We are interested in how adult stem cells make "decisions" to adopt and maintain different functional states
Chromatin in intestinal stem cell biology
Most adult tissues are maintained by somatic stem cells, which produce all of a tissue’s differentiated cells under normal conditions, initiate regeneration following injury, and are thought to drive tumorigenesis after acquiring oncogenic mutations. The intestinal epithelium exhibits significant stem cell activity via constant, rapid renewal throughout adult life. In fact, cells in the intestinal epithelium undergo near-total renewal every 5-7 days; during which time intestinal stem cells (ISCs) drive proliferation and differentiation along a crypt/villus axis. Recent studies have also shown that partially-differentiated progenitor cells can "de-differentiate" to acquire ISC characteristics and function in scenarios where normal ISCs become compromised, effectively forming two stem cell pools: "active" ISCs and progenitor cells that function as "reserve" or "facultative" ISCs. These characteristics place high demands on the cellular potential of ISC populations: how do these cells maintain normal function, make differentiation decisions, and retain the ability to revert to a less differentiated state under stress or damage?
To address these questions, we're studying how chromatin affects ISC potential to make reversible and irreversible differentiation and self-renewal decisions. Chromatin refers to the complement of post-translational modifications to DNA-associated histone proteins as well as modifications to DNA itself. Together, these epigenetic modifications (or "marks") have the potential to impact gene expression and cellular behavior on a global scale. Our studies are aimed at mapping these marks and determining their functional and mechanistic significance. By understanding global "epigenomic" regulation of ISCs, we hope to better understand how these regulatory networks change in the setting of injury, inflammatory disease, and cancer.
Cellular dynamics in biliary epithelium
The liver is key regulator of organismal homeostasis and is well known for its remarkable ability to regenerate following physical injury or chemically-induced damage. However, the liver is composed of a diverse array of cell types with specialized functions, and less is understood about how different cell and tissue types within the liver maintain their function under homeostasis and contribute to overall organ regeneration. We are pursuing a deeper understanding of biliary epithelial cells (AKA: cholangiocytes) which form bile ducts and are known to proliferate extensively following liver injury. While the basic physiology of biliary cells is appreciated, the identity of distinct cell types within the bile ducts is largely unknown. Importantly, it is unclear if the bile ducts harbor specialized stem or progenitor cells capable of driving regeneration following damage.
We are applying tools and techniques developed in our studies of intestinal stem cells (ISCs) to identify subpopulations of biliary epithelial cells and "hone in" on potential biliary stem cells (BSCs). Our long-term goal is to better understand phenotypic and genotypic heterogeneity among biliary epithelial cells in order to advance our understanding of hepatobiliary disease to inform the development of novel therapeutics.