Division for Therapies against Intractable Diseases
Link
・Division for Therapies against Intractable Diseases HP : http://info.fujita-hu.ac.jp/~nanbyou/English/index.html
Research Interests
Our research group focuses on investigation of pathophysiology and development of therapies against intractable diseases including neuromuscular diseases such as muscular dystrophy and related disorders, psychiatric disorders, diabetes/obesity and cancers. Development of rational molecular therapies against muscular atrophy by genetic inheritance and aging is one of the projects. Since cells derived from mesenchymal cells such as adipocytes (fatty degeneration), fibroblast (fibrosis) and ectopic bone formation are observed in diseases affecting skeletal muscles, obesity and aging, we are interested in understanding the molecular mechanism of differentiation of from mesenchymal progenitors localized in muscles.
We have a number of up-to-date technologies to study intractable diseases, such as fluorescence activated cell sorting (FACS) and differentiation culture, comprehensive genomic and proteomics analyses, miRNA and lncRNA analyses, development and analyses of animal models. These technologies are indispensable for interdisciplinary cooperation among medical and clinical sciences and pharmaceutical science.
I. Development of therapy for muscular atrophy
Muscular dystrophy is a prototype of intractable neuromuscular diseases. No effective therapy has not been realized yet. In addition to exon skipping of dystrophin genes, sparing of skeletal muscle in diseased condition is a promising therapeutic strategy. Myostatin and activin, members of the TGF-β superfamily, and their signaling pathways are regarded as novel drug targets for muscular atrophy, sarcopenia and cachexia. We have developed effective myostatin inhibitors, and made transgenic mice expressing these myostatin inhibitors. We have shown that myostatin inhibitors are effective to increase skeletal muscle mass both by hypertrophy and hyperplasia. Transgenic expression of developed myostatin inhibitor prevents muscle degeneration and atrophy of muscular dystrophy model mice (Faseb J 2008; Cell Communication and Signaling 2009). Transgenic mice with myostatin inhibition showed resistance to high fat diet-induced adiposity and fatty liver (AJP 2011). We are characterizing the mechanism how myostatin inhibition leads to skeletal myogenesis by miRNA analysis and proteome analysis. We have identified miRNA involved in downstream of myostatin inhibition and muscle hypertrophy by comprehensive miRNA analyses and cell biological analyses (Int J Biochem Cell Biol 2014; In Frontiers in Striated Muscle Physiology 2014).
II. Characterization of mesenchymal progenitors involved in fatty degeneration, fibrosis and ectopic bone formation in skeletal muscle
To understand the mechanism how adipocytes and fibroblasts and osteoblasts are generated from mesenchymal progenitors is important not only for therapy against muscular degeneration but also for diabetes and obesity. Using sophisticated cell sorting and culture system, we prospectively identified novel mesenchymal progenitors expressing PDGFRα+ cells, distinct from muscle satellite cells, in the muscle interstitium both in mouse and human. We show that, among the muscle-derived cell populations, only PDGFRα+ cells exhibit efficient adipogenic differentiation both in vitro and in vivo (Nat Cell Biol 2010). PDGFRα+ cells are also the major contributor to ectopic fat formation in skeletal muscle (PLosONE 2013). The cells also respond to profibrotic cytokine TGF-β and express genes involved in fibrosis (J Cell Sci 2011).
III. Development of novel model animals for neuropsychotic diseases
Activin A, a member of the TGF-β superfamily, is increased in activated neuronal circuits and regulates dendritic spine morphology and protects neuron from ischemic damage. To clarify the role of activin in the brain, we generated forebrain-specific activin- or follistatin-transgenic mice and found that the level of activin in the brain plays a key role in the maintenance of long-term memory. The mouse models would be useful to study novel molecular mechanism to explore memory formation and anxiety disorders (PLos One 2008; Learning & Memory 2010).
IV. Cooperative studies
Our studies are conducted cooperatively with joint research laboratories and Hospitals in Fujita Health University.
We have a number of up-to-date technologies to study intractable diseases, such as fluorescence activated cell sorting (FACS) and differentiation culture, comprehensive genomic and proteomics analyses, miRNA and lncRNA analyses, development and analyses of animal models. These technologies are indispensable for interdisciplinary cooperation among medical and clinical sciences and pharmaceutical science.
