Hypertrophic Scar Formation Following Burns and Trauma: New Approaches to Treatment

The authors examine the process of hypertrophic scar formation, the results of current treatments, and areas of research likely to lead to significant advances in the field

Stem Cell Niches for Skin Regeneration

Stem cell-based therapies offer tremendous potential for skin regeneration following injury and disease. Functional stem cell units have been described throughout all layers of human skin and the collective physical and chemical microenvironmental cues that enable this regenerative potential are known as the stem cell niche. Stem cells in the hair follicle bulge, interfollicular epidermis, dermal papillae, and perivascular space have been closely investigated as model systems for niche-driven regeneration. These studies suggest that stem cell strategies for skin engineering must consider the intricate molecular and biologic features of these niches. Innovative biomaterial systems that successfully recapitulate these microenvironments will facilitate progenitor cell-mediated skin repair and regeneration

Surgical Approaches to Create Murine Models of Human Wound Healing

Wound repair is a complex biologic process which becomes abnormal in numerous disease states. Although in vitro models have been important in identifying critical repair pathways in specific cell populations, in vivo models are necessary to obtain a more comprehensive and pertinent understanding of human wound healing. The laboratory mouse has long been the most common animal research tool and numerous transgenic strains and models have been developed to help researchers study the molecular pathways involved in wound repair and regeneration. This paper aims to highlight common surgical mouse models of cutaneous disease and to provide investigators with a better understanding of the benefits and limitations of these models for translational applications

Antimycotic Ciclopirox Olamine in the Diabetic Environment Promotes Angiogenesis and Enhances Wound Healing

Diabetic wounds remain a major medical challenge with often disappointing outcomes despite the best available care. An impaired response to tissue hypoxia and insufficient angiogenesis are major factors responsible for poor healing in diabetic wounds. Here we show that the antimycotic drug ciclopirox olamine (CPX) can induce therapeutic angiogenesis in diabetic wounds. Treatment with CPX in vitro led to upregulation of multiple angiogenic genes and increased availability of HIF-1α. Using an excisional wound splinting model in diabetic mice, we showed that serial topical treatment with CPX enhanced wound healing compared to vehicle control treatment, with significantly accelerated wound closure, increased angiogenesis, and increased dermal cellularity. These findings offer a promising new topical pharmacologic therapy for the treatment of diabetic wounds

Hyperbaric Oxygen Acutely Increases Wound Circulation as Assessed by Fluorescent Angiography

The efficacy of hyperbaric oxygen therapy (HBOT) to facilitate wound healing in diabetic lower extremity ulcers is well established. The exact mechanism of HBOT-mediated wound healing is unclear but is thought to relate to increased reactive oxygen species and reactive nitrogen species (ROS and RNS). ROS and RNS lead to many downstream affects that impact wound healing, including increased growth factors, diminished inflammatory responses, and improved neovascularization. The impact of HBOT, however, on tissue perfusion and flow is not known. The purpose of this pilot study was to ascertain the immediate effects of HBOT on the microvasculature of chronic wounds as assessed by fluorescent angiography

A multivariable miRNA signature delineates the systemic hemodynamic impact of arteriovenous shunt placement in a pilot study

Arteriovenous (AV) fistulas for hemodialysis can lead to cardiac volume loading and increased serum brain natriuretic peptide (BNP) levels. Whether short-term AV loop placement in patients undergoing microsurgery has an impact on cardiac biomarkers and circulating microRNAs (miRNAs), potentially indicating an increased hemodynamic risk, remains elusive. Fifteen patients underwent AV loop placement with delayed free flap anastomosis for microsurgical reconstructions of lower extremity soft-tissue defects. N-terminal pro-BNP (NT-proBNP), copeptin (CT-proAVP), and miRNA expression profiles were determined in the peripheral blood before and after AV loop placement. MiRNA expression in the blood was correlated with miRNA expression from AV loop vascular tissue. Serum NT-proBNP and copeptin levels exceeded the upper reference limit after AV loop placement, with an especially strong NT-proBNP increase in patients with preexistent cardiac diseases. A miRNA signature of 4 up-regulated (miR-3198, miR-3127-5p, miR-1305, miR-1288-3p) and 2 down-regulated miRNAs (miR30a-5p, miR-145-5p) which are related to cardiovascular physiology, showed a significant systemic deregulation in blood and venous tissue after AV loop placement. AV loop placement causes serum elevations of NT-proBNP, copeptin as well as specific circulating miRNAs, indicating a potentially increased hemodynamic risk for patients with cardiovascular comorbidities, if free flap anastomosis is delayed

