Atsushi Asakura, PhD
Associate Professor, Department of Neurology
Associate Professor, Department of Neurology
Faculty Member, Stem Cell Institute
Faculty, Masters Program in Stem Cell Biology
PhD, Institute of Medical Science and the National Institute of Neuroscience
Senior Post Doc, McMaster University and the Ottawa Health Research Institute
Dr. Atsushi Asakura is an Associate Professor of Neurology and a faculty member of the Stem Cell Institute in the University of Minnesota Medical School. He also belongs to Paul & Sheila Wellstone Muscular Dystrophy Center in the Medical School. Education Dr. Asakura received his Ph.D. at the Institute of Medical Science at the University of Tokyo Graduate School and the National Institute of Neuroscience in Tokyo with Dr. Yo-ichi Nabeshima where he learned the molecular biology of skeletal muscle differentiation. He trained at the post-doctoral level at the Fred Hutchinson Cancer Research Center in Seattle with Dr. Stephen J. Tapscott. His post-doctoral studies involved the transcription factors for skeletal muscle development during early embryogenesis. He trained at the senior post-doctoral level at McMaster University in Hamilton and the Ottawa Health Research Institute in Ottawa with Dr. Michael A. Rudnicki where he started projects on skeletal muscle stem cells that contribute to muscle regeneration.
Dr. Atsushi Asakura is an Associate Professor of Neurology and a faculty member of the Stem Cell Institute in the University of Minnesota Medical School. He also belongs to Paul & Sheila Wellstone Muscular Dystrophy Center in the Medical School.
Dr. Asakura received his Ph.D. at the Institute of Medical Science at the University of Tokyo Graduate School and the National Institute of Neuroscience in Tokyo with Dr. Yo-ichi Nabeshima where he learned the molecular biology of skeletal muscle differentiation.
He trained at the post-doctoral level at the Fred Hutchinson Cancer Research Center in Seattle with Dr. Stephen J. Tapscott. His post-doctoral studies involved the transcription factors for skeletal muscle development during early embryogenesis.
He trained at the senior post-doctoral level at McMaster University in Hamilton and the Ottawa Health Research Institute in Ottawa with Dr. Michael A. Rudnicki where he started projects on skeletal muscle stem cells that contribute to muscle regeneration.
Over the past 30 years, Dr. Asakura has studied the myogenic transcription factors and muscle stem cells with an emphasis onDuchennemusculardystrophy(DMD)therapy.Sincehewasagraduatestudentandpostdoctoralfellow in the laboratories of Drs. Yoichi Nabeshima, Stephen Tapscott and Michael Rudnicki, he has focused on MyoD gene regulation and muscle stem cells more than 60 peer-reviewed publications. His laboratory’s goals include attempting to understand the molecular mechanisms controlling muscle satellite cell (muscle stem cell) self-renewal and differentiation, and to develop novel therapeutic methods for DMD. This also involves the stem cell niche associated with vasculature in normal and regenerating skeletal muscle. And, he has recently begun exploration of cell-based therapy with induced Pluripotent Stem Cells (iPSCs) toward muscular dystrophy model animals.
Vascular niche for satellite cell self-renewal, muscle regeneration and muscular dystrophytherapy:
ForaneffectiveformoftherapyofDMD,boththemuscleandthevasculatureneedtobeaddressed.Toreveal the developmental relationship between DMD and vasculature, Dr. Asakura created mdx mice, an animal model for DMD, carrying Flt1 mutation with increased vasculature (Hum Mol Genet, 2010). Using the animal models, his study is the first showingthatdevelopmentally and pharmacologicallyincreasingvasculardensitycanrescuethedystrophicphenotypeinDMDmodel mice (PLoS Genet, 2019). This approach might be also effective to treat Facioscapulohumeral muscular dystrophy (FSHD) (J Clin invest, 2020). These data suggest that increasing the vasculature in DMD may ameliorate the histological and functionalphenotypesassociatedwiththisdisease.Apatentforthistechnologyhasbeengrantedin2018 (US Patent, 2018).In addition, he established a tissue clearing protocol for skeletal muscle. Using this protocol, he is the first to image murine whole skeletal muscle using confocal and two-photon microscopy (Methods Mol Biol, 2016), and demonstrate that satellite cells pattern the microvasculature to be in close proximity to them via VEGFA, keeps the satellite cells in a more quiescent state via Notch pathway, suggesting a beneficialcross-talk (Cell Stem Cell, 2018).
