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「糖尿病幹細胞(Diabetes Stem Cells, DSC)」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。

*ENDO2024 (Endocrine Society2024)、4th Edition of World Congress onEndocrinology, Diabetes and Metabolism、及びCommunications Biology 2003での発表内容

糖尿病における骨髄由来細胞の異常と臓器障害ついて、我々がこれまで行ってきた20年以上にわたる研究報告を臓器毎にまとめています。それぞれの論文ついて、糖尿病がいかに骨髄由来細胞の異常が関係しているかがご理解頂けるかと思います。

2023

Impaired circadian rhythm may disturb epithelialization in the wound healing of the skin in diabetic mice. Okano J, Katagi M, Nakagawa T, Kojima H. J Dermatol Sci. 2023 Apr;110(1):31-34. doi: 10.1016/j.jdermsci.2023.03.005. Epub 2023 Mar 21. PMID: 37012132.

Complete remission of diabetes with a transient HDAC inhibitor and insulin in streptozotocin mice. Kojima H, Katagi M, Okano J, Nakae Y, Ohashi N, Fujino K, Miyazawa I, Nakagawa T. Commun Biol. 2023 Jun 13;6(1):637. doi: 10.1038/s42003-023-05010-x. PMID: 37311905; PMCID: PMC10264456.

Expression of proinflammatory cytokines and proinsulin by bone marrow-derived cells for fracture healing in long-term diabetic mice. Fujikawa H, Kojima H, Terashima T, Katagi M, Yayama T, Kumagai K, Mori K, Saito H, Imai S. BMC Musculoskelet Disord. 2023 Jul 18;24(1):585. doi: 10.1186/s12891-023-06710-5. PMID: 37464323; PMCID: PMC10355075.

Aberrant bone marrow-derived microglia in the hypothalamus may dysregulate appetite in diabetes. Katagi M, Nakae Y, Okano J, Fujino K, Tanaka T, Miyazawa I, Ohashi N, Nakagawa T, Kojima H. Biochem Biophys Res Commun. 2023 Nov 19;682:132-137. doi: 10.1016/j.bbrc.2023.09.083. Epub 2023 Sep 27. PMID: 37806251.

2022

Ambient temperature is correlated with the severity of neonatal hypoxic- ischemic brain injury via microglial accumulation in mice. Zen R, Terashima T, Tsuji S, Katagi M, Ohashi N, Nobuta Y, Higuchi A, Kanai H, Murakami T, Kojima H. Frontiers in Pediatrics. May 06, 2022.

Bone marrow-derived inducible microglia-like cells ameliorate motor function and survival in a mouse model of amyotrophic lateral sclerosis. Kobashi S, Terashima T, Katagi M, Urushitani M, Kojima H. Cytotherapy, April 04, 2022.

2021

GLT1 gene delivery based on bone marrow-derived cells ameliorates motor function and survival in a mouse model of ALS. Ohashi N, Terashima T, Katagi M, Nakae Y, Okano J, Suzuki Y, Kojima H. Sci Rep, 11, 12803, 2021.

Malfunctioning CD106-positive, short-term hematopoietic stem cells trigger diabetic neuropathy in mice by cell fusion. Katagi M, Terashima T, Ohashi N, Nakae Y, Yamada A, Nakagawa T, Miyazawa I, Maegawa H, Okano J, Suzuki Y, Fujino K, Eguchi Y, Kojima H. Commun Biol, 4, 575, 2021.

A novel role for bone marrow-derived cells to recover damaged keratinocytes from radiation-induced injury. Okano J, Nakae Y, Nakagawa T, Katagi M, Terashima T, Nagakubo D, Nakayama T, Yoshie O, Suzuki Y, Kojima H. Sci Rep, 11, 5653, 2021.

2020

Enhancing the Therapeutic Efficacy of Bone Marrow-Derived Mononuclear Cells with Growth Factor-Expressing Mesenchymal Stem Cells for ALS in Mice. Terashima T, Kobashi S, Watanabe Y, Nakanishi M, Honda N, Katagi M, Ohashi N, Kojima H. iScience, 23(11), 101764, 2020.

Bone marrow-derived mononuclear cells relieve neuropathic pain after spinal nerve injury in mice. Takamura H, Terashima T, Mori K, Katagi M, Okano J, Suzuki Y, Imai S, Kojima H. Mol Ther Methods Clin Dev, 17, 657-665, 2020.