Overview of the Role for Calreticulin in the Enhancement of Wound Healing through Multiple Biological Effects

Calreticulin (CRT), an intracellular chaperone protein crucial for the proper folding and transport of proteins through the endoplasmic reticulum, has more recent acclaim as a critical regulator of extracellular functions, particularly in mediating cellular migration and as a requirement for phagocytosis of apoptotic cells. Consistent with these functions, we show that the topical application of CRT has profound effects on the process of wound healing by causing a dose-dependent increase in epithelial migration and granulation tissue formation in both murine and porcine normal and impaired animal models of skin injury. These effects of CRT are substantiated, in vitro, as we show that CRT strongly induces cell migration/wound closure of human keratinocytes and fibroblasts, using a wound/scratch plate assay, and stimulates cellular proliferation of human keratinocytes, fibroblasts, and vascular endothelial cells, providing mechanistic insight into how CRT functions in repair. Similarly, in both animal models, the histology of the wounds show marked proliferation of basal keratinocytes and dermal fibroblasts, dense cellularity of the dermis with notably increased numbers of macrophages and well-organized collagen fibril deposition. Thus, CRT profoundly affects the wound healing process by recruiting cells essential for repair into the wound, stimulating cell growth, and increasing extracellular matrix production

An Information Theoretic, Microfluidic-Based Single Cell Analysis Permits Identification of Subpopulations among Putatively Homogeneous Stem Cells

An incomplete understanding of the nature of heterogeneity within stem cell populations remains a major impediment to the development of clinically effective cell-based therapies. Transcriptional events within a single cell are inherently stochastic and can produce tremendous variability, even among genetically identical cells. It remains unclear how mammalian cellular systems overcome this intrinsic noisiness of gene expression to produce consequential variations in function, and what impact this has on the biologic and clinical relevance of highly ‘purified’ cell subgroups. To address these questions, we have developed a novel method combining microfluidic-based single cell analysis and information theory to characterize and predict transcriptional programs across hundreds of individual cells. Using this technique, we demonstrate that multiple subpopulations exist within a well-studied and putatively homogeneous stem cell population, murine long-term hematopoietic stem cells (LT-HSCs). These subgroups are defined by nonrandom patterns that are distinguishable from noise and are consistent with known functional properties of these cells. We anticipate that this analytic framework can also be applied to other cell types to elucidate the relationship between transcriptional and phenotypic variation

Impaired Neovascularization in Aging

Recent Advances: Several studies have found significant differences during wound healing between younger and older individuals. The hypoxia-inducible factor 1-alpha (HIF-1 alpha) signaling pathway has recently been identified as a major player in wound healing. Hypoxia-inducible factors (HIFs) are pleiotropic key regulators of oxygen homeostasis. HIF-1 alpha is essential to neovascularization through its regulation of cytokines, such as SDF-1 alpha (stromal cell-derived factor 1-alpha) and has been shown to upregulate the expression of genes important for a hypoxic response. Prolyl hydroxylase domain proteins (PHDs) and factor inhibiting HIF effectively block HIF-1 alpha signaling in normoxia through hydroxylation, preventing the signaling cascade from activating, leading to impaired tissue survival. Critical Issues: Aged wounds are a major clinical burden, resisting modern treatment and costing millions in health care each year. At the molecular level, aging has been shown to interfere with PHD regulation, which in turn prevents HIF-1 alpha from activating gene expression, ultimately leading to impaired healing. Other studies have identified loss of function in cells during aging, impeding processes such as angiogenesis. Future Directions: An improved understanding of the regulation of molecular mediators, such as HIF-1 alpha and PHD, will allow for manipulation of the various factors underlying delayed wound healing in the aged. The findings highlighted in this may facilitate the development of potential therapeutic approaches involved in the alteration of cellular dynamics and aging

Therapeutic potential of bone marrow-derived mesenchymal stem cells in cutaneous wound healing

Despite advances in wound care, many wounds never heal and become chronic problems that result in significant morbidity and mortality to the patient. Cellular therapy for cutaneous wounds has recently come under investigation as a potential treatment modality for impaired wound healing. Bone marrow-derived mesenchymal stem cells (MSCs) are a promising source of adult progenitor cells for cytotherapy as they are easy to isolate and expand and have been shown to differentiate into various cell lineages. Early studies have demonstrated that MSCs may enhance epithelialization, granulation tissue formation, and neovascularization resulting in accelerated wound closure. It is currently unclear if these effects are mediated through cellular differentiation or by secretion of cytokines and growth factors. This review discusses the proposed biological contributions of MSCs to cutaneous repair and their clinical potential in cell-based therapies