Dynamic Regulation Of Intestinal Stem Cell Niche And Colon Cancer Stem Cell Division
Tissue homeostasis requires rigorous control mechanisms for stem cell division and maintenance of a stable stem cell niche. Cancer stem cells are a subgroup of cancer cells that possess stem cell-like properties, including self-renewal and differentiation, but have subverted the control apparatus. We have identified that the tumor suppressor miR-34a, a noncoding small RNA targeting Notch, plays an important role regulating the division of colon cancer stem cells (CCSCs) and, in turn. controls the bimodality of heterogeneous population of colonic tumors. Moreover, we find out miR-34a directly suppresses the canonical cell fate determinant Numb to form an incoherent feedforward loop (iFFL) that enhances bimodality of CCSC cell fate determination. Integrative high-throughput analysis suggests that CCSCs and non-CCSCs might globally adopt reprogrammed metabolic functions leading to differential epigenetic regulation. In the normal intestine stem cell (ISC) niche, ISCs and Paneth cells form a stable pattern to control stem cell behavior. However, how the pattern manages to dynamically recover from damage is unclear. A novel optical approach integrating a highprecision femtosecond photo-ablation laser and in vivo imaging system revealed robust pattern recovery after local perturbation in intestine stem cell niche. Computationally and experimentally, we discovered a Notch1 positive feedback (PF) critical to regulate ISC selfrenewal and regeneration. In this dissertation, the integrative engineering approaches led us to understand dynamic regulation of normal ISCs and CCSCs. iii
intestine stem cell; cancer stem cell; Notch
Shuler,Michael Louis; Varner,Jeffrey D.
Ph. D., Electrical Engineering
Doctor of Philosophy
dissertation or thesis