Continuous Clonal Labeling Reveals Small Numbers of Functional Stem Cells in Intestinal Crypts and Adenomas

Kozar, Sarah; Morrissey, Edward; Nicholson, Anna M.; Heijden, Maartje van der; Zecchini, Heather I.; Kemp, Richard; Tavaré, Simon; Vermeulen, Louis; Winton, Douglas J.

doi:10.1016/j.stem.2013.08.001

Cited by 198 publications

(285 citation statements)

References 29 publications

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“…S5 A and C), similar to a previous estimate (5). Next, we calculated the effects of TgfβR2 mutation on ISC competition-driven drift.…”

Section: Significancementioning

confidence: 88%

“…Proliferating ISCs are the workhorses during normal homeostasis and are maintained within the niche by a close relationship with Paneth cells (3) and the stroma (4). The proliferating ISC population can be further divided into a smaller number (4-8) of functional ISCs (5,6), which are located at the bottom of the crypt and are biased toward survival within the niche (7). The proliferating ISCs use a population niche mechanism called neutral drift that combines differential ISC clone fates (8,9).…”

mentioning

confidence: 99%

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Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation

Fischer

Calabrese

Miller

et al. 2016

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

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Intestinal stem cells (ISCs) are maintained by a niche mechanism, in which multiple ISCs undergo differential fates where a single ISC clone ultimately occupies the niche. Importantly, mutations continually accumulate within ISCs creating a potential competitive niche environment. Here we use single cell lineage tracing following stochastic transforming growth factor β receptor 2 (TgfβR2) mutation to show cell autonomous effects of TgfβR2 loss on ISC clonal dynamics and differentiation. Specifically, TgfβR2 mutation in ISCs increased clone survival while lengthening times to monoclonality, suggesting that Tgfβ signaling controls both ISC clone extinction and expansion, independent of proliferation. In addition, TgfβR2 loss in vivo reduced crypt fission, irradiation-induced crypt regeneration, and differentiation toward Paneth cells. Finally, altered Tgfβ signaling in cultured mouse and human enteroids supports further the in vivo data and reveals a critical role for Tgfβ signaling in generating precursor secretory cells. Overall, our data reveal a key role for Tgfβ signaling in regulating ISCs clonal dynamics and differentiation, with implications for cancer, tissue regeneration, and inflammation.T he intestinal epithelium is constantly renewed by proliferating, multipotent, and self-renewing intestinal stem cells (ISCs) (1). There are two main populations of ISCs: (i) a proliferating ISC population that is important for homeostasis of the niche residing below the +4 position and expressing a set of markers [e.g., leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) and Olfm4] and (ii) a quiescent ISC population residing near the +4 position and expressing a different set of markers (e.g., Bmi1 and Hopx) (2). Proliferating ISCs are the workhorses during normal homeostasis and are maintained within the niche by a close relationship with Paneth cells (3) and the stroma (4). The proliferating ISC population can be further divided into a smaller number (4-8) of functional ISCs (5,6

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“…S5 A and C), similar to a previous estimate (5). Next, we calculated the effects of TgfβR2 mutation on ISC competition-driven drift.…”

Section: Significancementioning

confidence: 88%

mentioning

confidence: 99%

Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation

Fischer

Calabrese

Miller

et al. 2016

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

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“…Yet, through the reversible transfer of cells between the border and base regions, the heterogeneous population of ISCs functions long-term as a single equipotent stem cell pool (compare with Fig. 1C) (Lopez-Garcia et al, 2010;Kozar et al, 2013). Whether the short-term potency of ISCs correlates with the expression of the putative stem cell markers remains an intriguing unresolved issue.…”

Section: Intestinal Maintenancementioning

confidence: 99%

Dynamic stem cell heterogeneity

2015

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Recent lineage-tracing studies based on inducible genetic labelling have emphasized a crucial role for stochasticity in the maintenance and regeneration of cycling adult tissues. These studies have revealed that stem cells are frequently lost through differentiation and that this is compensated for by the duplication of neighbours, leading to the consolidation of clonal diversity. Through the combination of long-term lineage-tracing assays with short-term in vivo live imaging, the cellular basis of this stochastic stem cell loss and replacement has begun to be resolved. With a focus on mammalian spermatogenesis, intestinal maintenance and the hair cycle, we review the role of dynamic heterogeneity in the regulation of adult stem cell populations.

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“…Testing this hypothesis has proved challenging [57]. Lineage tracing studies to quantify tumour cell dynamics in mice have thus far only proved feasible in benign lesions, and analysis of human tumours has relied on xenotransplantation of sorted candidate CSCs, grossly perturbing the cellular microenvironment [6,19,58,59]. The studies highlighted here show that single oncogenic mutations tilt stem cell behaviour towards the production of proliferating cells, but do not fundamentally change cell dynamics [27,41,49].…”

Section: Perspectivementioning

confidence: 98%

“…In the intestine, it is the competition for space among the 5-10 stem cells in the intestinal stem cell niche at the crypt base that balances proliferation and differentiation [12,14,19]. The migration of a differentiating cell out of the crypt base is linked to the division of a neighbouring stem cell, which always produces two stem cell daughters, in a 'differentiation/replacement' event ( Figure 1).…”

Section: Neutral Competition: Stem Cells In Homeostatic Tissuementioning

confidence: 99%

Mutation, clonal fitness and field change in epithelial carcinogenesis

2014

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Developments in lineage tracing in mouse models have revealed how stem cells maintain normal squamous and glandular epithelia. Here we review recent quantitative studies tracing the fate of individual mutant stem cells which have uncovered how common oncogenic mutations alter cell behaviour, creating clones with a growth advantage that may persist long term. In the intestine this occurs by a mutant clone colonizing an entire crypt, whilst in the squamous oesophagus blocking differentiation creates clones that expand to colonize large areas of epithelium, a phenomenon known as field change. We consider the implications of these findings for early cancer evolution and the cancer stem cell hypothesis, and the prospects of targeted cancer prevention by purging mutant clones from normal-appearing epithelia.

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Continuous Clonal Labeling Reveals Small Numbers of Functional Stem Cells in Intestinal Crypts and Adenomas

Cited by 198 publications

References 29 publications

Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation

Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation

Dynamic stem cell heterogeneity

Mutation, clonal fitness and field change in epithelial carcinogenesis

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