Date of Award
Doctor of Philosophy (PhD)
Mature cells can reprogram into a proliferative, progenitor-like state to repair tissue following injury and inflammation. Differentiated cells in diverse tissues can become proliferative via a dedicated, evolutionarily conserved program we termed paligenosis. We detailed how paligenosis occurs, in both gastric chief and pancreatic acinar cells, in a step-wise manner that involves: 1) autodegradation of mature cell components; 2) re-expression of progenitor genes; 3) re-entry into the cell cycle. This process is governed by mTORC1, a fundamental cellular energy sensor and regulator of protein translation. Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re-entry at S-phase. Because paligenosis is a shared, conserved process, we reasoned that genes likely evolved specifically to regulate it. We characterized IFRD1 as a gene that is conserved throughout eukaryotes, upregulated by paligenosis-inducing injury, and largely dispensable for homeostatic regulation of proliferation and differentiation. IFRD1 is critical for the injury-induced recruitment of cells into the cell cycle in Drosophila intestine and multiple mouse tissues. Ifrd1−/− mice showed decreased mTORC1-mediated proliferation and increased apoptosis in gastric and pancreatic paligenotic cells. mTORC1 inhibition and Ifrd1−/−;Trp53−/− experiments revealed that IFRD1 works largely by preventing p53 from repressing the reactivation of mTORC1 during stage 3 of paligenosis. IFRD1 is the first gene shown to regulate the conserved cellular program that recruits mature cells for regeneration. Recruiting mature cells to proliferate following injury can reveal harbored mutations that increase the risk for preneoplastic lesions. Thus, we analyzed the expression of IFRD1 in colon cancer tumors and found it to be significantly associated with decreased 5-year patient survival. Pro-paligenotic genes like IFRD1 might be harnessed to increase cellular reprogramming to promote regeneration; alternatively, because recruiting old cells with potential stores of somatic mutations increases risk for cancer, blocking paligenosis might prevent or treat cancer.
Chair and Committee
Jason C. Mills
Deborah C. Rubin, David G. DeNardo, Blair B. Madison, Ting Wang,
Lewis, Mark Anthony, "The Role of IFRD1 in the Recruitment and Function of Reserve Stem Cells in Regeneration and Cancer" (2019). Arts & Sciences Electronic Theses and Dissertations. 1861.