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プレゼンテーション
“糖尿病幹細胞 ”を除去することによりマウスの糖尿病は完全寛解する
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「糖尿病幹細胞」と名付けた異常な造血幹細胞が、STZマウスの膵島再生を阻害し、糖尿病の寛解を妨げることを見いだした。そこで、インスリンとHDAC 阻害剤を組み合わせ、一定期間治療したところ「糖尿病幹細胞」が除去され、糖尿病は完全寛解した。
研究に関する総説のご紹介
（総説）糖尿病幹細胞の発見
糖尿病は慢性進行性に経過し、自然治癒することはない。体質と生活習慣や自己免疫などにより発症するとされるが，詳細は不明である。筆者らは造血幹細胞分画に、糖尿病と合併症を発症させ難治性の性質を作り出す異常細胞を見いだした。この細胞は血糖値を正常化させても消失せず、疾患幹細胞としての性質を維持し続けた。そして、その細胞の除去により糖尿病と合併症の完治をめざせる可能性が示されたことから，「糖尿病幹細胞」と名付けた。
（総説）糖尿病幹細胞を捕まえる
1型であっても2型であっても糖尿病は一旦発症したらどんなに良いコントロールを心がけても自然治癒することはない。この点は、糖尿病により引き起こされる合併症においても同様である。いや、むしろ悪化を止められれないというべきである。エドモントンプロトコールの予想外の成績にも、同じ原因が潜んでいるに違いない。そう考えるに至ったのは、高血糖により産み落とされて、がん細胞のように不気味にうごめく一軍の細胞たちに気付いたからである。
研究に関する論文のご紹介
糖尿病およびその合併症における骨髄由来細胞に関するこれまでの我々の研究報告(2003-2023)
骨
Malfunction of bone marrow-derived osteoclasts and the delay of bone fracture healing in diabetic mice
Toshiyuki Kasahara; Sinji Imai; Hideto Kojima; Miwako Katagi; Hiroshi Kimura; Lawrence Chan; Yoshitaka Matsusue
BONE, 2010
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2926189/Expression of proinflammatory cytokines and proinsulin by bone marrow-derived cells for fracture healing in long-term diabetic mice
Hitomi Fujikawa, Hideto Kojima, Tomoya Terashima, Miwako Katagi, Takafumi Yayama, Kosuke Kumagai, Kanji Mori, Hideki Saito & Shinji Imai
BMC Musculoskelet Disord 24, 585 (2023). 2023
https://bmcmusculoskeletdisord.biomedcentral.com/articles/10.1186/s12891-023-06710-5
脳・食欲
Haematopoietic cells produce BDNF and regulate appetite upon migration to the hypothalamus
Hiroshi Urabe, Hideto Kojima, Lawrence Chan, Tomoya Terashima, Nobuhiro Ogawa, Miwako Katagi, Kazunori Fujino, Asako Kumagai, Hiromichi Kawai, Akihiro Asakawa, Akio Inui, Hitoshi Yasuda, Yutaka Eguchi, Kazuhiro Oka, Hiroshi Maegawa, Atsunori Kashiwagi, Hiroshi Kimura
Nat Commun 2013:4:1526
https://pubmed.ncbi.nlm.nih.gov/23443554/Aberrant bone marrow-derived microglia in the hypothalamus may dysregulate appetite in diabetes.
