Research Interests

Research in the Powell lab focuses on small intestinal and colonic epithelial stem cell behavior. The intestinal epithelium is a highly dynamic tissue. Normal homeostasis requires intricate control of stem and progenitor cell proliferation, differentiation, migration and ultimately death and detachment. There are several unique populations of progenitor cells within the colonic crypt, and it is posited that each has a unique ability to differentially regulate intestinal homeostasis. These populations are marked by a number of different proteins and have different proliferative properties. The dynamic nature of these intestinal stem cells is likely exploited in normal process of development or repair after injury, but also in malignant transformation.

Our previous research has shown that Leucine rich repeats and immunoglobulin-like domains 1 (Lrig1), a pan-ErbB negative regulator, marks a distinct population of largely quiescent intestinal stem cells and the protein functions as a growth repressor. These discoveries about the Lrig1+ stem cell population tell us something about the role of the cells within the normal small intestinal and colonic crypts in regulating powerful growth factor signaling cascades, as well as inform us about the potential of both Lrig1 and Lrig1-expressing cells in epithelial repair and regeneration after injury. It is unknown how manipulation of one stem cell population affects the colonic tissue repair process in other stem or progenitor populations. Some fundamental questions we address are:

• What requirement, if any, is there for stem cells in tissue regeneration after injury?
• What role do negative regulators, like Lrig1, play in this repair process?
• How do the components of the developing stem cell niche- the epithelium and microenvironment- shape the formation of the adult gut stem cell niche?

The general approach of our research is to apply sophisticated mouse modeling with ex vivo crypt manipulations (organoid culture) coupled with high, or super-resolution microscopy and large-scale genomic scans to address the fundamental questions proposed above. Our studies take advantage of our unique ability to engineer cellular changes within the niche and directly examine effects on the stem cells and influences downstream on the niche. By employing both in vivo and ex vivo approaches, we hope to decipher the molecular cues important for intestinal stem cell maintenance and how these cues may go awry in disease states, such as inflammatory bowel disease and cancer.

The colonic epithelium (stem, transit-amplifying and differentiated cells) is dependent upon proper regulation of signaling cascades, which direct cell division, migration and maintenance. There is cross-talk between the stromal cells (brown) and the epithelium. Together, the stromal cells and the epithelium achieve proper barrier function. Colors in crypt illustration (left) coordinate with the lineage tree (right).

Cross-section of a distal portion of a mouse colon from an induced Lrig1-CreERT2/+;R26R-YFP mouse. U-shaped crypts are made of a single layer of epithelial cells, surrounded by supporting cells. In this lineage labeling experiment, some crypts have undergone genetic recombination to reveal daughter cells of Lrig1-expressing progenitors. These crypts express yellow fluorescent protein (green). All cells in the image are labeled with DAPI (purple).