I. Development of therapy for muscular atrophy
Muscular dystrophy is a prototype of intractable neuromuscular diseases. No effective therapy has not been realized yet. In addition to exon skipping of dystrophin genes, sparing of skeletal muscle in diseased condition is a promising therapeutic strategy. Myostatin and activin, members of the TGF-β superfamily, and their signaling pathways are regarded as novel drug targets for muscular atrophy, sarcopenia and cachexia. We have developed effective myostatin inhibitors, and made transgenic mice expressing these myostatin inhibitors. We have shown that myostatin inhibitors are effective to increase skeletal muscle mass both by hypertrophy and hyperplasia. Transgenic expression of developed myostatin inhibitor prevents muscle degeneration and atrophy of muscular dystrophy model mice (Faseb J 2008; Cell Communication and Signaling 2009). Transgenic mice with myostatin inhibition showed resistance to high fat diet-induced adiposity and fatty liver (AJP 2011). We are characterizing the mechanism how myostatin inhibition leads to skeletal myogenesis by miRNA analysis and proteome analysis. We have identified miRNA involved in downstream of myostatin inhibition and muscle hypertrophy by comprehensive miRNA analyses and cell biological analyses (Int J Biochem Cell Biol 2014; In Frontiers in Striated Muscle Physiology 2014).
II. Characterization of mesenchymal progenitors involved in fatty degeneration, fibrosis and ectopic bone formation in skeletal muscle
To understand the mechanism how adipocytes and fibroblasts and osteoblasts are generated from mesenchymal progenitors is important not only for therapy against muscular degeneration but also for diabetes and obesity. Using sophisticated cell sorting and culture system, we prospectively identified novel mesenchymal progenitors expressing PDGFRα+ cells, distinct from muscle satellite cells, in the muscle interstitium both in mouse and human. We show that, among the muscle-derived cell populations, only PDGFRα+ cells exhibit efficient adipogenic differentiation both in vitro and in vivo (Nat Cell Biol 2010). PDGFRα+ cells are also the major contributor to ectopic fat formation in skeletal muscle (PLosONE 2013). The cells also respond to profibrotic cytokine TGF-β and express genes involved in fibrosis (J Cell Sci 2011).
III. Development of novel model animals for neuropsychotic diseases
Activin A, a member of the TGF-β superfamily, is increased in activated neuronal circuits and regulates dendritic spine morphology and protects neuron from ischemic damage. To clarify the role of activin in the brain, we generated forebrain-specific activin- or follistatin-transgenic mice and found that the level of activin in the brain plays a key role in the maintenance of long-term memory. The mouse models would be useful to study novel molecular mechanism to explore memory formation and anxiety disorders (PLos One 2008; Learning & Memory 2010).
IV. Cooperative studies
Our studies are conducted cooperatively with joint research laboratories and Hospitals in Fujita Health University.
Selected Publications
1: Hitachi K, Nakatani M, Takasaki A, Ouchi Y, Uezumi A, Ageta H, Inagaki H, Kurahashi H, Tsuchida K. Myogenin promoter-associated lncRNA Myoparr is essential for myogenic differentiation. EMBO Rep. e47468. (2019) [Pubmed]
2: Ageta H, Ageta-Ishihara N, Hitachi K, Karayel O, Nakatani M, Kinoshita M, T. Ochiya T, Mann M, Setou M, Tsuchida K. 他. UBL3 modification influences protein sorting to small extracellular vesicles. Nature communications. 9; 3936. (2018) [Pubmed]
3: Hitachi K, Tsuchida K. Myostatin-deficiency in mice increases global gene expression at the Dlk1-Dio3 locus in the skeletal muscle. Oncotarget 8, 5943-53 (2017) [Pubmed]
