Initiation of wound healing is regulated by the convergence of mechanical and epigenetic cues.

Wound healing in the skin is a complex physiological process that is a product of a cell state transition from homeostasis to repair. Mechanical cues are increasingly being recognized as important regulators of cellular reprogramming, but the mechanism by which it is translated to changes in gene expression and ultimately cellular behavior remains largely a mystery. To probe the molecular underpinnings of this phenomenon further, we used the down-regulation of caspase-8 as a biomarker of a cell entering the wound healing program. We found that the wound-induced release of tension within the epidermis leads to the alteration of gene expression via the nuclear translocation of the DNA methyltransferase 3A (DNMT3a). This enzyme then methylates promoters of genes that are known to be down-regulated in response to wound stimuli as well as potentially novel players in the repair program. Overall, these findings illuminate the convergence of mechanical and epigenetic signaling modules that are important regulators of the transcriptome landscape required to initiate the tissue repair process in the differentiated layers of the epidermis.

Molecular characterization of a new begomovirus infecting Synedrella nodiflora in South India.

Begomoviruses (family Geminiviridae) cause important diseases in many crops. In addition, many wild plants are reservoirs of begomoviruses, which are a potential menace for nearby crops. A novel begomovirus was isolated from a weed of the species Synedrella nodiflora (Compositae) exhibiting yellow vein symptoms in South India. This virus had a typical monopartite Old World begomovirus genome and was accompanied by a betasatellite. Sequence comparison revealed that this virus represents a new species in the genus Begomovirus. Recombination analysis showed that the novel begomovirus originated through recombination between the begomoviruses ageratum yellow vein Sri Lanka virus and tomato leaf curl Sri Lanka virus.

Extracellular Caspase-1 induces hair stem cell migration in wounded and inflamed skin conditions.

The wound-healing process is a paradigm of the directed migration of various pools of stem cells from their niche to the site of injury where they replenish damaged cells. Two decades have elapsed since the observation that wounding activates multipotent hair follicle stem cells to infiltrate the epidermis, but the cues that coax these cells out of their niche remain unknown. Here, we report that Caspase-1, a protein classically known as an integral component of the cytosolic inflammasome, is secreted upon wounding and has a non-canonical role in the extracellular milieu. Through its caspase activation recruitment domain (CARD), Caspase-1 is sufficient to initiate the migration of hair follicle stem cells into the epidermis. Uncovering this novel function of Caspase-1 also facilitates a deeper understanding of the mechanistic basis of the epithelial hyperplasia found to accompany numerous inflammatory skin diseases.

Snail maintains the stem/progenitor state of skin epithelial cells and carcinomas through the autocrine effect of matricellular protein Mindin.

Preservation of a small population of cancer stem cells (CSCs) within a heterogeneous carcinoma serves as a paradigm to understand how select cells in a tissue maintain their undifferentiated status. In both embryogenesis and cancer, Snail has been correlated with stemness, but the molecular underpinning of this phenomenon remains largely ill-defined. In models of cutaneous squamous cell carcinoma (cSCC), we discovered a non-epithelial-mesenchymal transition function for the transcription factor Snail in maintaining the stemness of epidermal keratinocytes. Snail-expressing cells secrete the matricellular protein Mindin, which functions in an autocrine fashion to activate a Src-STAT3 pathway to reinforce their stem/progenitor phenotype. This pathway is activated by the engagement of Mindin with the leukocyte-specific integrin, CD11b (ITGAM), which is also unexpectedly expressed by epidermal keratinocytes. Interestingly, disruption of this signaling module in human cSCC attenuates tumorigenesis, suggesting that targeting Mindin would be a promising therapeutic approach to hinder cancer recurrence.

Interactions Between Epidermal Keratinocytes, Dendritic Epidermal T-Cells, and Hair Follicle Stem Cells.

The interplay of immune cells and stem cells in maintaining skin homeostasis and repair is an exciting new frontier in cutaneous biology. With the growing appreciation of the importance of this new crosstalk comes the requirement of methods to interrogate the molecular underpinnings of these leukocyte-stem cell interactions. Here we describe how a combination of FACS, cellular coculture assays, and conditioned media treatments can be utilized to advance our understanding of this emerging area of intercellular communication between immune cells and stem cells.