Research Projects

The treatment strategy for diabetic foot ulcers is a challenge in the medical community. Stem cell transplantation therapy, although provide hope but is also associated with its limitations. Our recent invention of cytocompatible and biodegradable polymer scaffolds (US Patent granted- US 9925298 B2) which efficaciously delivered bone marrow stem cells by increasing engraftment at the wound sites in pre-clinical murine models are the only existing scaffolds that are custom designed for stem cell delivery applications. The therapeutic efficacy of adoptive adult stem cells e.g., Mesenchymal stromal/stem cells (MSCs)-based transplantation therapies is often limited by the retort time required for differentiating into lineage-specific cells to initiate the function of the organ. Chemokines released at the injury microenvironment have their cognate receptor expressed on MSCs which get activated in the presence of a chemotactic signal that modulates their physiological responses. Our preliminary studies on the temporal expression of an array of chemokines at the wound bed revealed a significant increase in the expression of CXCL2. Thus, it was hypothesized that exogenous MSCs with stable overexpression and/or silencing of the cognate receptor of CXCL2, Cxcr2 will modulate MSC proliferation, migration, and differentiation. Interestingly, MSCCxcr2 (MSC with stable overexpression of Cxcr2) led to marked activation of STAT3 (p-STAT3) and ERK1/2 (p-ERK1/2) that was perturbed by its silencing, MSCCxcr2-KD. Activated STAT3 and ERK1/2 often translocate into the nucleus and act as a transcription cofactor. The central hypothesis of the proposal is, “Activated STAT3 and ERK1/2 in MSCCxcr2 transcriptionally upregulates FGFR2IIIb (Keratinocyte growth factor receptor) and potentiates keratinocyte differentiation in 3D skin organoids that regenerate damaged epidermis (keratinocytes-epithelialization) and dermis (vascularity-endothelialization using endothelial cells and fibroblasts) upon allografting on the chronic non-healing type 2 diabetic wounds”. These biodegradable 3D skin organoids would effectively regenerate the skin within the diabetic wound bed providing an efficacious and safe therapy. The proposed project intends to utilize state-of-the-art cellular and molecular techniques to evaluate the transcriptional and molecular signaling mechanisms during MSC trans-differentiation into keratinocytes followed by the generation of 3D skin organoids using the patented cytocompatible and biodegradable polymer scaffolds. Finally, the proof-of-concept of allograft transplantation of skin organoids-mediated skin regeneration will be accomplished using the preclinical chronic non-healing type 2 diabetic wound model.