Circadian transcriptional regulation in muscle stemcells:
Dr. Asakura has dedicated much of his professional career to studying MyoD function during myogenesis and muscle regeneration, and he has published more than 30 original research articles related to MyoD since he was a graduatestudent.Hisfirstcontributionstoscienceasanindependentinvestigatorweretodemonstrate:1)that MyoD negatively regulatessatellitecellself-renewal (PNAS, 2007) via a MyoD-mediated induction of apoptosis through microRNA-mediated Pax3 gene suppression (J Cell Biol, 2010): 2) that theCDKinhibitorp57 plays essential rolesinmuscledifferentiation asaMyoDdownstreamgene(Elife, 2018): 3) that myogenesis is regulated by an isomerase activity of Fkbp5 (Cell Rep, 2018): 4)thatthecorecircadianregulatorCry2 and Per2whichregulatesMyoD and IGF2expression promotesmyoblastproliferationandsubsequentmyocytefusiontoformmyotubesinacircadianmanner (Cell Rep, 2018; bioRxiv, 2020).Therefore, his hypothesis is that genetic modification of transplanted stem cells using a modification of MyoD cascade may be utilized to effectively treat DMD and improve musclefunction.
DMD therapy via induced Pluripotent Stem Cells(iPSCs):
Dr. Asakura also demonstrates that upon being infected with a retroviral vector expressing the four reprogramming factors, the satellite cell-derived myoblasts successfully gave rise to iPSC colonies. To the best of their knowledge, this study is the first showing that fully committed myogenic cells can be reprogrammed to iPSCs (Stem Cells. 2011). His hypothesis is that myoblast-derived iPSCs may maintain epigenetic memory of myogenic status, which might contribute to the higher myogenic differentiation potential. Recently, he established the blastocyst complementation to generate iPSC-derived skeletal muscle in chimeric animals (World Patent Application, 2016). A key to the generation of human myogenic cells and skeletal muscle in a host animal is the selective knockout of genes in the blastocyst that are critical for organ development. These concerted approaches will help us to create iPSC-derived myogenic cells in vivo, which can be transplanted into patients for a definitive cure of DMD. In addition, the generation of iPSC-derived DMD skeletal muscle in mice will serve as an animal model to study the characteristics and regeneration of the human skeletal muscle diseases and responses to pharmacological agents such as exon-skipping.
- S. Watanabe, H. Hirai, Y. Asakura, C. Tastad, M. Verma, C. Keller, J. R. Dutton, A. Asakura. (2011) MyoD gene suppression by Oct4 is required for reprogramming in myoblasts to produce induced pluripotent stem cells. Stem Cells. 29:505-516.
- M. Verma, A. Asakura. (2011) Efficient single muscle fiber isolation from alcohol fixed adult muscle following beta-galactosidase staining for satellite cell detection. J. Histochem. Cytochem.59:60-67.
- H. Hirai, M. Verma, S. Watanabe, C. Tastad, Y. Asakura, A. Asakura. (2010)MyoD regulates apoptosis of myoblasts through microRNA-mediated down-regulation of Pax3. J. Cell. Biol.191:347-365.
- M. Verma, Y. Asakura, H. Hirai, S. Watanabe, C. Tastad, G.-H. Fong,M. Ema, J. A. Call, D. A. Lowe, A. Asakura. (2010) Flt-1 haploinsufficiency ameliorates muscular dystrophy phenotype by developmentally increased vasculature in mdx mice.Hum. Mol. Genet. 19:4145-4159.
- H. Hirai, L. Romanova, S. Kellner, M. Verma, S. Rayner, A. Asakura*, N. Kikyo*. (2010) Post-mitotic role of nucleostemin as a promoter of skeletal muscle cell differentiation.Biochem. Biophys. Res. Commun. 39:299-304. (*double corresponding authors)
- A. Asakura, (2008) Stem Cells for Muscle Regeneration. Stem Cell Biology. World Scientific Press. 145-175
- A. Asakura. (2008) Vascular endothelial growth factor (VEGF) gene regulation by HEXIM1 in heart. Circ. Res. 102:398-400.
