Abstract
Rapidly renewing tissues such as the intestinal epithelium critically depend on the activity of small-sized stem cell populations that continuously generate new progeny to replace lost and damaged cells. The complex and tightly regulated process of intestinal homeostasis is governed by a variety of signalling pathways that balance cell proliferation and differentiation. Accumulating evidence suggests that stem cell control and daughter cell fate determination is largely dictated by the microenvironment. Here, we review recent developments in the understanding of intestinal stem cell dynamics, focusing on the roles, mechanisms and interconnectivity of prime signalling pathways that regulate stem cell behaviour in intestinal homeostasis. Furthermore, we discuss how mutational activation of these signalling pathways endows colorectal cancer cells with niche-independent growth advantages during carcinogenesis.
Highlights
Renewing tissues such as the intestinal epithelium critically depend on the activity of small-sized stem cell populations that continuously generate new progeny to replace lost and damaged cells
Maintenance of adult crypt proliferation remains dependent on Wnt signalling as conditional deletion of TCF4 in adult mice resulted in the loss of most proliferating crypts, coinciding with progressive loss of Wnt target gene expression [67]
Indian Hedgehog (Ihh) and Sonic Hedgehog (Shh) ligands secreted by transit amplifying (TA) cells interact with Ptch receptors localized on mesenchymal cells to induce bone morphogenetic protein (BMP) production [144,146,147]
Summary
Adult tissue homeostasis strictly depends on the balanced generation of new cells that replenish cells that are lost through natural attrition or tissue injury This process of tissue regeneration is fuelled by small populations of stem cells that are defined by their unique ability to renew themselves persistently (self-renewal) while giving rise to the specialized cell types of the pertinent tissue (multipotency) [1,2,3]. These adult stem cells are generally referred to by their tissue of origin (e.g. haematopoietic, neuronal or intestinal stem cells (ISCs)). We review current knowledge on how stem cells receive and interpret extracellular signals from their niche, focusing on the prototype model of ISCs, which undergo rapid self-renewal kinetics and give rise to the multiple specialized lineages of the intestinal epithelium [6]
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