a-mouse-model-mechanotransduction-driven-human-like-hypertrophic

A Mouse Model of Mechanotransduction-driven, Human-like Hypertrophic Scarring

Hypertrophic scarring (HTS) is an abnormal process of wound healing that results in excessive scar tissue formation. Over the past decade, we have ...

University of Arizona

While wound healing in humans occurs primarily through re-epithelization, in rodents it also occurs through contraction of the panniculus carnosus, an underlying muscle layer that humans do not possess. Murine experimental models are by far the most convenient and inexpensive research model to study wound healing, as they offer great variability in genetic alterations and disease models. To overcome the obstacle of contraction biasing wound healing kinetics, our group invented the splinted excisional wound model. While other rodent wound healing models have been used in the past, the splinted excisional wound model has persisted as the most used model in the field of wound healing. Here, we present a detailed protocol of updated and refined techniques necessary to utilize this model, generate results with high validity, and accurately analyze the collected data. This model is simple to conduct and provides an easy, standardizable, and replicable model of human-like wound healing.

Protocol for the Splinted, Human-like Excisional Wound Model in Mice.

According to the American Diabetes Association (ADA), 9-12 million patients suffer from chronic ulceration each year, costing the healthcare system over USD $25 billion annually. There is a significant unmet need for new and efficacious therapies to accelerate closure of non-healing wounds. Nitric Oxide (NO) levels typically increase rapidly after skin injury in the inflammatory phase and gradually diminish as wound healing progresses. The effect of increased NO concentration on promoting re-epithelization and wound closure has yet to be described in the context of diabetic wound healing.

Nitric oxide-releasing gel accelerates healing in a diabetic murine splinted excisional wound model.

Going Flat: Mastectomy without Breast Reconstruction.

Breast Cancer Survivorship: Understanding Breast Tissues' Potentiating Role in Precipitating Deviations from Baseline Sexual Function Post Oncologic Resection.

 Elevated shear stress (ESS) induces vascular remodeling in veins exposed to arterial blood flow, which can lead to arteriovenous (AV) fistula failure. The molecular mechanisms driving remodeling have not been comprehensively examined with a single-cell resolution before.  Using an  animal mode, single-cell RNA sequencing, and histopathology, we precisely manipulate blood flow to comprehensively characterize all cell subpopulations important during vascular remodeling.  AV loops were created in saphenous vessels of rats using a contralateral saphenous vein interposition graft to promote ESS. Saphenous veins with no elevated shear stress (NSS) were anastomosed as controls.  ESS promoted transcriptional homogeneity, and NSS promoted considerable heterogeneity. Specifically, ESS endothelial cells (ECs) showed a more homogeneous transcriptional response promoting angiogenesis and upregulating endothelial-to-mesenchymal transition inhibiting genes (). NSS ECs upregulated antiproliferation genes such as , , and . In macrophages, ESS promoted a large homogeneous subpopulation, creating a mechanically activated, proinflammatory and thus proangiogenic myeloid phenotype, whereas NSS myeloid cells expressed the anti-inflammatory and antiangiogenetic marker .  ESS activates unified gene expression profiles to induce adaption of the vessel wall to hemodynamic alterations. Targeted depletion of the identified cellular subpopulations may lead to novel therapies to prevent excessive venous remodeling, intimal hyperplasia, and AV fistula failure.

Elevated Shear Stress Modulates Heterogenous Cellular Subpopulations to Induce Vascular Remodeling.

The FOXC2 transcription factor has been tied to a wide range of disease states, serving as a promising prognostic biomarker associated with aggressive basal-like human breast cancers (increased cancer invasion and metastasis). Dysregulation of FOXC2 expression has also been found to promote defects in lymphatic remodeling and hyperplastic lymphedema-distichiasis (LD). Since chronic lymphedema is a forerunner of several malignancies and cancers have been known to arise from poorly healing chronic wounds (e.g., Marjolin ulcers), we examined the effect of Foxc2 dysfunction on skin wound healing.

Andrew C. Hostler

Department of Surgery

University of Arizona

A Mouse Model of Mechanotransduction-driven, Human-like Hypertrophic Scarring

Andrew C. Hostler

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Surgery

University of Arizona

A Mouse Model of Mechanotransduction-driven, Human-like Hypertrophic Scarring

Department of Surgery