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Loss of stemness in the normal crypt, intestinal wounding, and colon cancer

Creative Commons 'BY' version 4.0 license

The intestine performs essential functions to absorb water and nutrients and serve as an important barrier preventing pathogens from harming the body. The innermost layer of the intestinal mucosa is a single layer of epithelial cells that form invaginating crypt structures. Adult epithelial stem cells reside at the base of each of these structures. The stem cells are rapidly proliferating cells that give rise to daughter cells which differentiate into either the absorptive or secretory lineage. This stem cell activity is continuous and ensures that the intestine is an actively renewing tissue that can perform its normal homeostatic functions and can withstand injury by repairing itself rapidly. The precise mechanism(s) behind stem cell differentiation, wounding, and homeostasis are not very well understood. We used high throughput RNA sequencing to follow homeostatic and wounded processes. We determined that during normal colonic stem cell differentiation, loss of stemness is accompanied by a burst of mRNA processing but minimal changes in mRNA expression level. Upon colonic crypt wounding, the rapidly proliferating stem cells readily undergo apoptosis. We determined that the remaining, surviving cells respond by quickly fortifying an epithelial barrier, secreting protective proteins, and ramping up proliferation just four days following wounding. Differentiated cells also display a high level of plasticity, and eventually new stem cells emerge via de-differentiation. Proper wound healing enables the intestine to return to homeostasis, but in some instances of genetic insult as in cancer initiation, there is no return to homeostasis. Cancer can also be referred to as a wound that does not heal, and chronic wounding in the intestinal mucosa can even led to colorectal cancer. We determine that shifts in glutamine metabolism that facilitate stemness and differentiation of colonic cancer cells continue to be relevant in cancer. Overall, this dissertation investigates stemness as it relates to the normal colon, wounding, and colon cancer and highlights the dynamic nature of the intestine transcriptome and proteome.

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