The Dynamic Regulation of Intestinal Stem Cells by Notch Signaling.

intestinal stem cell;Notch signaling;Physiology;Science;Molecular and Integrative Physiology

Carulli, Alexis J.Schnell, Santiago David ;

University of Michigan

关键词: intestinal stem cell;    Notch signaling;    Physiology;    Science;    Molecular and Integrative Physiology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/120757/acarulli_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The intestinal epithelium has one of the fastest cellular turnover rates in the body, a process fueled by a highly active intestinal stem cell (ISC) compartment. Two ISC populations are thought to exist: the active crypt base columnar stem cell (CBCC) and quiescent stem cells (QSCs). The Notch signaling pathway is one of several pathways known to regulate ISC function. My thesis work has focused on understanding the specificity and kinetics underlying Notch regulation of CBCCs.First, I probed the specificity of Notch receptors in regulating intestinal homeostasis by conditionally deleting Notch1 (N1) and/or Notch2 (N2) in the intestinal epithelium in genetic mouse models. Deletion of N1 but not N2 led to increased numbers of secretory cells, demonstrating that N1 is the dominant receptor regulating cell fate decisions. Additionally, N1 deletion reduced the CBCC population by 50% and eliminated recovery after irradiation, discoveries that have clinical implications for using targeted anti-Notch drugs as cancer treatments.My thesis also investigated the cellular mechanism of decreased CBCCs and decreased transit-amplifying (TA) cell proliferation after Notch inhibition. I tracked the consequences of acute Notch inhibition on stem cells over time. Surprisingly, while acute inhibition resulted in decreased CBCC number it also led to increased TA proliferation rather than the decreased proliferation previously observed with chronic inhibition. I devised a compartmental mathematical model of the intestinal crypt to reconcile the proliferation differences observed with acute and chronic Notch inhibition. The model favored a mechanism where Notch signaling regulates both the symmetry of CBCC division into TA cells, as well as repopulation of the CBCC compartment, presumably by activation of QSCs. Further work investigating the role of Notch in QSCs suggests that Notch regulation of CBCC replacement is through regulation of the CBCC niche rather than direct regulation of QSCs.In summary, my thesis work has probed the role of Notch in intestinal epithelial homeostasis and CBCC maintenance. I show that loss of Notch signaling leads to a dynamic shift of CBCCs into the TA cell compartment and that N1 is the key receptor regulating these changes.