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Discrimination of Dormant and Active Hematopoietic Stem Cells by G 0 Markers Reveals Dormancy Regulation by Basal Cytoplasmic Calcium

81 Pages Posted: 26 Feb 2019 Publication Status: Review Complete

See all articles by Tsuyoshi Fukushima

Tsuyoshi Fukushima

University of Tokyo - Division of Cellular Therapy

Yosuke Tanaka

University of Tokyo - Division of Cellular Therapy

Fiona K. Hamey

University of Cambridge - Department of Haematology

Chih-Hsiang Chang

Kyoto University - Department of Molecular and Cellular BioAnalysis

Toshihiko Oki

University of Tokyo - Division of Cellular Therapy

Terumasa Umemoto

Kumamoto University - International Research Center for Medical Sciences

Shuhei Asada

University of Tokyo - Division of Cellular Therapy

Yasutaka Hayashi

University of Tokyo - Division of Cellular Therapy

Takeshi Fujino

University of Tokyo - Division of Cellular Therapy

Taishi Yonezawa

University of Tokyo - Division of Cellular Therapy

Reina Takeda

University of Tokyo - Division of Cellular Therapy

Kimihito Cojin Kawabata

University of Tokyo - Division of Cellular Therapy

Keiko Mikami

University of Tokyo - Division of Cellular Therapy

Tomofusa Fukuyama

University of Tokyo - Division of Cellular Therapy

Susumu Goyama

University of Tokyo - Division of Cellular Therapy

Hitoshi Takizawa

Kumamoto University - International Research Center for Medical Sciences

Yasushi Ishihama

Kyoto University - Department of Molecular and Cellular BioAnalysis

Hiroaki Honda

Cornell University - Division of Hematology and Oncology

Berthold Göttgens

University of Cambridge - Department of Haematology

Toshio Kitamura

University of Tokyo - Division of Cellular Therapy

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Abstract

Quiescent hematopoietic stem cells (HSCs) are typically dormant, and only a few quiescent HSCs are active. The relationship between “dormant” and “active” HSCs remains unresolved. Here we generated a G0 marker mouse line that visualizes quiescent cells. The G0 marker identifies a population of active HSCs (G0 markerlow) which are rare and distinct from dormant HSCs (G0 markerhigh) within the conventional quiescent HSC fraction. Single-cell RNA-sequencing analyses showed that the gene expression profiles of these populations were nearly identical, yet differed in their Cdk4/6 activity. Furthermore high-throughput small molecule screening revealed that high levels of basal cytoplasmic calcium (Ca2+) protected the dormancy of HSCs from cell cycle activation induced by calcium influx. These findings indicate that the G0 marker separates dormant and active adult HSCs, which are regulated by Cdk4/6 and Ca2+ levels. This G0 marker mouse line represents a useful new resource for investigating physiologically important stem cell subpopulations.

Keywords: Hematopoietic stem cell (HSC), cell cycle, G0 phase, p27, dormancy, CDK, calcium

Suggested Citation

Fukushima, Tsuyoshi and Tanaka, Yosuke and Hamey, Fiona K. and Chang, Chih-Hsiang and Oki, Toshihiko and Umemoto, Terumasa and Asada, Shuhei and Hayashi, Yasutaka and Fujino, Takeshi and Yonezawa, Taishi and Takeda, Reina and Kawabata, Kimihito Cojin and Mikami, Keiko and Fukuyama, Tomofusa and Goyama, Susumu and Takizawa, Hitoshi and Ishihama, Yasushi and Honda, Hiroaki and Göttgens, Berthold and Kitamura, Toshio, Discrimination of Dormant and Active Hematopoietic Stem Cells by G 0 Markers Reveals Dormancy Regulation by Basal Cytoplasmic Calcium (January 8, 2019). Available at SSRN: https://ssrn.com/abstract=3312121 or http://dx.doi.org/10.2139/ssrn.3312121
This version of the paper has not been formally peer reviewed.

Tsuyoshi Fukushima

University of Tokyo - Division of Cellular Therapy

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Yosuke Tanaka (Contact Author)

University of Tokyo - Division of Cellular Therapy ( email )

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Fiona K. Hamey

University of Cambridge - Department of Haematology

Cambridge
United Kingdom

Chih-Hsiang Chang

Kyoto University - Department of Molecular and Cellular BioAnalysis

Yoshida-Honmachi
Sakyo-ku
Kyoto, 606-8501
Japan

Toshihiko Oki

University of Tokyo - Division of Cellular Therapy

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Terumasa Umemoto

Kumamoto University - International Research Center for Medical Sciences

2-39-1 Kurokami, Chuo Ward
Kumamoto, 860-0862
Japan

Shuhei Asada

University of Tokyo - Division of Cellular Therapy

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Yasutaka Hayashi

University of Tokyo - Division of Cellular Therapy

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Takeshi Fujino

University of Tokyo - Division of Cellular Therapy

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Taishi Yonezawa

University of Tokyo - Division of Cellular Therapy

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Reina Takeda

University of Tokyo - Division of Cellular Therapy

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Kimihito Cojin Kawabata

University of Tokyo - Division of Cellular Therapy

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Keiko Mikami

University of Tokyo - Division of Cellular Therapy

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Tomofusa Fukuyama

University of Tokyo - Division of Cellular Therapy

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Susumu Goyama

University of Tokyo - Division of Cellular Therapy

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan

Hitoshi Takizawa

Kumamoto University - International Research Center for Medical Sciences

2-39-1 Kurokami, Chuo Ward
Kumamoto, 860-0862
Japan

Yasushi Ishihama

Kyoto University - Department of Molecular and Cellular BioAnalysis

Yoshida-Honmachi
Sakyo-ku
Kyoto, 606-8501
Japan

Hiroaki Honda

Cornell University - Division of Hematology and Oncology

1300 York Avenue
P.O. Box 24144
New York, NY 10065
United States

Berthold Göttgens

University of Cambridge - Department of Haematology

Cambridge
United Kingdom

Toshio Kitamura

University of Tokyo - Division of Cellular Therapy

4-6-1 Shirokanedai
Minato-ku
Tokyo, 108-8345
Japan