Skin Stem Cell Hypotheses and Long Term Clone Survival – Explored Using Agent-based Modelling

Li, X.; Upadhyay, Ajay Kumar; Bullock, Anthony J.; DiColandrea, Teresa; Xu, Junmei; Binder, Robert L.; Robinson, Michael K.; Finlay, Darren; Mills, Kevin J.; Bascom, Charles C.; Kelling, Christopher K.; Isfort, Robert J.; Haycock, John W.; MacNeil, Sheila; Smallwood, R. H.

doi:10.1038/srep01904

Cited by 47 publications

(64 citation statements)

References 59 publications

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“…The self-renewal capability observed in cells from the α6-integrin bri /CD71 dim subpopulation in HaCaT cells reported in this work, was similar to that reported in several works in the identification of both adult normal and cancer stem cells, where the isolated progenitor subpopulation was also able to reestablish the initial phenotype of the total population, increasing also the number of putative “progenitor” cells after each cycle of separation [46, 59, 60]. However, in a clear contrast with cancer stem cells, putative progenitor cell population in HaCaT was considerably lower and its enrichment after reseeding was not exponential.…”

Section: Discussionsupporting

confidence: 89%

HPV16-E2 protein modifies self-renewal and differentiation rate in progenitor cells of human immortalized keratinocytes

Domínguez-Catzín

Reveles-Espinoza

Sánchez-Ramos

et al. 2017

Virol J

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BackgroundCervical cancer is the fourth cause of death worldwide by cancer in women and is a disease associated to persistent infection with human papillomavirus (HPV), particularly from two high-risk types HPV16 and 18. The virus initiates its replicative cycle infecting cells located in the basal layer of the epithelium, where a small population of epithelial stem cells is located performing important functions of renewal and maintenance of the tissue. Viral E2 gene is one of the first expressed after infection and plays relevant roles in the replicative cycle of the virus, modifying fundamental processes in the infected cells. Thus, the aim of the present study was to demonstrate the presence of hierarchic subpopulations in HaCaT cell line and evaluate the effect of HPV16-E2 expression, on their biological processes.MethodsHaCaT-HPV16-E2 cells were generated by transduction of HaCaT cell line with a lentiviral vector. The α6-integrin-CD71 expression profile was established by immunostaining and flow cytometric analysis. After sorting, cell subpopulations were analyzed in biological assays for self-renewal, clonogenicity and expression of stemness factors (RT-qPCR).ResultsWe identified in HaCaT cell line three different subpopulations that correspond to early differentiated cells (α6-integrindim), transitory amplifying cells (α6-integrinbri/CD71bri) and progenitor cells (α6-integrinbri/CD71dim). The last subpopulation showed stem cell characteristics, such as self-renewal ability, clonogenicity and expression of the well-known stem cell factors SOX2, OCT4 and NANOG, suggesting they are stem-like cells. Interestingly, the expression of HPV16-E2 in HaCaT cells changed its α6-integrin-CD71 immunophenotype modifying the relative abundance of the cell subpopulations, reducing significantly the percentage of α6-integrinbri/CD71dim cells. Moreover, the expression of the stem cell markers was also modified, increasing the expression of SOX2 and NANOG, but decreasing notably the expression of OCT4.ConclusionsOur data demonstrated the presence of a small subpopulation with epithelial “progenitor cells” characteristics in the HaCaT cell line, and that HPV16-E2 expression on these cells induces early differentiation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-017-0736-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 89%

HPV16-E2 protein modifies self-renewal and differentiation rate in progenitor cells of human immortalized keratinocytes

Domínguez-Catzín

Reveles-Espinoza

Sánchez-Ramos

et al. 2017

Virol J

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“…For instance, phenotypic variability may be triggered by noise because fluctuations enable the exploration of the phase space through different types of dynamics891011. This variability has been observed in several natural systems such as the galactose utilization network in budding yeast12, the process of DNA uptake from the environment in B. subtilis1314, photoreceptor differentiation in the fruit fly retina15 and stem cell differentiation161718. By combining mathematical modeling and gene expression studies in zebrafish, Zhang et al demonstrated that noisy expression can actually facilitate boundary sharpening19.…”

