Extracellular vesicles (EVs) are nanoscale membrane-derived vesicles that serve as intercellular messengers carrying lipids, proteins, and genetic material. Substantial evidence has shown that cancer-derived EVs, secreted by tumor cells into the blood and other bodily fluids, play a critical role in modulating the tumor microenvironment and affecting the pathogenesis of cancer. Here we demonstrate for the first time that squamous cell carcinoma (SCC) EVs were enriched with the C-terminal fragment of desmoglein 2 (Dsg2), a desmosomal cadherin often overexpressed in malignancies. Overexpression of Dsg2 increased EV release and mitogenic content including epidermal growth factor receptor and c-Src. Inhibiting ectodomain shedding of Dsg2 with the matrix metalloproteinase inhibitor GM6001 resulted in accumulation of full-length Dsg2 in EVs and reduced EV release. When cocultured with Dsg2/green fluorescence protein-expressing SCC cells, green fluorescence protein signal was detected by fluorescence-activated cell sorting analysis in the CD90 + fibroblasts. Furthermore, SCC EVs activated Erk1/2 and Akt signaling and enhanced fibroblast cell proliferation. In vivo, Dsg2 was highly up-regulated in the head and neck SCCs, and EVs isolated from sera of patients with SCC were enriched in Dsg2 C-terminal fragment and epidermal growth factor receptor. This study defines a mechanism by which Dsg2 expression in cancer cells can modulate the tumor microenvironment, a step critical for tumor progression.-Overmiller, A.
Given the increasing aging population, the study and care of non-healing wounds in the elderly have become a priority for researchers and clinicians. Skin autografting can be the optimal approach to achieve complete healing of chronic wounds, and in vitro skin bioengineering has been explored to develop full-thickness skin equivalents for transplantation. However, available skin equivalents perform poorly during engraftment due to the lack of proper vasculature. Through advances in skin tissue engineering and induced pluripotent stem cell (iPSC) research, the quality and complexity of bioengineered skin equivalents may be significantly improved by inducing vascularization. In this study, we optimized approaches to derive endothelial cells (hiPSC-ECs) and keratinocytes (hiPSC-Ks) from human iPSCs and validated the contribution of these iPSC-derived cells into life-like 3D full thickness skin models using in vitro and in vivo assays. As a result, we established a vascularized skin graft equivalent through the co-culture of hiPSC-Ks and hiPSC-ECs with human fibroblasts in vitro. The incorporation of endothelial cells enhanced the reconstitution of human skin in an in vivo xenograft model. We are developing vascularized skin grafts solely from hiPSC-ECs, hiPSC-Ks and iPSC-derived fibroblasts. This study provides the foundation for using iPSCs to generate rejuvenated vascularized bioengineered skin equivalents to improve the long-term survival and functionality of skin grafts in elderly patients. This model will allow us to study the formation of the vasculature system and the dynamic interactions of skin fibroblasts and keratinocytes with vascular endothelial cells.
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