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: noboru.sato@ucr.edu

Welcome to the Stem Cell World!

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 mechanism that regulates pluripotency in embryonic stem cells (ESCs). Pluripotency is, as described above, the ability to generate any type of adult cells including germ cells. Because of this ability, human ESCs have been considered to be a potential source for cell-transplantation therapy to treat diseases such as Parkinson’s disease, myocardial infarction, and diabetes mellitus.

Recent studies have identified master transcriptional regulators and signaling pathways that control pluripotency in ESCs. 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 ESCs, 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 ESCs. 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 sustain the pluripotent state through regulation of master transcriptional regulators in both mouse and human ESCs.

To further gain insight into the molecular regulation of pluripotency, we are currently focusing on the following projects.

Main Projects

1. Identification of signaling pathways that initiate the molecular heterogeneity in pluripotent ESCs.

Recent studies have indicated that ESCs in the undifferentiated morphology of colonies are not homogeneous, but mixtures of molecularly heterogeneous populations that express different levels of pluripotent-specific transcriptional regulators and surface antigens. Moreover a certain population of cells expressing a mesoderm-related transcription factor, Brachyury (T), may not be pluripotent, raising a critical concern in using hESCs for the cell-therapeutic purposes.

We are investigating mechanisms by which this molecular heterogeneity occurs during the self-expansion process of ESCs by focusing on specific signal transduction pathways. This project will be not only vital to develop novel technologies to generate uniformly undifferentiated hESCs, but also to address a fundamental question; “How symmetrically self-replicating stem cells can trigger differentiation programs?”.

Heterogeneous expression of a pluripotent-specific transcriptional regulator, Nanog (green), in mouse ESCs (confocal image).

2. Generation of pluripotent stem cells from adult somatic cells through direct cell reprogramming.

Although hESCs are promising sources for future cell transplantation therapy, their immunogenicity is a critical hurdle to overcome unless hESCs are derived from patients themselves.

Nuclear transfer is an emerging technique to produce pluripotent embryonic stem cells from patient’s somatic cells while there are technical obstacles and ethical concerns due to the use of human oocytes.

Recently, it has been reported that a combination of genetic engineering can reprogram differentiated cells into pluripotent stem cells in mouse without using nuclear transfer method.

We are interested in exploring new approaches to generate human pluripotent stem cells through non-genetically invasive reprogramming that would further provide molecular basis of pluripotency, and would pioneer the next generation technologies required for future stem cell medicine.

Selected Publications

1. 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.

2. 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.

3. 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

4. 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

5. 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

6. 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.

7. 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.

---

Biochemistry Department Faculty Information     Sato, Noboru

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