Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations

Murai, Kiyohito; Skrupskelyte, Greta; Piedrafita, Gabriel; Hall, Michael W.; Kostiou, Vasiliki; Ong, Swee Hoe; Nagy, Tibor; Cagan, Alex; Goulding, David; Klein, Allon M.; Hall, Benjamin A.; Jones, Philip H.

doi:10.1016/j.stem.2018.08.017

Cited by 84 publications

(127 citation statements)

References 51 publications

(86 reference statements)

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“…Applying the MLE approach constrained by the cell-cycle time analysis at each body site yielded improved fits of the SP model to data from paw epidermis in Axin2-cre ERT R26 Rainbow animals and from ear and dorsal interfollicular epidermis in AhYFP mice compared with those fits reported in the original publications ( Fig. S8; Suppl. Methods) 11,21,30 . Despite differences in average keratinocyte division rates across territories (l » 2.0, 1.5, 1.2/week for hind paw, ear and dorsum, respectively), all analyzed regions share comparable intermediate proportions of progenitor basal cells r (~55%, the rest corresponding to differentiating basal cells) and a predominance of asymmetric cell divisions (i.e.…”

Section: Clonal Dynamics In Skin Epidermismentioning

confidence: 99%

“…Skin epidermis was then peeled away using fine forceps and processed as described above for the esophageal epithelium. Lineage-tracing data from Ah-cre ERT R26 flEYFP derived clones in esophagus 5 , ear 30 and dorsal epidermis 21 were obtained from experimental colleagues (data available upon request). Data on induced Axin2-cre ERT R26 Rainbow clones in hindpaw 11 and Lgr6-eGFPcre ERT R26 flConfetti in back epidermis 33 were kindly provided by the authors.…”

Section: Wholemount Preparation and Immunostainingmentioning

confidence: 99%

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The single-progenitor model as the unifying paradigm of squamous epithelial maintenance

Piedrafita

Kostiou

Wabik

et al. 2019

Preprint

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Adult tissues such as the epidermis of the skin and the epithelium lining the esophagus are continuously turned over throughout life. Cells are shed from the tissue surface and replaced by cell division. Yet, the cellular mechanisms that underpin these tissues homeostasis remain poorly established, having important implications for wound healing and carcinogenesis. Lineage tracing, in which of a cohort of proliferating cells and their descendants are genetically labelled in transgenic mice, has been used to study the fate behavior of the proliferating cells that maintain these tissues. However, based on this technique, distinct mutually irreconcilable models, differing in the implored number and hierarchy of proliferating cell types, have been proposed to explain homeostasis. To elucidate which of these conflicting scenarios should prevail, here we performed cell proliferation assays across multiple body sites in transgenic H2BGFP mouse epidermis and esophagus. Cell-cycle properties were then extracted from the H2BGFP dilution kinetics and adopted in a common analytic approach for a refined analysis of a new lineage-tracing experiment and eight published clonal data sets from esophagus and different skin territories. Our results show H2BGFP dilution profiles remained unimodal over time, indicating the absence of slow-cycling stem cells across all tissues analyzed. We find that despite using diverse genetic labelling approaches, all lineage-tracing data sets are consistent with tissues maintenance by a single population of proliferating cells. The outcome of a given division is unpredictable but, on average the likelihood of producing proliferating and differentiating cells is balanced, ensuring tissue homeostasis. The fate outcomes of sister cells are anticorrelated. We conclude a single cell population maintains squamous epithelial homeostasis.

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Section: Clonal Dynamics In Skin Epidermismentioning

confidence: 99%

Section: Wholemount Preparation and Immunostainingmentioning

confidence: 99%

The single-progenitor model as the unifying paradigm of squamous epithelial maintenance

Piedrafita

Kostiou

Wabik

et al. 2019

Preprint

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“…where A represents the basal layer progenitor cells, B the basal cells committed to 15 differentiate and C the suprabasal layer cells. Progenitor cells divide regularly with an 16 overall division rate λ and give rise to either two progenitor daughters (AA), two 17 differentiating daughters (BB) or one daughter of each type (AB) with fixed 18 probabilities. Given the fact that AA symmetric division leads to clone expansion and 19 BB symmetric division tends towards to clone extinction, the two symmetric division 20 rates should be equal in order for a steady state in terms of number of cells to be 21 maintained across the progenitor clone population.…”

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confidence: 99%

“…If 110 stratification is the next event, B cell stratifies, leaving an empty space, which 111 allows potential neighbouring "double state" daughters to be released. The study of p53 and DN Maml1 mutant clone dynamics in mouse epithelia indicated 115 that the mutant progenitor clones are not in homeostasis in a mixed tissue, and have a 116 fitness advantage over their wild-type counterparts [9,16]. This has been shown to be 117 achieved by having a bias towards the production of proliferating progeny.…”