Transplantation of M2-deviated microglia promotes recovery of motor function after spinal cord injury in mice. Kobashi S, Terashima T, Katagi M, Nakae Y, Okano J, Suzuki Y, Urushitani M, Kojima H. Mol Ther, 28, 254-265, 2020.

2019

Dynamics of host and graft after cell sheet transplantation: basic study for the application of amyotrophic lateral sclerosis. Nakanishi M, Watanabe Y, Honda N, Une M, Kazuki K, Kazuki Y, Terashima T, Katagi M, Nakashima K, Hanajima R. Brain Res, 1724, 146444, 2019.

Advanced technology for gene delivery with homing peptides to spinal cord through systemic circulation in mice. Terashima T, Ogawa N, Sato T, Katagi M, Nakae Y, Okano J, Maegawa H, Kojima H. Mol Ther Methods Clin Dev, 13, 474-483, 2019.

Efficient Prostate Cancer Therapy with Tissue-Specific Homing Peptides Identified by Advanced Phage Display Technology. Wada A, Terashima T, Kageyama S, Yoshida T, Narita M, Kawauchi A, Kojima H. Mol Ther Oncolytics, 12, 138-146, 2019.

A role for bone marrow-derived cells in diabetic nephropathy. Nobuta H, Katagi M, Kume S, Terashima T, Araki SI, Maegawa H, Kojima H, Nakagawa T. FASEB J., 33, 4067-76, 2019.

2018

Stem cell factor induces polarization of microglia to the neuroprotective phenotype in vitro. Terashima T, Nakae Y, Katagi M, Okano J, Suzuki Y, Kojima H. Heliyon, Volume 4, Issue 10, e00837, 2018.

Gene therapy for neuropathic pain using dorsal root ganglion-targeted helper-dependent adenoviral vectors with GAD67 expression. Ogawa N, Terashima T, Oka K, Chan L, Kojima H. PAIN Reports, 3, e695, 2018.

Gene Therapy for Neuropathic Pain through siRNA-IRF5 Gene Delivery with Homing Peptides to Microglia. Terashima T, Ogawa N, Nakae Y, Sato T, Katagi M, Okano J, Maegawa H, Kojima H. Mol Ther Nucleic Acids., 11, 203-215, 2018.

2017

Charcot-Marie-Tooth disease type 2A with an autosomal-recessive inheritance: the first report of an adult-onset disease. Hikiami R, Yamashita H, Koita N, Jingami N, Sawamoto N, Furukawa K, Kawai H, Terashima T, Oka N, Hashiguchi A, Takashima H, Urushitani M, Takahashi R. J Hum Genet. Epub 2017 Nov 13.

2016

Hyperglycemia Induces Skin Barrier Dysfunctions with Impairment of Epidermal Integrity in Non-Wounded Skin of Type 1 Diabetic Mice. Okano J, Kojima H, Katagi M, Nakagawa T, Nakae Y, Terashima T, Kurakane T, Kubota M, Maegawa H, Udagawa J. PLoS One, 11, e0166215, 2016.

Clinical Phenotype and Segregation of Mitochondrial 3243A>G Mutation in 2 Pairs of Monozygotic Twins. Maeda K, Kawai H, Sanada M, Terashima T, Ogawa N, Idehara R, Makiishi T, Yasuda H, Sato S, Hoshi K, Yahikozawa H, Nishi K, Itoh Y, Ogasawara K, Tomita K, Indo HP, Majima HJ. JAMA Neurol., 73, 990-3, 2016.

Ablation of a small subpopulation of diabetes-specific bone marrow-derived cells in mice protects against diabetic neuropathy. Urabe H, Terashima T, Kojima H, Chan L. Am. J. Physio.l Endocrinol. Metab., 310, E269-75, 2016.

Late-onset spinal form xanthomatosis without brain lesion: a case report. Yanagihashi M, Kano O, Terashima T, Kawase Y, Hanashiro S, Sawada M, Ishikawa Y, Shiraga N, Ikeda K, Iwasaki Y. BMC Neurol., 16, 21, 2016

2015

Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice. Buras ED, Yang L, Saha P, Kim J, Mehta P, Yang Y, Hilsenbeck S, Kojima H, Chen W, Smith CW, Chan L. FASEB J., 29, 3537-48, 2015.

