Tissue Adaptation to Environmental Cues by Symmetric and Asymmetric Division Modes of Intestinal Stem Cells

Abstract

Tissues must adapt to the different external stimuli so that organisms can survive in their environments. The intestine is a vital organ involved in food processing and absorption, as well as in innate immune response. Its adaptation to environmental cues such as diet and biotic/abiotic stress involves regulation of the proliferative rate and a switch of division mode (asymmetric versus symmetric) of intestinal stem cells (ISC). In this review, we outline the current comprehension of the physiological and molecular mechanisms implicated in stem cell division modes in the adult Drosophila midgut. We present the signaling pathways and polarity cues that control the mitotic spindle orientation, which is the terminal determinant ensuring execution of the division mode. We review these events during gut homeostasis, as well as during its response to nutrient availability, bacterial infection, chemical damage, and aging. JNK signaling acts as a central player, being involved in each of these conditions as a direct regulator of spindle orientation. The studies of the mechanisms regulating ISC divisions allow a better understanding of how adult stem cells integrate different signals to control tissue plasticity, and of how various diseases, notably cancers, arise from their alterations.

The Emerging Roles of JNK Signaling in Drosophila Stem Cell Homeostasis

“…Environmental cues can cause ISCs to switch from homeostatic asymmetric stem cell division (in which one daughter cell retains stemness and the other differentiates) to symmetric division (in which both daughter cells retain stemness) [ 69 ]. This involves changing the orientation of ISC mitotic spindle relative to the plane of the epithelium from an oblique angle (asymmetric) to parallel (symmetric) [ 70 ]. In Drosophila ISCs, JNK induces symmetric cell divisions by phosphorylating and recruiting Wdr62 to the centrosome and by repressing transcription of Kif1a, a kinesin implicated in promoting asymmetric divisions [ 71 , 72 ].…”

“…However, when symmetric divisions become chronic, for example, during stress or aging, tissue homeostasis is compromised and the lifespan is shortened (see below). While spindle reorientation favoring symmetric divisions has been observed in mouse ISCs, it is not known whether JNK regulates this process [ 70 , 73 ].…”

Cytoskeletal Control and Wnt Signaling—APC’s Dual Contributions in Stem Cell Division and Colorectal Cancer

“…The mode of stem cell division in the gut is a controversial topic—both symmetric and asymmetric stem cell division are proposed to contribute to homeostasis. The division pattern of stem cells is regulated by intrinsic cell polarity cues, cell shape and/or environmental signals [ 122 , 123 , 124 ]. Biased spindle orientation in asymmetric cell divisions will either couple intrinsically the orientation of the division plane with the asymmetric segregation of cell fate determinants or change the respective surroundings encountered by the two daughter cells [ 62 , 125 , 126 , 127 ].…”

“…Yet, more recently, a counter-proposal has favoured instead an asymmetric cell division-dominant neutral drift model also validated in vivo [ 129 ]. These contrasting findings could be related to experimental details, e.g., nutrient availability, harsh environment or aging [ 124 , 130 ]. Indeed, the frequency of self-renewing asymmetric division changes as a function of age to respond to developmental or local effects as well as stress associated with micro-injuries both in mice and flies [ 7 ].…”

Identification of a new allele of O-fucosyltransferase 1 involved in Drosophila intestinal stem cell regulation

“…Previous studies have shown that the proliferation and differentiation of ISCs under physiological and stressed conditions are regulated by many signaling pathways including the Notch, Wingless (Wg), Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), Epidermal Growth Factor Receptor (EGFR), Hippo (Hpo), Insulin, Hedgehog (Hh), and Bone Morphogenetic Protein (BMP) pathways (see reviews by Colombani and Andersen, 2020 ; Gervais and Bardin, 2017 ; Guo et al, 2016 ; Jiang et al, 2016 ; Joly and Rousset, 2020 ; and references therein). The evolutionarily conserved Notch signaling pathway plays essential roles in the control of cell proliferation and specification/differentiation during animal development ( Artavanis-Tsakonas and Muskavitch, 2010 ).…”