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confidence: 99%

Different responses to cell crowding determine the clonal fitness of p53 and Notch inhibiting mutations in squamous epithelia

Kostiou

et al. 2020

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The growth and competition of cells in epithelial tissues plays an important role in both tissue homeostasis and the robustness of normal tissues to pre-cancer mutation. Whilst wild-type cells compete neutrally for dominance in the un-mutated tissue, naturally occurring mutations in individual cells may lend them a fitness advantage that can allow tissue colonisation. In mouse oesophageal epithelia, the growth of p53 mutants and a dominant negative mutant of the Notch downstream target Maml1 (DN Maml1 ) have been shown to have different colonisation properties despite strong quantitative similarities in the growth of individual clones. Here we show that in order to recapitulate these behaviours whilst maintaining tissue turnover models need to take account of the response of cells to increased areal density in the tissue colonised by mutant cells. We demonstrate that p53 mutant clone growth approximates a logistic curve, but that without including limitations on mutation induced expansion the overall proliferation rate of the tissue drops due to space restrictions. In contrast, the ability of DN Maml1 mutations to displace the wild-type population reflects a feedback that effects both mutant and wild-type cells equally. We go on to show how these distinct feedbacks are consistent with the distribution of mutations observed in human datasets.

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“…TP53 mutations protect against cell death and require sunlight for selection because TP53 subclones are smaller 94 in non-sun exposed skin 13 . Normal sun-exposed skin does not exist because the extent of sun exposure varies 95 massively between patients.…”

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confidence: 99%

Clonal Architecture of the Epidermis: Homeostasis Limits Keratinocyte Evolution

Schenck

Kim

Bravo

et al. 2019

Preprint

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15The skin is the largest human organ, functioning to serve as the protective barrier to the harsh, outside world. 16 Recent studies have revealed that large numbers of somatic mutations accumulate, which can be used to infer 17 normal human skin cell dynamics 1-6 . Here we present the first realistic mechanistic epidermal model, that uses 18 the 'Gattaca' method to incorporate cell-genomes, that shows homeostasis imposes a characteristic log-linear 19 subclone size distribution for both neutral and driver mutations, where the largest skin subclones are the oldest 20 subclones. Because homeostasis inherently limits proliferation and therefore clonal sweeps, selection for driver 21 mutations (NOTCH1 and TP53) in normal epidermis is instead conferred by greater persistence, which leads 22 to larger subclone sizes. These results reveal how driver mutations may persist and expand in normal epidermis 23 while highlighting how the integration of mechanistic modeling with genomic data provides novel insights into 24 evolutionary cell dynamics of normal human homeostatic tissues. 25 Recent studies have documented that substantial numbers of mutations accumulate in normal human tissues, with 26 evidence for selection of canonical, oncogenic driver mutations 2-7 . Typically, selection for these driver mutations is 27 modeled by increased cell proliferation; however, requirements of skin homeostasis imposes spatial constraints that 28 inherently limit selective sweeps. Because these mutations do not appear to disrupt homeostasis, these mutations can 29 also provide important new information on normal human tissue dynamics, which are typically studied with 30 experimental fate markers in animal systems. 31 Although substantial numbers of mutations accumulate with age, and a quarter of all cells carry driver mutations 2 , 32 skin thickness and mitotic activity do not significantly change. A controversy currently exists between our 33 understanding of mutation selection and neutral evolution within tissues 1,2,8,9 , in part because our understanding of 34 how a mutant clone is able to expand within normal tissue is completely lacking. Furthermore, most mutations are 35 passengers and skin subclone size/frequency distributions are consistent with neutral evolution or the absence of 36 detectable selection. There is strong evidence of selection by driver mutations (NOTCH and TP53) manifested by 37 dN/dS ratios and their generally larger subclone sizes in normal skin 2 . Varying exposures to sunlight between 38 2 individuals also complicates our understanding of mutation accumulation. The challenge is to develop a model that 38 integrates selection, neutral evolution, and sunlight. The reward would be a realistic model of lifelong human skin cell 39 dynamics. 40 In the scope of the epidermis, first principles dictate a constant cell number through equal loss and replacement of 41 cells, a constant tissue height, and constant stem cell numbers. Using these principles, we built a three-dimensional 42 mechanistic model of the ...

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Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations

Cited by 84 publications

References 51 publications

The single-progenitor model as the unifying paradigm of squamous epithelial maintenance

The single-progenitor model as the unifying paradigm of squamous epithelial maintenance

Different responses to cell crowding determine the clonal fitness of p53 and Notch inhibiting mutations in squamous epithelia

Clonal Architecture of the Epidermis: Homeostasis Limits Keratinocyte Evolution

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