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Stem cells are the key subset of cells in the body that function as ancestor cells to produce a variety of functionally specialized (differentiated) mature cells in a given tissue. At the same time, they maintain the capacity to continuously divide and reproduce (self-renewal). This self-renewal process is controlled by intrinsic genetic pathways that are subject to regulation by extrinsic signals from the microenvironment in which stem cells reside. Stem cells play essential roles, ranging from embryonic development and organogenesis (fetal stem cells, embryonic stem cells) to tissue homeostasis and regeneration (adult stem cells). Stem cell development is a complex process and a precise balance is maintained amongst different cell events including self-renewal, differentiation, apoptosis (cell death), and migration. Loss of this balance tends to lead to uncontrolled cell growth or cell death, causing a variety of diseases including cancer and tissue defects. Our studies of stem cell development mainly focus on two systems, the hematopoietic (bone marrow) and the intestinal, and their respective stem cell compartments. The hematopoietic system facilitates functional characterization of stem cells as bone marrow transplantation experiments can be readily performed. The intestinal system has a well-organized developmental architecture in which stem cell marking and lineage tracing can be used to investigate how stem cells are maintained by their microenvironment (niche), how stem cells undergo asymmetric division to maintain the balance between self-renewal and lineage commitment, and what molecular signals are involved in this regulation. To investigate the molecular mechanisms that control stem cell properties we use combined approaches described as follows: A global view of the changes in gene expression patterns during hematopoietic stem cell development to reveal important pathways regulating hematopoietic stem cell self-renewal and lineage commitment. The Notch, Wnt, BMP, and PTEN signal pathways have been well documented to be involved in developmental regulation and tumorigenesis. Expression of Notch, BMP4, and beta-Catenin (a transcription factor) in hematopoietic stem cells suggests that these pathways may play important roles in the regulation of hematopoietic stem cell proliferation and differentiation. Further characterization of the functions of these pathways We use genetic approaches such as transgenic or gene targeting animal models to examine their influence on stem cell development. Our goal is to understand how these signal pathways or mechanisms regulate normal development in the hematopoietic and intestinal system. This information should reveal how they may malfunction or be altered in association with human diseases, such as leukemia and colon cancer. Current research focus areas include: 1. Molecular basis of multipotentiality of stem cells What determines the multipotentiality of stem cells is a fundamental question. Through analysis of gene expression profiles during early hematopoietic stem cell (HSC) development we found that the step-wise decrease in promiscuity (diversity) for multiple lineage-affiliated genes correlates with a progressive restriction of developmental potential in early hematopoiesis. These results support the hypothesis that stem cells maintain their multipotentiality via a wide-open chromatin structure (Blood 2003). 2. Identification of the hematopoietic stem cell niche In 1978 R. Schofield first proposed the hypothesis that the niche (cellular components of microenvironment) plays an essential role in the maintenance of HSCs; however, the HSC niche has remained a mystery since then. Using a Bmpr1a conditional knock-out (KO) model we have identified that spindle-shaped N-cadherin+ osteoblastic cells are a key component of the HSC niche. This is the first stem cell niche in the mammalian system to be identified at the cellular level. As an increase in the HSC number resulted from an increase in the size of the HSC niche in Bmpr1a mutant mice, we showed that BMP signaling controls the HSC number via regulation of the niche size (Nature 2003). The clinical implication of this discovery is its potential for maintaining and expanding hematopoietic stem cells in vitro. 3. BMP and Wnt signaling Ying-Yang controls intestinal stem cell (ISC) properties Juvenile polyposis syndrome (JPS) is known to be caused by defects in the bone morphogenetic protein receptor-IA (BMPR1A) in humans. However, the molecular mechanism underlying JPS remains largely unknown. Inactivation of Bmpr1a in mice results in JPS, providing an animal model for studying this disease. Using this model, we found that the BMP and Wnt signaling pathways are antagonistic, ensuring balanced control of stem cell self-renewal and proliferation versus differentiation. Based on this finding, we propose that BMP signaling inhibits Wnt signaling through either Smad-dependent transcriptional repression or by inhibiting β-catenin activity via the PTEN-PI3K/Akt pathway (Nature Genetics 2004). 4. Normal stem cells versus cancer stem cells While studying the Bmpr1a mutant mouse model we found that the PTEN (a tumor suppressor) controlled PI3K-Akt pathway may mediate cross-talk between BMP and Wnt signaling pathways. We therefore examined the consequences of inactivation of PTEN in both hematopoietic and intestinal systems. Loss of PTEN leads to enhanced proliferation and mobilization of stem cells, which in turn results in acute myeloid/lymphoid leukemia in the hematopoietic system and intestinal polyposis in the intestinal system. Mechanistic studies of the PTEN deficient mouse model revealed that PTEN plays a critical role in maintaining normal hematopoietic stem cells and preventing leukemia development (Nature 2006) and loss of PTEN results in conversion of normal stem cells into cancer initiating stem cells and we documented the process of how cancer stem cells initiate tumorigenesis in intestinal polyposis (Nature Genetics 2007). Future Directions We plan to extend our findings of the HSC niche to further dissect the niche signals and to investigate how these signals coordinate to regulate stem cell self-renewal. We will also attempt to systematically map out the different microenvironments required for different stages of hematopoietic lineage commitment and maturation. As cancer is derived from cancer stem cells, a key to alleviating cancer may depend on whether we can successfully target therapy towards cancer stem cells (not just the tumor mass). To this end, identification and characterization of cancer stem cells will be an essential step. We are currently engaged in identification of cancer stem cells in hematopoietic and intestinal tissues, and hope to follow with characterization of cancer stem cells at both the cellular and molecular levels. Academic Appointment: Associate Professor, Department of Pathology & Laboratory Medicine, The University of Kansas School of Medicine Selected publications
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