Miwako Katagi; Yuki Nakae; Junko Okano; Kazunori Fujino; Tomoki Tanaka; Itsuko Miyazawa; Natsuko Ohashi; Takahiko Nakagawa; Hideto Kojima
Biochemical and biophysical research communications, 2023
https://doi.org/10.1016/j.bbrc.2023.09.083
https://pubmed.ncbi.nlm.nih.gov/23443554/
循環
Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice
Eric Dale Buras, Lina Yang, Pradip Saha, Jongoh Kim, Pooja Mehta, Yisheng Yang, Susan Hilsenbeck, Hideto Kojima, Wenhao Chen, C. Wayne Smith, and Lawrence Chan
FASEB J. 2015 Aug; 29(8): 3537–3548.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511209/
代謝
Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes
Mineko Fujimiya, Hideto Kojima, Masumi Ichinose, Ryohachi Arai, Hiroshi Kimura, Atsunori Kashiwagi, and Lawrence Chan
Proc Natl Acad Sci U S A. 2007 March 6, 2007 104 (10) 4030-4035
https://www.pnas.org/doi/abs/10.1073/pnas.0700220104Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice
Eric Dale Buras, Lina Yang, Pradip Saha, Jongoh Kim, Pooja Mehta, Yisheng Yang, Susan Hilsenbeck, Hideto Kojima, Wenhao Chen, C. Wayne Smith, Lawrence Chan
FASEB J. 2015
https://doi.org/10.1096/fj.15-271452
膵島
NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice
Hideto Kojima, Mineko Fujimiya, Kazuhiro Matsumura, Patrick Younan, Hirotsugu Imaeda, Makiko Maeda, Lawrence Chan
Nat Med. 2003 May;9(5):596-603.
https://doi.org/10.1038/nm867Complete remission of diabetes with a transient HDAC inhibitor and insulin in streptozotocin mice
Hideto Kojima, Miwako Katagi, Junko Okano, Yuki Nakae, Natsuko Ohashi, Kazunori Fujino, Itsuko Miyazawa & Takahiko Nakagawa
Communications Biology volume 6, Article number: 637 (2023)
https://www.nature.com/articles/s42003-023-05010-x
消化
Homing of the bone marrow-derived interstitial cells of Cajal is decreased in diabetic mouse intestine
Yimin Li, Hideto Kojima, Kazunori Fujino, Kazuhiro Matsumura, Miwako Katagi, Hiroshi Urabe, Lawrence Chan, Yutaka Eguchi, Linghui Zhao, Hiroshi Kimura
J Gastroenterol Hepatol. 2011
https://doi.org/10.1111/j.1440-1746.2011.06670.x
末梢神経
The fusion of bone-marrow-derived proinsulin-expressing cells with nerve cells underlies diabetic neuropathy
Tomoya Terashima, Hideto Kojima, Mineko Fujimiya, Kazuhiro Matsumura, Jiro Oi, Manami Hara, Atsunori Kashiwagi, Hiroshi Kimura, Hitoshi Yasuda, and Lawrence Chan
Proc Natl Acad Sci U S A. August 22, 2005 102 (35) 12525-12530
https://doi.org/10.1073/pnas.0505717102Inactivation of TNF-α ameliorates diabetic neuropathy in mice
Isamu Yamakawa,Hideto Kojima,Tomoya Terashima,Miwako Katagi,Jiro Oi,Hiroshi Urabe,Mitsuru Sanada,Hiromichi Kawai,Lawrence Chan,Hitoshi Yasuda,Hiroshi Maegawa, andHiroshi Kimura
Am J Physiol Endocrinol Metab. 2011
https://doi.org/10.1152/ajpendo.00029.2011Bone marrow expression of poly(ADP-ribose) polymerase underlies diabetic neuropathy via hematopoietic-neuronal cell fusion
Tomoya Terashima, Hideto Kojima, and Lawrence Chan
FASEB J. 2012
https://doi.org/10.1096%2Ffj.11-186262Hyperglycemia induces abnormal gene expression in hematopoietic stem cells and their progeny in diabetic neuropathy
Miwako Katagi, Tomoya Terashima, Junko Okano, Hiroshi Urabe, Yuki Nakae, Nobuhiro Ogawa, Jun Udagawa, Hiroshi Maegawa, Kazuhiro Matsumura, Lawrence Chan, Hideto Kojima
FEBS Lett. 2014 Mar 18;588(6)
