Epigenetic Regulation of Epidermal Stem Cell Biomarkers and Their Role in Wound Healing

As an actively renewable tissue, changes in skin architecture are subjected to the regulation of stem cells that maintain the population of cells responsible for the formation of epidermal layers. Stems cells retain their self-renewal property and express biomarkers that are unique to this population. However, differential regulation of the biomarkers can initiate the pathway of terminal cell differentiation. Although, pockets of non-clarity in stem cell maintenance and differentiation in skin still exist, the influence of epigenetics in epidermal stem cell functions and differentiation in skin homeostasis and wound healing is clearly evident. The focus of this review is to discuss the epigenetic regulation of confirmed and probable epidermal stem cell biomarkers in epidermal stratification of normal skin and in diseased states. The role of epigenetics in wound healing, especially in diseased states of diabetes and cancer, will also be conveyed

Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition.

Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients' intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients' post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction of tumor. Our findings indicate that GE modulates the microbiome in humanized mice that may contribute to its effects on increasing the latency of breast tumor and reducing tumor growth

Patient summary.

<p>Patient summary.</p

Microbiota change four weeks after introduction of GE diet.

<p>(a) Phylum level changes in microbial abundance four weeks after introduction of GE diet. There was a significant increase in Verrucomicrobia (p = 0.02) in mice on the GE diet. (b)Weighted unifrac 2. (c) 3D PCoA plots (Bray Curtis) showing a distinct clustering of the control-fed (red) and GE-fed diet groups (blue).</p

Heat maps showing relative abundance of bacteria before and after tumor induction.

<p>(a) Heat map of the pre-tumor microbial abundance between control and GE groups. (b) Heat map of the post-tumor microbial abundance between control and GE diet groups. Dendogram shows a distinct clustering of GE-fed group vs control-fed group. Red color denotes high abundance; yellow color denotes low abundance. Post-tumor abundances are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0189756#pone.0189756.t003" target="_blank">Table 3</a>. The lineages are abbreviated, the details of which are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0189756#pone.0189756.s001" target="_blank">S1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0189756#pone.0189756.s002" target="_blank">S2</a> Tables.</p

Humanization of mice.

<p>Alpha diversity represented in the form of box plots show similar richness and evenness in humanized mice and human donors four weeks after humanization of the mice using FMT. The phylogenetic diversity (PD) evaluates the length of all branches of the phylogenetic tree of a given population. Chao1 estimates the total species richness and observed species (OS) counts the unique OTU’s. The median, the first quartile and third quartile values in humans resemble that of mice. Whiskers in the boxplot represent the range of minimum and maximum alpha diversity values within a population, excluding outliers. The range of values for human and mice are similar. These results indicate that the summary statistics (measures of central tendencies) of human and mice data are alike further enforcing the fact that the humanization of mice was successful.</p

Bacterial species showing significant changes in relative abundance after induction of tumor.

<p>Bacterial species showing significant changes in relative abundance after induction of tumor.</p

Microbiota change four weeks after induction of tumor.

<p>(a) Phylum level changes in microbial abundance after induction of tumor. There was no distinct difference in microbial composition between control and GE diet groups. (b) 3D-PCoA plot (Bray Curtis) does not show any distinct clustering of control-fed (red) and GE-fed mice (blue).</p

GE metabolism in mice.

<p>Schematic drawing of the ways in which GE is metabolized in mice. GE <b>1</b> undergoes both sulfate <b>2</b> and glucuronide <b>4</b> conjugation, as well as cleavage reactions to generate 4-ethylphenol <b>5</b> and 2-(4-hydroxyphenyl) propionic acid <b>8</b>. Both of these cleaved metabolites undergo sulfate <b>6, 9</b> and glucuronide conjugation <b>7, 10</b>. SULT = 3’-phosphoadenosine 5’-phosphosulfate sulfotransferase, UGT = uridine 5'-diphospho glucuronosyltransferase.</p