How the structural complexity of the niche enables stem cell function during development and homeostatsis

About This Grant

PROJECT SUMMARY/ABSTRACT In the developing embryo, in adult tissues such as the skin and intestine, and in many types of cancer, stem cells exist in close association with a supporting niche. The importance of the niche cannot be overstated. It both regulates stem cells’ ability to self-renew and controls these cells’ survival and differentiation. As a result, niche function influences many aspects of human health and disease. Niche function is often associated with the proximal signals they send to direct stem cell behavior. How a niche coordinates the timing, intensity and duration of the signals controlling stem cell activity remains poorly understood and represents a critical knowledge gap in our understanding of basic stem cell biology. Niches often have a precisely defined spatial organization that includes multiple cellular and extracellular matrix components. This organization is critical for niche function which suggests that niche structure is likely critical for stem cell regulation. My lab’s long-term goal is to discover how the structure and organization of a niche facilitate its ability to precisely control the signaling environment experienced by stem cells. We study the germ line in C. elegans as a model for this process. The germ line’s simple, well-understood developmental program, along with the extensive genetic toolkit and ease of 4D in vivo imaging available in C. elegans, make it an ideal system to investigate the structure and function of a niche. In worms, assembly of a functional niche is essential for controlling germline stem cell quiescence during embryo development and for balancing proliferation and differentiation in larval and adult animals. We focus on two components of niche structure which control these processes and are found in many different types of niches in other animals. First, we are investigating how the organization of the extracellular matrix in the niche contributes to its function. The extracellular matrix provides both biochemical and mechanical signals to adjacent cells. Our research will uncover how this essential niche component is constructed and remodeled during embryonic and larval development, and how it’s mechanical properties determine stem cell quiescence and proliferation. Second, a prominent yet poorly understood feature of many stem cell niches is that niche cells extend membrane protrusions over the surfaces of stem cells. This is called wrapping. We are studying the developmental basis of wrapping in the germline niche to identify fundamental adhesive, signaling and polarity mechanisms driving cellular wrapping. We are also investigating how wrapping functions to modulate the signaling environment experienced by germline stem cells, either by amplifying useful signals from the niche or by excluding signals from surrounding tissues. Our research is uncovering fundamental mechanisms for niche-stem cell regulation, advancing our basic understanding of basement membrane structure and function, and providing new insights into the mechanisms cells use to modulate signal transduction.