- A. Asakura, H. Hirai, B. Kablar, S. Morita, J. Ishibashi, B. A. Piras, A. J. Christ, M. Verma, K. A. Vineretsky, M. A. Rudnicki. (2007) Increased survival of muscle stem cells lacking the MyoDgene after transplantation into regenerating skeletal muscle. Proc. Natl. Acad. Sci. U S A104:16552-16557.
- A. Asakura. (2007) Hematopoietic potential cells in skeletal muscle. Cell Rec. 17:836-838.
- G. Grenier, A. Scimè, F. Le Grand, A. Asakura, C. Perez-Iratxeta, M. A. Andrade-Navarro, P. A. Labosky, M. A. Rudnicki.(2007) Resident Endothelial Precursors in Muscle, Adipose and Dermis Contribute to Post-Natal Vasculogenesis. Stem Cells. 25:3101-3110.
- Y. Nakamura, X. Wang, C. Xu, A. Asakura, M. Yoshiyama, A. H. From, J. Zhang. (2007)Xenotransplantation of Long Term Cultured Swine Bone Marrow-Derived Mesenchymal Stem Cells. Stem Cells.25:612-20.
- J. Ishibashi, R. L. Perry, A. Asakura, M. A. Rudnicki. (2005) MyoD induces myogenic differentiation through cooperation of its NH2- and COOH-terminal regions.J. Cell Biol.171:471-482.
- J. Lee, A. Asakura, J. Zhang. (2005) Experimental cell transplantation for myocardial repair.Handbook of Cardiac Anatomy, Physiology and Devices. Humana Press. 427-438.
- C. J. Storbeck, K. Daniel, Y. H. Zhang, J. Lunde, A. Scime, A. Asakura, B. Jasmin, R. G. Korneluk, L. A. Sabourin. (2004) Ste20-like kinase SLK displays myofiber type specificity and is involved in C2C12 myoblast differentiation.Muscle Nerve 29:553-64.
- M. Komaki, A. Asakura, M. A. Rudnicki, S. Cheifetz, J. Sodek. (2004) MyoD enhances BMP-induced osteogenic differentiation of myogenic cell cultures. J. Cell Sci. 117:1457-1468.
- A. Asakura, M. A. Rudnicki. (2003) Rhabdomyosarcomagenesis-Novel pathway found. Cancer Cell 4: 421-422.
- A. Asakura. (2003) Stem cells in adult skeletal muscle. Trends Cardiovasc. Med. 13:123-128.
- A. Asakura, P. Seale, A. Girgis-Gabardo, M. A. Rudnicki. (2002) Myogenic specification of side population cells in skeletal muscle. J. Cell Biol. 159:123-134.
- A. Asakura, M. A. Rudnicki. (2002) Side population cells from diverse adult tissues are capable of in vitro hematopoietic differentiation. Exp. Hematol. 30:1339-1345.
- A. Asakura, M. A. Rudnicki. (2002) Cellular and Molecular Mechanisms Regulating Skeletal Muscle development. Mouse Development: Patterning, Morphogenesis, and Organogenesis. Academic Press. 253-278.
- P. Seale, A. Asakura, M. A. Rudnicki. (2001) The potential of Muscle Stem Cells. Dev. Cell 1: 333-342.
- A. Asakura, M. Komaki, M. A. Rudnicki. (2001) Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation 68:245-253.
- J. M. Olson*, A. Asakura*, L. Snider, R. Hawkes, A. Strand, S. J. Tapscott, (2001) NeuroD2 is necessary for normal development and survival of central nervous system neurons. Dev. Biol.238:174-187. (*contributed equally).
- A. Asakura, S. J. Tapscott. (1998) Apoptosis of epaxial myotome in Danforth's short-tail (Sd) mice in somites that form following notochord degeneration. Dev. Biol., 203:276-289.
- A. Asakura, G. E. Lyons, S. J. Tapscott. (1995) The regulation of myoD gene expression: Conserved elements mediated expression in embryonic axial muscle. Dev. Biol. 171:386-398.
- A. Asakura, A. Fujisawa-Sehara, T. Komiya, Y. Nabeshima, and Y.-I. Nabeshima. (1993) MyoD and myogenin act on the chicken myosin light chain 1 gene as distinct transcriptional factors.Mol. Cell. Biol. 13:7153-7162.