MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes via Pancreatic β-Cell Proliferation

Sohei Tsukita; Tetsuya Yamada; Kei Takahashi; Yuichiro Munakata; Shinichiro Hosaka; Hironobu Takahashi; Junhong Gao; Yuta Shirai; Shinjiro Kodama; Yoichiro Asai; Takashi Sugisawa; Yumiko Chiba; Keizo Kaneko; Kenji Uno; Shojiro Sawada; Junta Imai; Hideki Katagiri

doi:10.1016/j.ebiom.2016.12.002

MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes via Pancreatic β-Cell Proliferation

Sohei Tsukita, Tetsuya Yamada, Kei Takahashi, Yuichiro Munakata, Shinichiro Hosaka, Hironobu Takahashi, Junhong Gao, Yuta Shirai, Shinjiro Kodama, Yoichiro Asai, Takashi Sugisawa, Yumiko Chiba, Keizo Kaneko, Kenji Uno, Shojiro Sawada, Junta Imai, Hideki Katagiri

Research output: Contribution to journal › Article › peer-review

70 Citations (Scopus)

Abstract

Major symptoms of diabetes mellitus manifest, once pancreatic β-cell numbers have become inadequate. Although natural regeneration of β-cells after injury is very limited, bone marrow (BM) transplantation (BMT) promotes their regeneration through undetermined mechanism(s) involving inter-cellular (BM cell-to-β-cell) crosstalk. We found that two microRNAs (miRNAs) contribute to BMT-induced β-cell regeneration. Screening murine miRNAs in serum exosomes after BMT revealed 42 miRNAs to be increased. Two of these miRNAs (miR-106b-5p and miR-222-3p) were shown to be secreted by BM cells and increased in pancreatic islet cells after BMT. Treatment with the corresponding anti-miRNAs inhibited BMT-induced β-cell regeneration. Furthermore, intravenous administration of the corresponding miRNA mimics promoted post-injury β-cell proliferation through Cip/Kip family down-regulation, thereby ameliorating hyperglycemia in mice with insulin-deficient diabetes. Thus, these identified miRNAs may lead to the development of therapeutic strategies for diabetes.

Original language	English
Pages (from-to)	163-172
Number of pages	10
Journal	EBioMedicine
Volume	15
DOIs	https://doi.org/10.1016/j.ebiom.2016.12.002
Publication status	Published - 2017 Feb 1

Keywords

Cip/Kip family
Diabetes
Exosomes
MicroRNAs
β-cell regeneration

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ebiom.2016.12.002

Cite this

Tsukita, S., Yamada, T., Takahashi, K., Munakata, Y., Hosaka, S., Takahashi, H., Gao, J., Shirai, Y., Kodama, S., Asai, Y., Sugisawa, T., Chiba, Y., Kaneko, K., Uno, K., Sawada, S., Imai, J., & Katagiri, H. (2017). MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes via Pancreatic β-Cell Proliferation. EBioMedicine, 15, 163-172. https://doi.org/10.1016/j.ebiom.2016.12.002

Tsukita, S, Yamada, T, Takahashi, K, Munakata, Y, Hosaka, S, Takahashi, H, Gao, J, Shirai, Y, Kodama, S , Asai, Y, Sugisawa, T, Chiba, Y, Kaneko, K, Uno, K, Sawada, S, Imai, J & Katagiri, H 2017, 'MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes via Pancreatic β-Cell Proliferation', EBioMedicine, vol. 15, pp. 163-172. https://doi.org/10.1016/j.ebiom.2016.12.002

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title = "MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes via Pancreatic β-Cell Proliferation",

abstract = "Major symptoms of diabetes mellitus manifest, once pancreatic β-cell numbers have become inadequate. Although natural regeneration of β-cells after injury is very limited, bone marrow (BM) transplantation (BMT) promotes their regeneration through undetermined mechanism(s) involving inter-cellular (BM cell-to-β-cell) crosstalk. We found that two microRNAs (miRNAs) contribute to BMT-induced β-cell regeneration. Screening murine miRNAs in serum exosomes after BMT revealed 42 miRNAs to be increased. Two of these miRNAs (miR-106b-5p and miR-222-3p) were shown to be secreted by BM cells and increased in pancreatic islet cells after BMT. Treatment with the corresponding anti-miRNAs inhibited BMT-induced β-cell regeneration. Furthermore, intravenous administration of the corresponding miRNA mimics promoted post-injury β-cell proliferation through Cip/Kip family down-regulation, thereby ameliorating hyperglycemia in mice with insulin-deficient diabetes. Thus, these identified miRNAs may lead to the development of therapeutic strategies for diabetes.",

