts in vivo are truly induced regenerated myocardial cells derived from cardiac fibroblasts, or cardiac fibroblasts and surrounding myocardial cells.

It was unclear whether it was a myocardial cell that was being regenerated and formed by fusing. Therefore, in this study, we have shown that the new cardiomyocytes produced in vivo using genetically modified mice, are the genealogy and fusion of cells that are true regenerated cardiomyocytes derived from cardiac fibroblasts. This is the first time this has been revealed.

In this study, it was found that cardiomyocytes can be directly induced from cardiac fibroblasts by introducing a myocardial reprogramming gene into a mouse body. The results of this study greatly advance the realization of new cardiac regenerative medicine for heart disease.

Circulation     143:2123–2125(2021)
Overexpression of Gata4, Mef2c, and Tbx5 Generates Induced Cardiomyocytes Via Direct Reprogramming and Rare Fusion in the Heart


Research Outline (PDF In Japanese language)

Publication

Published:
11 June 2021

Development of technology to amplify hematopoietic stem cells in vitro and enable free gene transfer


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

Hematopoietic stem cells have the ability to differentiate into various blood cells such as red blood cells, white blood cells, and platelets, and are being applied to the treatment of blood cancer and hereditary blood diseases. However, hematopoietic stem cells are rarely present in the bone marrow, and post-collection amplification is essential.


As a technique for mass amplification of hematopoietic stem cells derived from donor mice in vitro, a method using a medium supplemented with polyvinyl alcohol (PVA) has been reported. Therefore, this research team applied this method to maintain the function of hematopoietic stem cells from bone marrow cells containing a very small amount of hematopoietic stem cells by only immunomagnetic cell separation method using magnetic beads and subsequent simple culture operation. We have developed a technology that can be selectively purified and concentrated as it is. This facilitates gene transfer into hematopoietic stem cells outside the body, and at the same time, it can be amplified in large quantities, making it possible to transplant without using conventional pretreatment such as irradiation. Furthermore, by devising when introducing the target gene, by selecting and transplanting only the hematopoietic stem cells into which the gene has been correctly introduced, the target gene can be expressed in the blood cells in the mouse body at any time after transplantation. Was successful. With this method, there is no tissue damage caused by radiation to the recipient mice after transplantation, and stable breeding and observation can be performed for a long period of time. In addition, there is little invasion and tissue damage to living mice, and it is considered to be an excellent method from the viewpoint of animal welfare. By using these platforms, it has become possible to freely design the function of hematopoietic stem cells according to the purpose of treatment.

Nature Communications
12, Article number: 3568 (2021)     DOI 10.1038/s41467-021-23763-z
Non-conditioned bone marrow chimeric mouse generation using culture based enrichment of hematopoietic stem and progenitor cells.

Research Outline (PDF In Japanese language)

Publication

Published:
30 Apr 2021

Transcriptome analysis of gravitational effects on mouse skeletal muscles under microgravity and artificial 1 g onboard environment


- Discovery of genes that induce muscle atrophy under microgravity -

(Note: Text has been auto translated from Japanese language.)
Gravity is a constant mechanical stimulus and a constant factor that also affects the evolution of living things on Earth. In addition, skeletal muscle is a tissue that can change its structure and metabolism in response to gravity and exercise load, but with the rapid aging, it maintains the amount and function of skeletal muscle and leads a healthy life. Measures are required to continue. On the other hand, it has been reported that astronauts staying in space have a rapid decrease in skeletal muscle mass and bone mass and have symptoms similar to those of the elderly. They are considered to be a model for increases in muscular atrophy and osteoporosis.


In this study, we investigated in detail the effect of gravity on skeletal muscle using a mouse breeding system that can change the gravity environment by a centrifuge developed by the Japan Aerospace Exploration Agency (JAXA). In the Japanese "Kibo" experimental laboratory of the International Space Station (ISS), mice were bred for near on one month in both the micro-gravity environment of space and in an artificial gravity environment (1G) in space. The changes in their muscle was analyzed.

For the first time ever, it has been shown that the artificial gravity environment suppresses the decrease in muscle weight and changes in muscle fiber type and gene expression that occurs in the micro-gravity environment. In addition, we discovered a new gene involved in muscular atrophy that was previously unknown.

The results of this research will provide basic data for long-term manned space exploration on the Moon and Mars, and may also be a key to clarifying part of the mechanism of muscular atrophy seen in the elderly and in the bed-ridden on Earth.

