Atsushi Asakura, Ph.D. , Stem Cell Institute at the University of Minnesota

asakura@umn.edu

Dr. Atsushi Asakura is an Assistant 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.

Research Interests

My laboratory’s goal is to understand the molecular mechanisms controlling stem cell self-renewal and differentiation during heart and skeletal muscle regeneration.

• MyoD is a muscle-specific transcription factor that plays essential roles in muscle satellite cell differentiation and regeneration. We have demonstrated that myoblasts derived from MyoD^-/- satellite cells engrafted with significantly higher efficacy compared to wild-type myoblasts after injection into regenerating muscle and infarcted heart. Importantly, in MyoD^-/- myoblasts, anti-apoptotic genes were up-regulated, while some pro-apoptotic genes were down-regulated. Consistent with these expression profiles, MyoD^-/- myoblasts were revealed to possess remarkable resistance to apoptosis and increased survival during differentiation and after apoptotic inductions, compared to wild-type myoblasts. Therefore, these data suggest that MyoD is not only regulating terminal differentiation but also regulating apoptosis during myogenic differentiation. In addition, down-regulation of MyoD expression may be required for maintenance of self-renewing muscle stem cells. Furthermore, our data offer evidence for novel therapeutic stem cell transplantation for muscular dystrophy, in which suppression of MyoD in myogenic progenitor cells would be beneficial to the therapy by providing a selective advantage for expansion of the stem cells.
  
  
•  We have demonstrated that novel muscle stem cells called side population (SP) cells that exclude Hoechst dye possess a myogenic potential and contribute to muscle regeneration following transplantation. Recent work demonstrates that mesoangioblasts isolated from muscle display pericyte-like characteristics and that transplantation of these cells can repair muscular dystrophy phenotype. To reveal biological role of muscle SP cells, we further purified muscle SP fraction. We noticed that muscle SP cells contain endothelial cells and perivascular cells termed mural cells or pericytes. These results suggest that muscle SP cells are closely associated with vascular development and that the major role of SP cells in muscle regeneration is to contribute to repairing vasculatures.

 In the future, my laboratory will carry out the following projects:

• Genetically modified myoblasts: Our data provide evidence that a novel myoblast cell type with suppressed function of MyoD or MyoD-downstream proteins is potentially useful for therapeutic stem cell transplantation for muscular dystrophy and heart failure patients. We will determine efficiency of engraftment of genetically modified myoblasts in skeletal muscle and heart in muscular dystrophy model mice to correct the contractile properties and muscle mechanics in muscular dystrophy. We will also elucidate molecular mechanisms in which MyoD positively regulate apoptotic cascade and negatively regulate self-renewal in satellite cells.
  
  
•  Tissue-derived pericytes: We will purify tissue-specific pericytes from different organs, bone marrow, skeletal muscle and heart of adult mice. Then, we will compare their biological similarities and differences using in vitro and in vivo differentiation systems and DNA microarrays. For this purpose, we are going to use two different tissue injury models, skeletal muscle and heart. In addition, we will identify molecular cascades regulating cell differentiation of these tissue-derived pericytes using genetically mutated mice which affect tissue regeneration. We will also test whether these tissue-derived progenitor cells are capable of restoring infarcted mouse heart and skeletal muscle of muscular dystrophy model mice.
  
  
• Our outcomes will reveal the developmental relationship between satellite cells and pericytes as well as the molecular biology of cell differentiation, apoptosis and self-renewal processes. Furthermore, we will use satellite cells and tissue-derived pericytes for therapeutic purposes. Such insights and developments will potentially lead to new cell-based therapeutic interventions for heart and muscle diseases.

Selected Publications

• A. Asakura, H. Hirai, B. Kablar, S. Morita, J. Ishibashi, B. A. Piras, A. J. Christ, M. Verma, K. A. Vineretsky, M. A. Rudnicki. Increased survival of muscle stem cells lacking the MyoD gene after transplantation into regenerating skeletal muscle. Proc. Natl. Acad. Sci. U. S. A., 104 (42), 16552-16557 2007.
• A. Asakura. Hematopoietic potential cells in skeletal muscle. Cell Rec.,17,  836-838, 2007 (Review)
• M. Komaki, A. Asakura, M. A. Rudnicki, S. Cheifetz, J. Sodek. MyoD enhances BMP-induced osteogenic differentiation of myogenic cell cultures. J. Cell Sci., 117, 1457-1468, 2004.
• A. Asakura, M. A. Rudnicki. Rhabdomyosarcomagenesis-Novel pathway found. Cancer Cell, 4(6): 421-422, 2003 (Review).
• A. Asakura. Stem cells in adult skeletal muscle. Trends Cardiovasc. Med., 13(3): 123-128, 2003 (Review).
• A. Asakura, P. Seale, A. Girgis-Gabardo, M. A. Rudnicki. Myogenic specification of side population cells in skeletal muscle. J. Cell Biol., 159, 123-134, 2002
• A. Asakura, M. A. Rudnicki. Side population cells from diverse adult tissues are capable of in vitro hematopoietic differentiation. Exp. Hematol., 30, 1339-1345, 2002
• P. Seale, A. Asakura, M. A. Rudnicki. The potential of Muscle Stem Cells. Dev. Cell, 1: 333-342, 2001 (Review).
• A. Asakura, M. Komaki, M. A. Rudnicki. Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation 68, 245-253, 2001.
• J. M. Olson*, A. Asakura*, L. Snider, R. Hawkes, A. Strand, S. J. Tapscott, NeuroD2 is necessary for normal development and survival of central nervous system neurons. Dev. Biol., 238, 174-187, 2001. (*These authors contributed equally).
• B. Kablar, A. Asakura, K. Krastel, C. Ying, L. L. May, S. J. Tapscott, D. Goldhamer, M. A. Rudnicki. MyoD and Myf-5 specify skeletal musculature in respect to their embryonic origin. Biochem. Cell. Biol., 76, 1079-1091, 1999.
• A. Asakura, S. J. Tapscott. Apoptosis of epaxial myotome in Danforth's short-tail (Sd) mice in somites that form following notochord degeneration. Dev. Biol., 203, 276-289, 1998.
• A. Asakura, G. E. Lyons, S. J. Tapscott. The regulation of myoD gene expression: Conserved elements mediated expression in embryonic axial muscle. Dev. Biol., 171:386-398, 1995.
• A. Asakura, A. Fujisawa-Sehara, T. Komiya, Y. Nabeshima, and Y.-I. Nabeshima. MyoD and myogenin act on the chicken myosin light chain 1 gene as distinct transcriptional factors. Mol. Cell. Biol., 13:7153-7162, 1993.