keywords = "Cip/Kip family, Diabetes, Exosomes, MicroRNAs, β-cell regeneration",

author = "Sohei Tsukita and Tetsuya Yamada and Kei Takahashi and Yuichiro Munakata and Shinichiro Hosaka and Hironobu Takahashi and Junhong Gao and Yuta Shirai and Shinjiro Kodama and Yoichiro Asai and Takashi Sugisawa and Yumiko Chiba and Keizo Kaneko and Kenji Uno and Shojiro Sawada and Junta Imai and Hideki Katagiri",

note = "Funding Information: We thank T. Takasugi, K. Namiki, S. Fukasawa, M. Hoshi and J. Fushimi for technical assistance. This work was supported by Grants-in-aid for Scientific Research (to S.T, T.Y. and H.K.) from the Japan Society for the Promotion of Science (16K19528 to S.T., 26293215 to T.Y., 25253067 to H.K.). This work was also supported by a Grant-in-Aid for Scientific Research on Innovative Areas (to H.K.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (22126006 to H.K.). Publisher Copyright: {\textcopyright} 2016 The Authors",

year = "2017",

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doi = "10.1016/j.ebiom.2016.12.002",

language = "English",

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T1 - MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes via Pancreatic β-Cell Proliferation

AU - Tsukita, Sohei

AU - Yamada, Tetsuya

AU - Takahashi, Kei

AU - Munakata, Yuichiro

AU - Hosaka, Shinichiro

AU - Takahashi, Hironobu

AU - Gao, Junhong

AU - Shirai, Yuta

AU - Kodama, Shinjiro

AU - Asai, Yoichiro

AU - Sugisawa, Takashi

AU - Chiba, Yumiko

AU - Kaneko, Keizo

AU - Uno, Kenji

AU - Sawada, Shojiro

AU - Imai, Junta

AU - Katagiri, Hideki

N1 - Funding Information: We thank T. Takasugi, K. Namiki, S. Fukasawa, M. Hoshi and J. Fushimi for technical assistance. This work was supported by Grants-in-aid for Scientific Research (to S.T, T.Y. and H.K.) from the Japan Society for the Promotion of Science (16K19528 to S.T., 26293215 to T.Y., 25253067 to H.K.). This work was also supported by a Grant-in-Aid for Scientific Research on Innovative Areas (to H.K.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (22126006 to H.K.). Publisher Copyright: © 2016 The Authors

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Major symptoms of diabetes mellitus manifest, once pancreatic β-cell numbers have become inadequate. Although natural regeneration of β-cells after injury is very limited, bone marrow (BM) transplantation (BMT) promotes their regeneration through undetermined mechanism(s) involving inter-cellular (BM cell-to-β-cell) crosstalk. We found that two microRNAs (miRNAs) contribute to BMT-induced β-cell regeneration. Screening murine miRNAs in serum exosomes after BMT revealed 42 miRNAs to be increased. Two of these miRNAs (miR-106b-5p and miR-222-3p) were shown to be secreted by BM cells and increased in pancreatic islet cells after BMT. Treatment with the corresponding anti-miRNAs inhibited BMT-induced β-cell regeneration. Furthermore, intravenous administration of the corresponding miRNA mimics promoted post-injury β-cell proliferation through Cip/Kip family down-regulation, thereby ameliorating hyperglycemia in mice with insulin-deficient diabetes. Thus, these identified miRNAs may lead to the development of therapeutic strategies for diabetes.

AB - Major symptoms of diabetes mellitus manifest, once pancreatic β-cell numbers have become inadequate. Although natural regeneration of β-cells after injury is very limited, bone marrow (BM) transplantation (BMT) promotes their regeneration through undetermined mechanism(s) involving inter-cellular (BM cell-to-β-cell) crosstalk. We found that two microRNAs (miRNAs) contribute to BMT-induced β-cell regeneration. Screening murine miRNAs in serum exosomes after BMT revealed 42 miRNAs to be increased. Two of these miRNAs (miR-106b-5p and miR-222-3p) were shown to be secreted by BM cells and increased in pancreatic islet cells after BMT. Treatment with the corresponding anti-miRNAs inhibited BMT-induced β-cell regeneration. Furthermore, intravenous administration of the corresponding miRNA mimics promoted post-injury β-cell proliferation through Cip/Kip family down-regulation, thereby ameliorating hyperglycemia in mice with insulin-deficient diabetes. Thus, these identified miRNAs may lead to the development of therapeutic strategies for diabetes.

KW - Cip/Kip family

KW - Diabetes

KW - Exosomes

KW - MicroRNAs

KW - β-cell regeneration

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DO - 10.1016/j.ebiom.2016.12.002

M3 - Article

C2 - 27974246

AN - SCOPUS:85008222752

SN - 2352-3964

VL - 15

SP - 163

EP - 172

JO - EBioMedicine

JF - EBioMedicine

ER -

MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes via Pancreatic β-Cell Proliferation

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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