Center Director: Hideyuki Okano (Professor, School of Medicine)
Campus: Shinanomachi
Center Overview
Stem cells exist in essentially all organs throughout the life of an individual, from the early embryo to death, and are closely related to the pathology and treatment of various diseases. Therefore, establishing an education and research system centered on "stem cell medicine" will lead to an improvement in the overall educational and research vitality of the Doctoral Programs of the Graduate School of Medicine.
The Education and Research Center for Stem Cell Medicine is reorganizing the graduate school and improving the research environment to cultivate world-class human resources who have mastered these concepts, and is forming an education and research hub characterized by:
(1) Building a sustainable education and research system and creating a virtuous cycle of human resource development where senior students mentor junior students [Acquiring "self-renewal ability"];
(2) Cultivating diverse human resources [Acquiring "multipotency"];
(3) Personnel exchange for building international collaborative systems [Acquiring "migration ability"].
Keywords and Main Research Themes
Stem cells, regenerative medicine, cancer stem cells, metastasis, inflammation and immunology
Action Plan for FY2012
■ Background, Rationale, and Goals for Activities Continuing from the Previous Fiscal Year
Tissue stem cell regulation and in vivo experimental medicine: We will advance the functional analysis of downstream molecules of transcription factors that respond to hypoxia. Furthermore, we will analyze epigenetics, including the analysis of microRNA and piRNA in stem cell regulation, to elucidate the gene expression regulatory mechanism by piRNA and clarify the relationship between transcription levels and small RNAs in stem cell regulation. Additionally, using a differentiation system of ES cells into motor neurons, we will clarify the mechanism of differentiation suppression of ES cells by microRNA.
Inflammation/immune regulation and tissue regeneration: We aim to compare the dynamics of stem cells and immune cells in development and regeneration, their interactions, and their interactions with factors in the tissue microenvironment. We will also elucidate the dynamics of cancer stem cells and immune cells, their interactions, and their interactions with factors in the tissue microenvironment.
Development of new cancer therapies targeting cancer stem cells and EMT: Regarding cancer stem cells, we will clarify the interaction between cancer stem cells and non-cancer stem cells and identify molecules that regulate this interaction. We will develop antibodies and small molecule compounds that inhibit CD44 function. In addition, we will examine the in vivo therapeutic effects of cancer antigens expressed on cancer stem cells identified in the previous fiscal year, attempt to construct humanized mice with immune systems capable of analyzing immune responses to human cancer stem cells and EMT, and examine the therapeutic effects of various inhibitors.
Development of regenerative medicine for intractable diseases: We will confirm functional recovery using cardiomyocytes and nerve cells generated from human iPS cells in mouse models of myocardial infarction and spinal cord injury, and conduct preclinical trials using primate models. For hypertrophic cardiomyopathy, a hereditary heart muscle disease, we will establish iPS cells and induce differentiation into cardiomyocytes. Using these, we will analyze the Ca reactivity, contraction dynamics, etc., of abnormal myocardium. Using hosts obtained by crossing immunodeficient mice with Hirschsprung's disease model mice, we will verify the transplantation and differentiation of human NSCSs and functionally analyze the transplanted intestine.
Practice of feasible regenerative medicine: Regarding clinical research using human corneal stem cells, we will scrutinize and verify the results of the Early Phase and begin preparations for application to the Advanced Medical Care system. We also aim to transition to the Late Phase (Phase III trials) of clinical research on hair and bone using hair follicle stem cells and bone marrow stromal stem cells. For research using bone marrow stromal stem cells and neural crest-derived stem cells, we will prepare cells at the GMP level, confirm their safety, and move to the final stage of preclinical research.
■ New Activity Goals, Content, and Implementation Background for FY2012
Tissue stem cell regulation and in vivo experimental medicine: Based on the research above, we will construct an ex vivo culture system that maintains the undifferentiated state of stem cells by regulating the hematopoietic stem cell niche and the glycolytic metabolism of hematopoietic stem cells under hypoxia, and explore the possibility of stem cell proliferation. We will also elucidate the function of mouse homologs of Drosophila piRNA target genes and piRNA biosynthesis-related genes. Furthermore, based on findings from mouse ES cells, we will develop an efficient method for inducing iPS cells using microRNA.
Inflammation/immune regulation and tissue regeneration: Establishment of methods for controlling stem cell dynamics based on an understanding of the molecular mechanisms of inflammation and through the control of immune cell dynamics and the tissue microenvironment.
Development of new cancer therapies targeting cancer stem cells and EMT: We will advance the characterization of cancer stem cells and EMT cancer cells using clinical specimens and attempt to develop cancer diagnostic methods based on their characteristics. We will also conduct drug screening to develop therapies that disrupt the mutualistic relationship between cancer stem cells and non-cancer stem cells. Using mouse models, we will examine the in vivo therapeutic effects of treatments targeting CD44.