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confidence: 99%

The linear interplay of intrinsic and extrinsic noises ensures a high accuracy of cell fate selection in budding yeast

Zou

2014

Sci Rep

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To gain insights into the mechanisms of cell fate decision in a noisy environment, the effects of intrinsic and extrinsic noises on cell fate are explored at the single cell level. Specifically, we theoretically define the impulse of Cln1/2 as an indication of cell fates. The strong dependence between the impulse of Cln1/2 and cell fates is exhibited. Based on the simulation results, we illustrate that increasing intrinsic fluctuations causes the parallel shift of the separation ratio of Whi5P but that increasing extrinsic fluctuations leads to the mixture of different cell fates. Our quantitative study also suggests that the strengths of intrinsic and extrinsic noises around an approximate linear model can ensure a high accuracy of cell fate selection. Furthermore, this study demonstrates that the selection of cell fates is an entropy-decreasing process. In addition, we reveal that cell fates are significantly correlated with the range of entropy decreases.

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“…They looked at transport and nutrient intake, cell population, ECM deposition, cell attachment, and migration . Agent‐based models have been used to investigate the role of growth factors, organisation of keratinocytes, presence of fibroblasts, and the importance of stem cells in long‐term skin epithelium regeneration . In silico models may be useful theoretically and in combination with other models but are lacking the physical characteristics of human skin …”

Section: Resultsmentioning

confidence: 99%

Non‐animal models of wound healing in cutaneous repair: In silico, in vitro, ex vivo, and in vivo models of wounds and scars in human skin

Uddin

Bayat

2017

Wound Repair Regeneration

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Tissue repair models are essential to explore the pathogenesis of wound healing and scar formation, identify new drug targets/biomarkers and to test new therapeutics. However, no animal model is an exact replicate of the clinical situation in man as in addition to differences in the healing of animal skin; the response to novel therapeutics can be variable when compared to human skin. The aim of this review is to evaluate currently available non-animal wound repair models in human skin, including: in silico, in vitro, ex vivo, and in vivo. The appropriate use of these models is extremely relevant to wound-healing research as it enables improved understanding of the basic mechanisms present in the wound healing cascade and aid in discovering better means to regulate them for enhanced healing or prevention of abnormal scarring. The advantage of in silico models is that they can be used as a first in virtue screening tool to predict the effect of a drug/stimulus on cells/tissues and help plan experimental research/clinical trial studies but remain theoretical until validated. In vitro models allow direct quantitative examination of an effect on specific cell types alone without incorporating other tissue-matrix components, which limits their utility. Ex vivo models enable immediate and short-term evaluation of a particular effect on cells and its surrounding tissue components compared with in vivo models that provide direct analysis of a stimulus in the living human subject before/during/after exposure to a stimulus. Despite clear advantages, there remains a lack of standardisation in design, evaluation and follow-up, for acute/chronic wounds and scars in all models. In conclusion, ideal models of wound healing research are desirable and should mimic not only the structure but also the cellular and molecular interactions, of wound types in human skin. Future models may also include organ/skin-on-a-chip with potential application in wound healing research.

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Skin Stem Cell Hypotheses and Long Term Clone Survival – Explored Using Agent-based Modelling

Cited by 47 publications

References 59 publications

HPV16-E2 protein modifies self-renewal and differentiation rate in progenitor cells of human immortalized keratinocytes

HPV16-E2 protein modifies self-renewal and differentiation rate in progenitor cells of human immortalized keratinocytes

The linear interplay of intrinsic and extrinsic noises ensures a high accuracy of cell fate selection in budding yeast

Non‐animal models of wound healing in cutaneous repair: In silico, in vitro, ex vivo, and in vivo models of wounds and scars in human skin

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