4: Uezumi A, Nakatani M, Takeda S.-I., Nishino I, Tsuchida.他. Cell surface protein profiling identifies distinctive markers of progenitor cells in human skeletal muscle. Stem Cell Report 7(2) : 263-78 (2016) [Pubmed]
5: Uezumi A, Fukada S, Nakatani M, Tsuchida K. 他. Identification and characterization of PDGFRα mesenchymal progenitors in human skeletal muscle. Cell Death Disease (Nature Publishing Group) 5, e1186 (2014) [Pubmed]
6: Hitachi K, Nakatani M, Tsuchida K. Myostatin signaling regulates Akt activity via the regulation of miR-486 expression. Int J Biochem Cell Biol. 2014; 47: 93-103. [Pubmed][Faculty of 1000 recommended]
7: Ikeda D, Ageta H, Tsuchida K, Yamada H. iTRAQ-based proteomics reveals novel biomarkers of osteoarthritis. Biomarkers. 2013; 18(7): 565-72. [Pubmed][Faculty of 1000 recommended]
8: Oishi T, Uezumi A, Kanaji A, Yamamoto N, Yamaguchi A, Yamada H, Tsuchida K. Osteogenic differentiation capacity of human skeletal muscle-derived progenitor cells. PLoS One. 2013; 8(2): e56641. [Pubmed]
9: Nakatani M, Kokubo M, Ohsawa Y, Sunada Y, Tsuchida K. Follistatin-derived peptide expression in muscle decreases adipose tissue mass and prevents hepatic steatosis. Am J Physiol Endocrinol Metab. 2011; 300(3): E543-53. [Pubmed]
10: Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol. 2010; 12(2): 143-52. [Pubmed][Faculty of 1000 recommended]
11: Nakatani M, Takehara Y, Sugino H, Matsumoto M, Hashimoto O, Hasegawa Y, Murakami T, Uezumi A, Takeda S, Noji S, Sunada Y, Tsuchida K. Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice. FASEB J. 2008; 22(2): 477-87. [Pubmed]
2: Ageta H, Ageta-Ishihara N, Hitachi K, Karayel O, Nakatani M, Kinoshita M, T. Ochiya T, Mann M, Setou M, Tsuchida K. 他. UBL3 modification influences protein sorting to small extracellular vesicles. Nature communications. 9; 3936. (2018) [Pubmed]
3: Hitachi K, Tsuchida K. Myostatin-deficiency in mice increases global gene expression at the Dlk1-Dio3 locus in the skeletal muscle. Oncotarget 8, 5943-53 (2017) [Pubmed]
4: Uezumi A, Nakatani M, Takeda S.-I., Nishino I, Tsuchida.他. Cell surface protein profiling identifies distinctive markers of progenitor cells in human skeletal muscle. Stem Cell Report 7(2) : 263-78 (2016) [Pubmed]
5: Uezumi A, Fukada S, Nakatani M, Tsuchida K. 他. Identification and characterization of PDGFRα mesenchymal progenitors in human skeletal muscle. Cell Death Disease (Nature Publishing Group) 5, e1186 (2014) [Pubmed]
6: Hitachi K, Nakatani M, Tsuchida K. Myostatin signaling regulates Akt activity via the regulation of miR-486 expression. Int J Biochem Cell Biol. 2014; 47: 93-103. [Pubmed][Faculty of 1000 recommended]
7: Ikeda D, Ageta H, Tsuchida K, Yamada H. iTRAQ-based proteomics reveals novel biomarkers of osteoarthritis. Biomarkers. 2013; 18(7): 565-72. [Pubmed][Faculty of 1000 recommended]
8: Oishi T, Uezumi A, Kanaji A, Yamamoto N, Yamaguchi A, Yamada H, Tsuchida K. Osteogenic differentiation capacity of human skeletal muscle-derived progenitor cells. PLoS One. 2013; 8(2): e56641. [Pubmed]
9: Nakatani M, Kokubo M, Ohsawa Y, Sunada Y, Tsuchida K. Follistatin-derived peptide expression in muscle decreases adipose tissue mass and prevents hepatic steatosis. Am J Physiol Endocrinol Metab. 2011; 300(3): E543-53. [Pubmed]
10: Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol. 2010; 12(2): 143-52. [Pubmed][Faculty of 1000 recommended]
11: Nakatani M, Takehara Y, Sugino H, Matsumoto M, Hashimoto O, Hasegawa Y, Murakami T, Uezumi A, Takeda S, Noji S, Sunada Y, Tsuchida K. Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice. FASEB J. 2008; 22(2): 477-87. [Pubmed]