Epidermis-dermis junction as a novel location for bone marrow-derived cells to reside in response to ionizing radiation. Okano J, Kojima H, Katagi M, Nakae Y, Terashima T, Nakagawa T, Kurakane T, Okamoto N, Morohashi K, Maegawa H, Udagawa J. Biochem. Biophys. Res. Commun., 461, 695-701, 2015.

Bone marrow-derived TNF-α causes diabetic neuropathy in mice. Urabe H, Terashima T, Lin F, Kojima H, Chan L. Diabetologia, 58, 402-10, 2015.

2014

Emerging roles of hematopoietic cells in the pathobiology of diabetic complications. Kojima H, Kim J, Chan L. Trends Endocrinol. Metab., 25, 178-87, 2014.

Stem Cell Factor-Activated Bone Marrow Ameliorates Amyotrophic Lateral Sclerosis by Promoting Protective Microglial Migration. Terashima T, Kojima H, Urabe H, Yamakawa I, Ogawa N, Kawai H, Chan L, Maegawa H. J. Neurosci. Res., 92, 856-69, 2014.

Hyperglycemia induces abnormal gene expression in hematopoietic stem cells and their progeny in diabetic neuropathy. Katagi M, Terashima T, Okano J, Urabe H, Nakae Y, Ogawa N, Udagawa J, Maegawa H, Matsumura K, Chan L, Kojima H. FEBS letters, 588, 1080-6, 2014.

Gene therapy for neuropathic pain by silencing of TNF-α expression with lentiviral vectors targeting the dorsal root ganglion in mice. Ogawa N, Kawai H, Terashima T, Kojima H, Oka K, Chan L, Maegawa H. PLoS One, 9, e92073, 2014.

A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease. Tamiya G, Makino S, Hayashi M, Abe A, Numakura C, Ueki M, Tanaka A, Ito C, Toshimori K, Ogawa N, Terashima T, Maegawa H, Yanagisawa D, Tooyama I, Tada M, Onodera O, Hayasaka K. Am. J. Hum. Genet., 95, 294-300, 2014.

Polyglycerol-functionalized nanodiamond as a platform for gene delivery: Derivatization, characterization, and hybridization with DNA. Zhao L, Nakae Y, Qin H, Ito T, Kimura T, Kojima H, Chan L, Komatsu N. Beilstein J. Org. Chem., 10, 707-13, 2014.

2013

Haematopoietic cells produce BDNF and regulate appetite upon migration to the hypothalamus. Urabe H, Kojima H, Chan L, Terashima T, Ogawa N, Katagi M, Fujino K, Kumagai A, Kawai H, Asakawa A, Inui A, Yasuda H, Eguchi Y, Oka K, Maegawa H, Kashiwagi A, Kimura H. Nat. Commun., 4, 1526, 2013.

2012

Interleukin-7 induces recruitment of monocytes/macrophages to endothelium. Li R, Paul A, Ko KW, Sheldon M, Rich BE, Terashima T, Dieker C, Cormier S, Li L, Nour EA, Chan L, Oka K. Eur. Heart J., 33, 3114-23, 2012.

Bone marrow expression of poly(ADP-ribose) polymerase underlies diabetic neuropathy via hematopoietic-neuronal cell fusion. Terashima T, Kojima H, Chan L. FASEB J., 26, 295-308, 2012.

Brain-Derived Neurotrophic Factor from Bone Marrow-Derived Cells Promotes Post-Injury Repair of Peripheral Nerve. Takemura Y, Imai S, Kojima H, Katagi M, Yamakawa I, Kasahara T, Urabe H, Terashima T, Yasuda H, Chan L, Kimura H, Matsusue Y. PLoS One, 7, e44592, 2012.

2011

Pathogenesis of diabetic neuropathy: bad to the bone. Chan L, Terashima T, Urabe H, Lin F, Kojima H. Endocrinol. Metab., 301, E844-852, 2011.

Transfer of bone marrow progenitors prevents coronary insufficiency and systolic dysfunction in the mechanical unloaded heart in mice. Koike M, Kojima H, Fujimiya M, Matsubayashi K, Aimi Y, Kimura H, Asai T. J. Surg. Res., 171, 47-57, 2011.

