Maintaining tissue homeostasis: dynamic control of somatic stem cell activity

Abstract

Long-term maintenance of tissue homeostasis relies on the accurate regulation of somatic stem cell activity. Somatic stem cells have to respond to tissue damage and proliferate according to tissue requirements while avoiding overproliferation. The regulatory mechanisms involved in these responses are now being unraveled in the intestinal epithelium of Drosophila, providing new insight into strategies and mechanisms of stem cell regulation in barrier epithelia. Here, we review these studies and highlight recent findings in vertebrate epithelia that indicate significant conservation of regenerative strategies between vertebrate and fly epithelia.

Figure 1. Similarities and differences between stem cell lineages in mouse and flies

A: Drosophila intestinal stem cell (ISC) lineage. ISC proliferation can be induced by stress signals. ISCs express the Notch ligand Delta (Dl), and their division has an asymmetric outcome, generating a new ISC and an Enteroblast (EB), which differentiates into either an Enterocyte (EC; in response to high Notch activation) or an Enteroendocrine cell (EE, in response to low Notch activation). B: Mouse airway epithelial stem cells (basal cells, BC) divide asymmetrically to give rise to an early progenitor (EP) cell and a new BC. Lineage decision between Clara cells and Ciliated cells is achieved by differential Notch signaling, similar to the fly ISC lineage (see Rock et al., 2011). C. The crypt of the mammalian small intestine is composed of two different stem cell populations that can regenerate the full tissue. Lgr5+ cells appear to be continuously cycling and give rise to new Lgr5+ cells as well as transit amplifying (TA) cells that proliferate and differentiate into one of several cell fates (enterocytes, ECs; enteroendocrine cells, EEs; and Goblet cells). Differentiated Paneth cells serve as support cells in the basal crypt. Bmi1+ cells divide more rarely and have been proposed to serve as reservoir to replace Lgr5+ cells after injury. See Barker et al., 2007 and Tian et al., 2011.

Figure 2. Signaling pathways regulating Intestinal Stem Cell proliferation and self-renewal in Drosophila

ISCs integrate local and systemic cues with cell-intrinsic signals to adapt their proliferation rate to tissue demand. Signaling pathways required for homeostatic proliferation are represented in green, pathways required for stress and injury-induced ISC proliferation are represented in red.

Figure 3. Controversies and open questions in somatic stem cell plasticity

A: The mechanism of stem cell ‘activation’: Due to technical limitations, it is difficult to differentiate in vivo between a situation in which increased regeneration after a stimulus occurs by a transition of a number of stem cells from an ‘inactive’ quiescent state to an active state, and a mechanism in which the cell cycle of a majority of stem cells is simply accelerated. Extensive lineage tracing, preferentially in ex-vivo cultured tissues where individual stem cells can be followed might help resolve this question. B: Generating asymmetry: In the Drosophila intestine, ISC divisions result in a consistently asymmetric outcome, it remains unclear, however, if ISC divisions are intrinsically asymmetric, or if daughter cells are asymmetrically specified by local cues. C. Maintaining homeostasis: A stable pool of stem cells can be maintained within the tissue by either consistently asymmetric cell divisions (hierarchical model), or by mechanisms that control the overall number of stem cells generated by random symmetric/asymmetric divisions (stochastic model). While the Drosophila inestinal epithelium appears to be maintained primarily through the hierarchical model, stem cell homeostasis in the mouse crypt might be maintained by stochastic mechanisms (Snippert et al. 2010, but see also Tian et al., 2011).