Development of regenerative medicine for intractable diseases: We will establish human iPS cells derived from patients, regenerate cardiomyocytes and nerve cells, and complete preclinical trials using primate models. We will complete preparations such as GMP-level culturing, creation of clinical protocols, and application to the IRB.
Practice of feasible regenerative medicine: For clinical research using human corneal stem cells, we will attempt to popularize it as general medical care under the Advanced Medical Care system. Furthermore, we will promote collaboration with industries such as pharmaceutical and medical device manufacturers for the Late Phase. We will also similarly refine research on hair and bone using hair follicle stem cells and bone marrow stromal stem cells for implementation in the Late Phase. Regarding myocardial damage and spinal cord injury using bone marrow stromal stem cells and neural crest-derived stem cells, we will complete preclinical research and proceed with preparations for Early Phase clinical research.
Activity Report for FY2011
■ Implementation Details, Research Results, and Degree of Achievement for the Fiscal Year's Action Plan
At the Education and Research Center for Stem Cell Medicine,
Tissue stem cell regulation and in vivo experimental medicine
Inflammation/immune regulation and tissue regeneration
Development of new cancer therapies targeting cancer stem cells and EMT
Development of regenerative medicine for intractable diseases
Practice of feasible regenerative medicine
education and research are conducted, centered on these five subgroups.
The achievements of each group for FY2011 are as follows.
Tissue stem cell regulation and in vivo experimental medicine: We are advancing the functional analysis of downstream molecules of transcription factors that respond to hypoxia. We are also analyzing epigenetics, including microRNA and piRNA, in stem cell regulation to elucidate the gene expression regulatory mechanism by piRNA and clarify the relationship between transcription levels and small RNAs. Furthermore, using a differentiation system of ES cells into motor neurons, we are clarifying the mechanism of differentiation suppression of ES cells by microRNA.
Inflammation/immune regulation and tissue regeneration: We are elucidating the comparison of stem cell dynamics and immune cell dynamics in development and regeneration, their interaction, and their interaction with factors in the tissue microenvironment. We are also elucidating the dynamics of cancer stem cells and immune cells, their interactions, and their interactions with factors in the tissue microenvironment.
Development of new cancer therapies targeting cancer stem cells and EMT: Regarding cancer stem cells, we are clarifying the interaction between cancer stem cells and non-cancer stem cells and identifying molecules that regulate this interaction. We are also examining the in vivo therapeutic effects of cancer antigens expressed on cancer stem cells, attempting to construct humanized mice with immune systems capable of analyzing immune responses to human cancer stem cells and EMT, and examining the therapeutic effects of various inhibitors.
Development of regenerative medicine for intractable diseases: We are conducting functional recovery confirmation using cardiomyocytes and nerve cells generated from human iPS cells in mouse models of myocardial infarction and spinal cord injury, as well as preclinical trials using primate models. For hypertrophic cardiomyopathy, a hereditary heart muscle disease, we have established iPS cells, induced differentiation into cardiomyocytes, and are using these to analyze the Ca reactivity, contraction dynamics, etc., of abnormal myocardium. Using hosts obtained by crossing immunodeficient mice with Hirschsprung's disease model mice, we are verifying the transplantation and differentiation of human NSCSs and functionally analyzing the transplanted intestine.
Practice of feasible regenerative medicine: Regarding clinical research using human corneal stem cells, we have scrutinized and verified the results of the Early Phase and have begun preparations for application to the Advanced Medical Care system. For research using bone marrow stromal stem cells and neural crest-derived stem cells, we are preparing cells at the GMP level and confirming their safety.
■ Number of Published Papers (with names of major journals), Number of Conference Presentations (Domestic and International), and Achievements in Social Contribution such as Events (Date, Location)
Public Lectures
COEX MEETING* #84–#92 (April 15, June 17, July 15, August 19, September 16, October 21, November 18, December 16, 2011; January 20, 2012; Lounge, 1st floor, Center for Integrated Medical Research)
STEMCELL SEMINAR #47–#58 (April 19, May 20, May 26, May 31, June 22, September 14, September 14, September 20, October 3, November 9, 2011; January 26, February 8, 2012; Lounge, 1st floor, Center for Integrated Medical Research)
*The COEX MEETING is held once a month as a forum for discussing unpublished data, serving as the next stage of discussion after internal research group meetings. The language used is English, and it is positioned as a place to hone presentation skills to a global standard.
■ Special Achievements Through the Center's Activities
Following the one from FY2009, we published the "Research Highlight Collection 2011."
Project Members
Principal Investigator
Hideyuki Okano
ProfessorPhysiologyHaruhiko Shiomi
ProfessorMolecular Biology