Inactivation of TNF-α Ameliorates Diabetic Neuropathy in Mice. Yamakawa I, Kojima H, Terashima T, Katagi M, Oi J, Urabe H, Sanada M, Kawai H, Chan L, Yasuda H, Maegawa H, Kimura H. Am. J. Physiol. Ann. NY. Acad. Sci., 1240, 70-76, 2011.

Pathogenesis of diabetic neuropathy: bad to the bone. Chan L, Terashima T, Urabe H, Lin F, Kojima H. Ann. NY. Acad. Sci., 1240, 70-76, 2011.

Homing of the bone marrow-derived interstitial cells of Cajal is decreased in diabetic mouse intestine. Li Y, Kojima H, Fujino K, Matsumura K, Katagi M, Urabe H, Chan L, Eguchi Y, Zhao L, Kimura H. J. Gastroenterol. Hepatol., 26, 1072-8, 2011.

2010

Chronic foot-shock stress potentiates the influx of bone marrow-derived microglia into hippocampus. Brevet M, Kojima H, Asakawa A, Atsuchi K, Ushikai M, Ataka K, Inui A, Kimura H, Sevestre H, Fujimiya M. J. Neurosci. Res., 88, 1890-7, 2010.

Hyperglycemia induces oxidative stress and impairs axonal transport rates in mice. Sharma R, Buras E, Terashima T, Serrano F, Massaad CA, Hu L, Bitner B, Inoue T, Chan L, Pautler RG. PLoS One, 5, e13463, 2010.

Malfunction of bone marrow-derived osteoclasts and the delay of bone fracture healing in diabetic mice. Kasahara T, Imai S, Kojima H, Katagi M, Kimura H, Chan L, Matsusue Y. Bone, 47(3):617-25, 2010.

2009

Neurogenin3 is sufficient for transdetermination of hepatic progenitor cells into neo-islets in vivo but not transdifferentiation of hepatocytes. Yechoor V, Liu V, Espiritu C, Paul A, Oka K, Kojima H, Chan L. Dev. Cell, 16, 358-73, 2009.

Pathological roles of bone marrow-derived stellate cells in a mouse model of alcohol-induced fatty liver. Fujimiya T, Liu J, Kojima H, Shirafuji S, Kimura H, Fujimiya M. Am. J. Physiol. Gastrointest. Liver Physiol., 297, G451-60, 2009.

A neuronal VLDLR variant lacking the third complement-type repeat exhibits high capacity binding of apoE containing lipoproteins. Sakai K, Tiebel O, Ljungberg MC, Sullivan M, Lee HJ, Terashima T, Li R, Kobayashi K, Lu HC, Chan L, Oka K. Brain Research., 18, 11-21, 2009.

DRG-targeted helper-dependent adenoviruses mediate selective gene delivery for therapeutic rescue of sensory neuronopathies in mice. Terashima T, Oka K, Kritz AB, Kojima H, Baker AH, Chan L. J. Clin. Invest., 119, 2100-2112, 2009.

2008

Isolation of specific peptides that home to dorsal root ganglion neurons in mice. Oi J, Terashima T, Kojima H, Fujimiya M, Maeda K, Arai R, Chan L, Yasuda H, Kashiwagi A, Kimura H. Neuroscience Letters., 43, 266-72, 2008.

2007

T2*-weighted MR images of a patient with familial cerebral cavernous malformation. Maeda K, Terashima T, Kawai H, Sanada M. Intern. Med., 46, 541-2, 2007.

Rationale and usefulness of newly devised abbreviated diagnostic criteria and staging for diabetic polyneuropathy. Yasuda H, Sanada M, Kitada K, Terashima T, Kim H, Sakaue Y, Fujitani M, Kawai H, Maeda K, Kashiwagi A.Diabetes Res. Clin. Pract., 77 Suppl. 1: 78-83, 2007.

2006

Chronic Diabetic Complications: The Body’s Adaptive Response to Hyperglycemia Gone Awry? Chan L, Terashima T, Fujimiya M, and Kojima H. Trans. Am. Clin. Climatol. Assoc., 117: 341-352, 2006.

Paraneoplastic cerebellar degeneration in olfactory neuroepithelioma. Maeda K, Sasaki T, Murata Y, Terashima T, Kawai H, Yasuda H, Okabe H, Tanaka K. J. Neurol. Neurosurg. Psychiatry., 77, 123-124, 2006.

