Research on control of in vitro differentiation of stem cells into specific tissues and organs is critical not only for the realization of regenerative medicine, but also for creating experimental model systems for understanding the mechanism of organogenesis. We have been using undifferentiated cells of amphibians to develop in vitro differentiation systems for various tissues and organs by the treatments with activin and other inducers under simple culture conditions. We have been also searching for novel genes and proteins involved in cell differentiation and organ formation by these experimental systems. Recently, by culturing mouse and human embryonic stem cells (ES cells) in serum-free cultures, we have established highly-reproducible experimental systems to control cell differentiation. To search for novel factors that function in nuclear reprogramming of somatic cells, we are using proteomics to analyze protein factors specifically expressed in undifferentiated cells. In addition to developing techniques for controlling differentiation of stem cells, these research projects are useful for creating uniform criteria to evaluate various states of cellular differentiation and to classify various types of cells comprehensively.

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Human T-cell leukemia virus type 1 (HTLV-1) is a replication-competent human retrovirus associated with two distinct types of disease: the malignancy known as adult T-cell leukemia (ATL) and a chronic inflammatory central nervous system disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), whereas the vast majority of infected individuals remain asymptomatic carriers of the virus in lifetime. It is not yet fully understood why do certain individuals develop ATL or HAM/TSP, and how does HTLV-1 persist in spite of host immune response. This review focuses on the complex virus-host interactions and the cellular immune responses to HTLV-1 infection seen in HAM/TSP patients, which are important factors in determining HTLV-1 proviral load and the risk of developing disease.

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Cartilaginous extracellular matrix (ECM) is a unique assembly of macromolecules such as type II collagen and proteoglycans. In association with a number of accessory molecules, it confers special biological functions on cartilage. Among these various accessory molecules, growth-modulating functions have been identified only in several instances, and in many cases functional properties therefore remain to be elucidated. Chondromodulin-I (ChM-I) is a 25-kDa glycoprotein, which was initially identified in our laboratory as a cartilage-specific functional matrix component that stimulates the growth and matrix synthesis of primary chondrocytes in vitro. We subsequently purified an endothelial cell growth inhibitor from guanidinium extracts of fetal bovine cartilage, which was surprisingly found to be identical to ChM-I. Purified ChM-I was found to inhibit the proliferation of vascular endothelial cells as well as tube morphogenesis in vitro. The generation of a ChM-I null mouse has enabled us to examine the functional roles of this unique ECM component in vivo. In this review, we describe the identification and biological characterization of ChM-I as an example of a growth-modulating functional matrix in cartilage.

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The formation of heart is regulated by coordinated complex processes: cardiac progenitors migrate from both sides of the anterior lateral plate mesoderm toward the midline and differentiate into the heart tube including atrium and ventricle. Forward genetic analysis using zebrafish has identified several mutants defective in myocardial migration, resulting in two hearts known as cardia bifida. Identification of genes responsible for the cardia bifida mutations has revealed key players that regulate the migration and assembly of cardiac progenitors. Both anterior endoderm and the extraembryonic tissue yolk syncytial layer (YSL) provide for this process, thereby controlling the coordinated movement of cardiac progenitors. Further, the signaling pathway mediated by sphingosine 1-phosphate (S1P) is essential for the migration of cardiac progenitors in zebrafish.

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We accomplished the following three very important break-through 1) we established technology for Superproliferation of MSC and developed Automatic cell culture system, 2) we conducted pre-clinical tests in animal experiments designed for dental applications and 3) we participated and supported clinical research into actual treatment of periodontal disease.
We developed Automatic Cell Culture system for mesencymal stem cells(MSC) ‘YURIKAGO’ in 2007. The system has various characteristics 1) size is smaller than other system, 2) weight is lighter than other systems, 3) culture program is all automatic (culture, passage and harvest) and 4) we can proliferate MSC for the vast numbers required for treatment with having kept retention of multilineage differentiation potential. The key to this system is original MSC proliferation technology obtained by TWO CELLS that utilize basic Fibroblast Growth Factor(bFGF) that takes a few MSC and produces the vast numbers required for treatment. It is a wish that an intractable disease can be treated using our system and MSC.

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