Noboru Sato
Assistant Professor of Biochemistry

Stem Cell Biology Biomedical Research M.D., Oita University, School of Medicine, 1987 Ph.D., Juntendo University, School of Medicine, 1996 Postdoctoral fellow, Weill Medical College of Cornell University, 1996-2000 Research fellow, Memorial Sloan-Kettering Cancer Center, 2000-2002 Research Associate, Rockefeller University, 2002-2005 Staff Scientist, National Institute of Environmental Health Sciences, 2005-2006 VOICE: (951) 827-3644 FAX: (951) 827-4294 EMAIL: saton@ucr.edu

We study stem cell biology that bridges basic science and medical applications.

Stem cells self-renew to generate themselves while maintaining differentiation capacities. Stem cells can be classified based on their competence to give rise to distinct progenies.

The top of the hierarchy is totipotent stem cells that can generate all three germ layer-derived tissues, germ cells, and placenta. Fertilized eggs and each blastomere of preimplantation embryos until early eight cell stage retain this ability.

The next group is pluripotent stem cells whose capacity is identical to that of totipotent stem cells except the lack of the function to form placenta*. The inner cell mass (ICM) of the blastocyst, and its in vitro derivatives, embryonic stem cells (ESCs), represent this group.

The third group is multipotent stem cells whose differentiation capacity is limited within their original lineage. Adult stem cells typically belong to this class.

The last group is unipotent stem cells that can differentiate into only single cell type.

*: Human embryonic stem cells could differentiate into trophoblasts that are the founding cells of placenta but mouse embryonic stem cells can not.

Molecular Regulation of Pluripotency

During early embryogenesis, master transcriptional regulators (gene names in bold) and signaling pathways play essential roles to determine each cell fate.

We focus on understanding the molecular mechanisms that regulate unique biological functions of pluripotent stem cells.

Pluripotency is, as described above, the ability to generate any type of adult cells including germ cells. Because of this ability, human pluripotent stem cells have been considered potential sources for cell-transplantation therapy to treat diseases such as Parkinson’s disease, myocardial infarction, and diabetes mellitus although molecular basis of their unique biological functions remains to be determined.

Recent studies have identified master transcriptional regulators and signaling pathways that control pluripotency. For instance, homeodomain transcription factors, Oct3/4 and Nanog, play essential roles for regulating the pluripotent state.

To dissect molecular pathways underlying pluripotency, we have conducted genome-wide gene expression analyses targeting human ES cells, and found that components of major signal transduction pathways including Wnt signaling are specifically enriched in the pluripotent state. This finding led us to focus on the role of the Wnt signaling pathway in controlling the stem cell state in ES cells. By using a novel chemical GSK (glycogen synthase kinase)-3 inhibitor, 6-bromo-indirubin-3’-oxime (BIO), we have demonstrated that activation of Wnt signaling can support the pluripotent state through regulation of master transcriptional regulators in both mouse and human ES cells.

In order to explore a new dimension of regulatory machineries that determine unique pluripotent stem cell functions, we have initiated new projects that focus on molecular control of structural-functional integrity of pluripotent stem cells.

Projects

1. Investigation of the molecular mechanisms that regulate basic cellular interactions of pluripotent stem cells.

We are investigating how basic cell-cell and cell-matrix interactions are regulated in pluripotent stem cells at the molecular level through focusing on specific signal transduction pathways.

We have recently determined that the Rho-Rock-Myosin (RRM) signaling axis plays an essential role in controlling cellular interactions of human and mouse ES cells (Harb et al. 2008).

We are currently testing the hypothesis that the self-renewal regulators (master transcription factors and signaling pathways) and cellular interaction machineries such as the RRM signaling axis are mutually integrated to execute multi-dimensional developmental programs that are required for spatially and temporally structured early embryogenesis.

Furthermore, using the knowledge obtained through studies addressing basic regulatory mechanisms, we are developing novel technologies to control pluripotent stem cell growth.