Scientific Reports -     11, Article number: 9168 (2021)
    doi/10.1038/s41598-021-88392-4


Research Outline (PDF In Japanese language)

New Publication

Published:
23 Feb 2021

Generation of reconstituted hemato-lymphoid murine embryos by placental transplantation into embryos lacking HSCs



In order to increase the contribution of donor HSC cells, irradiation and DNA alkylating agents have been commonly used as experimental methods to eliminate HSCs for adult mice. But a technique of HSC deletion for mouse embryo for increase contribution of donor cells has not been published. Here, we established for the first time a procedure for placental HSC transplantation into E11.5 Runx1-deficient mice mated with G1-HRD-Runx1 transgenic mice (Runx1-/-::Tg mice) that have no HSCs in the fetal liver. Following the transplantation of fetal liver cells from mice (allogeneic) or rats (xenogeneic), high donor cell chimerism was observed in Runx1-/-::Tg embryos. Furthermore, chimerism analysis and colony assay data showed that donor fetal liver hematopoietic cells contributed to both white blood cells and red blood cells. Moreover, secondary transplantation into adult recipient mice indicated that the HSCs in rescued Runx1-/-::Tg embryos had normal abilities. These results suggest that mice lacking fetal liver HSCs are a powerful tool for hematopoiesis reconstruction during the embryonic stage and can potentially be used in basic research on HSCs or xenograft models. (Read More –> )



Published in Scientific Reports 11, Article number: 4374 (2021)

Research Outline (PDF In Japanese language)

New Publication

Published:
3 Feb 2021

DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes

Key Points

• DHODH inhibition synergizes with DNA-demethylating agents in the treatment of MDS.
• DHODH inhibition enhances the incorporation of decitabine into DNA in MDS cells.


Blood Advances - Issue: Blood Adv(2021) 5 (2): 438–450
    https://doi.org/10.1182/bloodadvances.2020001461

New Publication

Published:
20 Jan 2021

Environment-based object values learned by local network in the striatum tail



Value and reward are known to be encoded in the part of the brain called the basal ganglia. Research has identified the specific neuronal circuits underlying environment-based value learning.

Obtaining valuables is one of the most important actions for the survival of animals, including humans. And even if they are the same, their value to animals changes depending on the environment and circumstances in which they are placed. Animals make good judgments about their value based on experience and learning. So what is the mechanism by which we learn the value of things?


Published in PNAS January 26, 2021 118 (4) e2013623118

Tsukuba Journal - University of Tsukuba

Research Outline (PDF In Japanese language)

New Publication

Published:
6 Jan 2021

Environment-based object values learned by local network in the striatum tail


In skeletal muscle, quiescent satellite cells maintain low levels of protein synthesis, mediated in part through the phosphorylation of eIF2α (P-eIF2α). Paradoxically, P-eIF2α also increases the translation of specific mRNAs, which is mediated by P-eIF2α dependent read through of inhibitory upstream open reading frames (uORFs). Here, we ask whether P-eIF2α dependent mRNA translation enables expansion of satellite cells. We demonstrate that uORFs in the 5’UTR of mRNA for the mitotic spindle stability gene Tacc3 direct P-eIF2α dependent translation. Satellite cells deficient for TACC3 exhibit defects in expansion, self-renewal and regeneration of skeletal muscle.

Satellite cell expansion is mediated by P-eIF2α-dependent Tacc3 translation
Development DOI: 10.1242/dev.194480

Tsukuba Journal - University of Tsukuba (Japanese language)

Research Outline (PDF In Japanese language)

New Publication

Published:
25 Nov 2020

Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration.



Research on astronaut health and model organisms have revealed six features of spaceflight biology that guide current understanding of fundamental molecular changes that occur during space travel.

Cell – Volume 183, Issue 5, 25 November 2020, Pages 1162-1184

New Publication

Published:
11 Dec 2020

Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo.



In vitro data and molecular dynamics simulations suggest that KS-58 enters cells and blocks intracellular Ras–effector protein interactions. KS-58 selectively binds to K-Ras(G12D) and suppresses the in vitro proliferation of the human lung cancer cell line A427 and the human pancreatic cancer cell line PANC-1, both of which express K-Ras(G12D). Moreover, KS-58 exhibits anti-cancer activity when given as an intravenous injection to mice with subcutaneous or orthotropic PANC-1 cell xenografts. The anti-cancer activity is further improved by combination with gemcitabine.

Scientific Reports – 10, Article number: 21671 (2020)