Apoptotic cells represent a dynamic stem cell niche governing proliferation and tissue regeneration

Ankawa, Roi; Goldberger, Nitzan; Yosefzon, Yahav; Koren, Elle; Yusupova, Marianna; Rösner, Daniel; Feldman, Alona; Baror-Sebban, Shulamit; Buganim, Yosef; Simon, David; Tessier‐Lavigne, Marc; Fuchs, Yaron

doi:10.1016/j.devcel.2021.06.008

Cited by 34 publications

(26 citation statements)

References 81 publications

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“…The main difference between the two cases is the amount of time deleterious cells spend in the tissue before being removed by immune cells. Interestingly, similar phenomena take place in vertebrate epithelia and exactly the same actors appear to be in place 40 .…”

Section: Discussionmentioning

confidence: 61%

A single WNT enhancer drives specification and regeneration of the Drosophila wing

et al. 2022

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Wings have provided an evolutionary advantage to insects and have allowed them to diversify. Here, we have identified in Drosophila a highly robust regulatory mechanism that ensures the specification and growth of the wing not only during normal development but also under stress conditions. We present evidence that a single wing-specific enhancer in the wingless gene is used in two consecutive developmental stages to first drive wing specification and then contribute to mediating the remarkable regenerative capacity of the developing wing upon injury. We identify two evolutionary conserved cis-regulatory modules within this enhancer that are utilized in a redundant manner to mediate these two activities through the use of distinct molecular mechanisms. Whereas Hedgehog and EGFR signalling regulate Wingless expression in early primordia, thus inducing wing specification from body wall precursors, JNK activation in injured tissues induce Wingless expression to promote compensatory proliferation. These results point to evolutionarily linked conservation of wing specification and regeneration to ensure robust development of the wing, perhaps the most relevant evolutionary novelty in insects.

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Section: Discussionmentioning

confidence: 61%

A single WNT enhancer drives specification and regeneration of the Drosophila wing

et al. 2022

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“…Recently the unique role of apoptosis during steady-state regeneration was shown in hair follicle stem cell (HFSC) self-renewal and differentiation. It was shown that deficiency of caspase-9, a crucial apoptotic initiator caspase, leads to accumulation of caspase-3 and inappropriate mitogenic signaling by continuously releasing Wnt3 from apoptotic HFSCs and instructing proliferation ( 70 ). Also, in the intestine a link between stem cell proliferation and apoptosis was shown.…”

Section: Discussionmentioning

confidence: 99%

Executioner caspases 3 and 7 are dispensable for intestinal epithelium turnover and homeostasis at steady state

Ghazavi

Huysentruyt

Coninck

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Apoptosis is widely believed to be crucial for epithelial cell death and shedding in the intestine, thereby shaping the overall architecture of the gastrointestinal tract, but also regulating tolerance induction, pinpointing a role of apoptosis intestinal epithelial cell (IEC) turnover and maintenance of barrier function, and in maintaining immune homeostasis. To experimentally address this concept, we generated IEC-specific knockout mice that lack both executioner caspase-3 and caspase-7 (Casp3/7ΔIEC), which are the converging point of the extrinsic and intrinsic apoptotic pathway. Surprisingly, the overall architecture, cellular landscape, and proliferation rate remained unchanged in these mice. However, nonapoptotic cell extrusion was increased in Casp3/7ΔIEC mice, compensating apoptosis deficiency, maintaining the same physiological level of IEC shedding. Microbiome richness and composition stayed unaffected, bearing no sign of dysbiosis. Transcriptome and single-cell RNA sequencing analyses of IECs and immune cells revealed no differences in signaling pathways of differentiation and inflammation. These findings demonstrate that during homeostasis, apoptosis per se is dispensable for IEC turnover at the top of intestinal villi intestinal tissue dynamics, microbiome, and immune cell composition.

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“…So far, this process was mostly characterised either in conditions of massive death induction through irradiation and genetic induction of apoptosis in large domains [31, 32], or through the perturbation of the core apoptotic pathway (e.g. : by blocking some of the essential caspases, caspase3 in Drosophila [33], or caspase9 in mammalian epidermis[34]). However, to our knowledge there is no study that has clearly identified biases in cell proliferation distribution in the vicinity of physiological apoptosis in vivo .…”

Section: Discussionmentioning

confidence: 99%

Patterned apoptosis has an instructive role for local growth and tissue shape regulation in a fast-growing epithelium

Cumming

Davidović

Levayer

2022

Preprint

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What regulates organ size and shape remains one of the big mystery of modern biology. So far, this was mostly addressed by deciphering the regulation in time and space of growth and cell division, while the contribution of cell death has been much more neglected. This includes studies of the Drosophila wing imaginal disc, the prospective fly wing which undergoes massive growth during larval stage, one the best characterized system for the study of growth and patterning. So far, it was assumed that cell death was relatively neglectable in this tissue and as a result growth pattern is usually assimilated to the distribution of cell division. Here, using systematic mapping and registration combined with quantitative clone size/disappearance assessment, we show for the first time that cell death is not neglectable and outlined a persistent pattern of cell death and clone elimination in the disc. The local increase of cell death is associated with a significant reduction of clone size suggesting that cell death has a an impact on local growth and is not fully compensated by proliferation. Using morphometric analysis of adult wing shape and genetic perturbations, we provide evidence that patterned death affects adult wing shape. This study describes a roadmap for the proper assessment of contribution of cell death to tissue shape and outlines for the first time an important instructive role of cell death in the morphogenesis of a fast growing tissue.

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Apoptotic cells represent a dynamic stem cell niche governing proliferation and tissue regeneration

Cited by 34 publications

References 81 publications

A single WNT enhancer drives specification and regeneration of the Drosophila wing

A single WNT enhancer drives specification and regeneration of the Drosophila wing

Executioner caspases 3 and 7 are dispensable for intestinal epithelium turnover and homeostasis at steady state

Patterned apoptosis has an instructive role for local growth and tissue shape regulation in a fast-growing epithelium

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