Extrapancreatic Proinsulin/Insulin-expressing Cells in Diabetes Mellitus: Is History Repeating Itself? Kojima H, Fujimiya M, Terashima T, Kimura H, Chan L. Endocr. J., 53, 715-722, 2006.

2005

The fusion of bone-marrow-derived proinsulin-expressing cells with nerve cells underlies diabetic neuropathy. Terashima T, Kojima H, Fujimiya M, Matsumura K, Oi J, Hara M, Kashiwagi A, Kimura H, Yasuda H, Chan L. Proc. Natl. Acad. Sci. U.S.A. 102, 12525-12530, 2005.

Antiganglion neuron antibodies correlate with neuropathy in Sjögren syndrome. Murata Y, Maeda K, Kawai H, Terashima T, Okabe H, Kashiwagi A, Yasuda H. NeuroReport, 16: 677-681, 2005.

2004

Metabolic adaptations in the absence of perilipin: increased beta-oxidation and decreased hepatic glucose production associated with peripheral insulin resistance but normal glucose tolerance in perilipin-null mice. Saha PK, Kojima H, Martinez-Botas J, Sunehag AL, Chan L. J. Biol. Chem., 279, 35150-35158, 2004.

Extrapancreatic insulin-producing cells in multiple organs in diabetes. Kojima H, Fujimiya M, Matsumura K, Nakahara T, Hara M, Chan L. Proc. Natl. Acad. Sci. U. S. A., 101, 2458-2463, 2004.

2003

NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, Maeda M, Chan L. Nat. Med., 9, 596-603, 2003.

2002

Combined Expression of Pancreatic Duodenal Homeobox 1 and lslet Factor 1 Induces Immature Enterocytes to Produce Insulin,Kojima H, Nakamura T, Fujita Y, Kishi A, Fujimiya M, Yamada S, Kudo M, Nishio Y, Maegawa H, Haneda M, Yasuda H, Kojima I, Seno M, Norman CW.Wong, Kikkawa R, Kashiwagi A. Diabetes, 51, 1398-1408, 2002.

Increased beta-oxidation but no insulin resistance or glucose intolerance in mice lacking adiponectin. Ma K, Cabrero A, Saha PK, Kojima H, Li L, Chang BH, Paul A, Chan L. J. Biol. Chem., 277, 34658-34661, 2002.

SUMO-1 co-localized with mutant atrophin-1 with expanded polyglutamines accelerates intranuclear aggregation and cell death. Terashima T, Kawai H, Fujitani M, Maeda K, Yasuda H. NeuroReport, 13: 2359-2364, 2002.

2001

Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Lee MH, Lu K, Hazard S, Yu H, Shulenin S, Hidaka H, Kojima H, Allikmets R, Sakuma N, Pegoraro R, Srivastava AK, Salen G, Dean M, Patel SB. Nat. Genet., 27, 79-83, 2001.

Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. Lu K, Lee MH, Hazard S, Brooks-Wilson A, Hidaka H, Kojima H, Ose L, Stalenhoef AF, Mietinnen T, Bjorkhem I, Bruckert E, Pandya A,Brewer HB Jr, Salen G, Dean M, Srivastava A, Patel SB. Am. J. Hum. Genet., 69, 278-290, 2001.

Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities. Lee MH, Gordon D, Ott J, Lu K, Ose L, Miettinen T, Gylling H, Stalenhoef AF, Pandya A, Hidaka H, Brewer B Jr, Kojima H, Sakuma N, Pegoraro R, Salen G, Patel SB. Eur. J. Hum. Genet., 9, 375-384, 2001.

Differentiation of immature enterocytes into enteroendocrine cells by Pdx1 overexpression, Yamada S, Kojima H, Fujimiya M, Nakamura T, Kashiwagi A, Kikkawa R. Am. J. Physiol. Gastrointest. Liver Physiol., 281, G229-G236, 2001.

Expression of Rho-family GTPases (Rac, cdc42, RhoA) and their association with p-21 activated kinase in adult rat peripheral nerve. Terashima T, Yasuda H, Terada M, Kogawa S, Maeda K, Haneda M, Kashiwagi A, Kikkawa R. J. Neurochem., 77: 986-992, 2001.