We have recently reported a new method to culture human ES cells under completely animal-free defined conditions by chemically engineering the activity of the RRM signaling axis (Harb et al. 2008).

Because of its simplicity by eliminating variable factors (e.g. Matrigel coating) from culture procedures, this new method also provides a unique advantage in that researchers can easily and reproducibly grow human ES cells without prior experiences in human ES cell culture.

2. Identification of cell-architectural remodeling mechanisms required for complete cellular reprogramming of iPS cells.

The recent innovation of a reprogramming method to generate pluripotent stem cells by introducing defined factors into differentiated adult somatic cells paved the way to derive patient-specific pluripotent stem cells without any ethical concerns. Although this induced pluripotent stem (iPS) cell technology is a promising method to generate sources for cell-replacement therapy, due to its short history, there are many important biological questions and practical hurdles to overcome.

To fully reprogram adult somatic cells, it is critical that the cell structural remodeling process is precisely synchronized with nuclear reprogramming to accurately mirror embryonic stem cell architectures and functions. This is obvious especially in the case of fibroblasts reprogramming as they need to acquire RRM signaling and E-cadherin-mediated cell adhesion machineries that are essential for multi-differentiation capacities of pluripotent stem cells.

We are studying how synchronization of nuclear programming and cell-architectural remodeling processes are regulated by focusing on re-establishment of RRM signaling machineries and what mechanisms are involved in regulating each remodeling process.

Also we are interested in testing the possibility that incomplete cell restructuring may, in turn, lead to incomplete epigenetic reprogramming or cell death of original somatic cells.

Moreover, we are developing unique technologies to derive and expand new human iPS cell lines by applying the fully defined culture method that augments RRM signaling activity.

The goal of our study is to contribute to further understanding molecular basis of self-renewal and pluripotency, and to pioneer the next generation platform technologies to generate human pluripotent stem cells essential for future stem cell medicine.

Selected Publications

Sato N, Leopold PL., and Crystal RG. Induction of the hair growth phase in postnatal mice by localized transient expression of Sonic hedgehog. J. Clin. Invest. 104: 855-864, 1999

Sato N, Leopold PL., and Crystal RG. Localized, transient, enhanced expression of sonic hedgehog accelerates hair regrowth following chemotherapy-induced alopecia. J. Natl. Cancer Inst. 93, 1858-1864, 2001.

Bergstein I, Leopold P, Sato N, Panteleyev A, Christiano A, and Crystal R. In vivo enhanced expression of patched dampens the sonic hedgehog pathway. Mol Ther. 2, 258-264, 2002

Sato N, Sanjuan IM, Heke M, Uchida M, Naef F, and Brivanlou AH. Molecular signature of human embryonic stem cells and its comparison with the mouse. Dev Biol. 260, 404-413, 2003

Sato N, Meijer L, Skaltsounis L, Greengard P, and Brivanlou AH. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat. Med. 10, 55-63, 2004

Scott A, Sato N, and Brivanlou AH. Feeder-free culture of human embryonic stem cells. Stem Cells: From Bench to Bedside. 2005; 144-60

Sato N and Brivanlou AH. Microarray Approach to Identify the Signaling Network Responsible for Self-renewal of Human Embryonic Stem Cells. Methods Mol Biol. 2006;331:267-83.

Sato N and Brivanlou AH. Manipulation of Self-renewal in Human Embryonic Stem Cells through a Novel Pharmacological GSK-3 Inhibitor. Methods Mol Biol. 2006;331:115-28.

Harb N, Archer TK, and Sato N. The Rho-Rock-Myosin signaling axis determines cell-cell integrity of self-renewing pluripotent stem cells. PLoS ONE. 2008 Aug 20;3(8):e3001.

---

Biochemistry Department Faculty Information     Sato, Noboru

Page created by Center for Visual Computing Maintained by Webmaster Last modified