Clonal analysis of hematopoietic stem cell biology:
Tremendous progress has been achieved in the characterization of the hematopoietic system over the past two decades. Historically, the main experimental approach used to elucidate and define these cellular relationships in the bone marrow (BM) has been the transplantation assay. For this reason, most of our knowledge about the in vivo properties of hematopoietic stem cells (HSCs) and progenitor cells has been derived from studies in the transplant context. Because of the lack of tractable systems, the mechanistic nature of non-transplant hematopoiesis has remained largely unexplored. Over the past several years, my laboratory has developed novel genetic tools for the clonal tracing and imaging of hematopoietic populations in the unperturbed niche that aim to bring insight into the biology of stem and progenitor cells in situ. We are particularly on understanding stem and progenitor biology during embryonic hematopoiesis, in the severely aged hematopoietic system, and at multiple stages of liquid malignancies.
Hippo/YAP signaling in somatic stem cells and cancer:
Despite fantastic progress in developmental biology research over the past decade, one aspect of development and tissue homeostasis for which very little is understood is how individual tissues reach and then maintain their appropriate size. Classic studies have demonstrated that tissues are able to ‘sense’ their size and expand or shrink until a correct dimension has been reached. Nevertheless, the nature of the molecules and pathways involved in this process remain mysterious. Our laboratory utilizes a variety of genetic, biochemical, and high throughput technologies to identify molecules and mechanisms that regulate this fascinating process in mammals. We are particularly interested in studying the function of the newly discovered Hippo signaling pathway and its effects on tissue size, homeostasis and cancer. We have demonstrated that Hippo signaling can be a very potent regulator of organ size in mice and have provided a conceptual link between organ size regulation and stem cell activity through Hippo signals. Our studies are aimed at fully dissecting the components and the role of this cascade in somatic stem cells. Insight into these processes will shed light on fundamental aspects of tissue regeneration and will facilitate the development of therapeutic approaches based on cellular transplantation. Additionally, our group is investigating the relevance of organ size regulatory mechanisms as new components of a tumor suppressor pathway.