%0 Journal Article %J PLoS Biol %D 2022 %T Initiation of wound healing is regulated by the convergence of mechanical and epigenetic cues. %A Bhatt, Tanay %A Dey, Rakesh %A Hegde, Akshay %A Ketkar, Alhad Ashok %A Pulianmackal, Ajai J %A Deb, Ashim P %A Rampalli, Shravanti %A Jamora, Colin %K Biomarkers %K Caspase 8 %K Cues %K Epigenesis, Genetic %K Wound Healing %X

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.

%B PLoS Biol %V 20 %P e3001777 %8 2022 09 %G eng %N 9 %R 10.1371/journal.pbio.3001777 %0 Journal Article %J Cell Rep %D 2022 %T Snail maintains the stem/progenitor state of skin epithelial cells and carcinomas through the autocrine effect of matricellular protein Mindin. %A Badarinath, Krithika %A Dam, Binita %A Kataria, Sunny %A Zirmire, Ravindra K %A Dey, Rakesh %A Kansagara, Gaurav %A Ajnabi, Johan %A Hegde, Akshay %A Singh, Randhir %A Masudi, Tafheem %A Sambath, Janani %A Sachithanandan, Sasikala P %A Kumar, Prashant %A Gulyani, Akash %A He, You-Wen %A Krishna, Sudhir %A Jamora, Colin %K Carcinoma, Squamous Cell %K Cell Line, Tumor %K Epithelial Cells %K Extracellular Matrix Proteins %K Humans %K Integrins %K Neoplasm Proteins %K Neoplasm Recurrence, Local %K Neoplastic Stem Cells %K Skin Neoplasms %K Snail Family Transcription Factors %X

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.

%B Cell Rep %V 40 %P 111390 %8 2022 09 20 %G eng %N 12 %R 10.1016/j.celrep.2022.111390 %0 Journal Article %J Methods Mol Biol %D 2019 %T Interactions Between Epidermal Keratinocytes, Dendritic Epidermal T-Cells, and Hair Follicle Stem Cells. %A Badarinath, Krithika %A Dutta, Abhik %A Hegde, Akshay %A Pincha, Neha %A Gund, Rupali %A Jamora, Colin %X

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.

%B Methods Mol Biol %V 1879 %P 285-297 %8 2019 %G eng %R 10.1007/7651_2018_155