https://doi.org/10.1016/j.febslet.2014.02.030Bone marrow-derived TNF-α causes diabetic neuropathy in mice
Hiroshi Urabe, Tomoya Terashima, Fan Lin, Hideto Kojima & Lawrence Chan
Diabetologia. 2015
https://link.springer.com/article/10.1007/s00125-014-3440-4Ablation of a small subpopulation of diabetes-specific bone marrow-derived cells in mice protects against diabetic neuropathy
Hiroshi Urabe,Tomoya Terashima,Hideto Kojima, andLawrence Chan
Am J Physiol Endocrinol Metab. 2016
https://doi.org/10.1152/ajpendo.00381.2015Malfunctioning CD106-positive, short-term hematopoietic stem cells trigger diabetic neuropathy in mice by cell fusion
Miwako Katagi, Tomoya Terashima, Natsuko Ohashi, Yuki Nakae, Akane Yamada, Takahiko Nakagawa, Itsuko Miyazawa, Hiroshi Maegawa, Junko Okano, Yoshihisa Suzuki, Kazunori Fujino, Yutaka Eguchi & Hideto Kojima
Communications Biology volume 4, Article number: 575 (2021)
https://www.nature.com/articles/s42003-021-02082-5
全身
Extrapancreatic insulin-producing cells in multiple organs in diabetes
Hideto Kojima, Mineko Fujimiya, Kazuhiro Matsumura, Tamio Nakahara, Manami Hara, and Lawrence Chan
Proc Natl Acad Sci U S A. 2004 101 (8) 2458-2463
https://doi.org/10.1073/pnas.0308690100
排泄
A role for bone marrow-derived cells in diabetic nephropathy.
Nobuta, H., Katagi, M., Kume, S., Terashima, T., Araki, S., Maegawa, H., Kojima, H., Nakagawa, T.
FASEB J. 33, 4067–4076 (2019)
https://doi.org/10.1096/fj.201801825R
皮膚
Epidermis–dermis junction as a novel location for bone marrow-derived cells to reside in response to ionizing radiation
Junko Okano, Hideto Kojima, Miwako Katagi, Yuki Nakae, Tomoya Terashima, Takahiko Nakagawa, Takeshi Kurakane, Naoki Okamoto, Keita Morohashi, Hiroshi Maegawa, Jun Udagawa
Biochemical and Biophysical Research Communications Volume 461, Issue 4, 12 June 2015, Pages 695-701
https://doi.org/10.1016/j.bbrc.2015.04.094Hyperglycemia Induces Skin Barrier Dysfunctions with Impairment of Epidermal Integrity in Non-Wounded Skin of Type 1 Diabetic Mice
Junko Okano ,Hideto Kojima,Miwako Katagi,Takahiko Nakagawa,Yuki Nakae,Tomoya Terashima,Takeshi Kurakane,Mamoru Kubota,Hiroshi Maegawa,Jun Udagawa
PLoS One. November 15, 2016
https://doi.org/10.1371/journal.pone.0166215Impaired circadian rhythm may disturb epithelialization in the wound healing of the skin in diabetic mice
Junko Okano, Miwako Katagi, Takahiko Nakagawa, Hideto Kojima
J Dermatol Sci. 2023
https://doi.org/10.1016/j.jdermsci.2023.03.005
骨髄
The fusion of bone-marrow-derived proinsulin-expressing cells with nerve cells underlies diabetic neuropathy
Tomoya Terashima, Hideto Kojima, Mineko Fujimiya, Kazuhiro Matsumura, Jiro Oi, Manami Hara, Atsunori Kashiwagi, Hiroshi Kimura, Hitoshi Yasuda, and Lawrence Chan
Proc Natl Acad Sci U S A. 2004
https://doi.org/10.1073/pnas.0505717102Emerging Roles of Hematopoietic Cells in the Pathobiology of Diabetic Complications
Hideto Kojima, Jongoh Kim, and Lawrence Chan1
Trends Endocrinol Metab. 2014 Apr; 25(4): 178–187.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975817/Complete remission of diabetes with a transient HDAC inhibitor and insulin in streptozotocin mice
Hideto Kojima, Miwako Katagi, Junko Okano, Yuki Nakae, Natsuko Ohashi, Kazunori Fujino, Itsuko Miyazawa & Takahiko Nakagawa
Communications Biology volume 6, Article number: 637 (2023)
https://www.nature.com/articles/s42003-023-05010-x
