Selective Ablation of BCL11A in Epidermal Keratinocytes Alters Skin Homeostasis and Accelerates Excisional Wound Healing In Vivo.

Transcriptional regulator BCL11A plays a crucial role in coordinating a suite of developmental processes including skin morphogenesis, barrier functions and lipid metabolism. There is little or no reports so far documenting the role of BCL11A in postnatal adult skin homeostasis and in the physiological process of tissue repair and regeneration. The current study establishes for the first time the In Vivo role of epidermal BCL11A in maintaining adult epidermal homeostasis and as a negative regulator of cutaneous wound healing. Conditional ablation of Bcl11a in skin epidermal keratinocytes (Bcl11aep-/-mice) enhances the keratinocyte proliferation and differentiation program, suggesting its critical role in epidermal homeostasis of adult murine skin. Further, loss of keratinocytic BCL11A promotes rapid closure of excisional wounds both in a cell autonomous manner likely via accelerating wound re-epithelialization and in a non-cell autonomous manner by enhancing angiogenesis. The epidermis specific Bcl11a knockout mouse serves as a prototype to gain mechanistic understanding of various downstream pathways converging towards the manifestation of an accelerated healing phenotype upon its deletion.

Codelivery of 1α,25-Dihydroxyvitamin D3 and CYP24A1 Inhibitor VID400 by Nanofiber Dressings Promotes Endogenous Antimicrobial Peptide LL-37 Induction.

Surgical site infections represent a significant clinical problem. Herein, we report a nanofiber dressing for topical codelivery of immunomodulating compounds including 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and VID400, a CYP24A1 inhibitor in a sustained manner, for inducing the expression of the endogenous cathelicidin antimicrobial peptide (CAMP) gene encoding the hCAP18 protein, which is processed into the LL-37 peptide. Nanofiber wound dressings with coencapsulation of 1,25(OH)2D3 and VID400 were generated by electrospinning. Both 1,25(OH)2D3 and VID400 were coencapsulated into nanofibers with loading efficiencies higher than 90% and exhibited a prolonged release from nanofiber membranes longer than 28 days. Incubation with 1,25(OH)2D3/VID400-coencapsulated poly(ϵ-caprolactone) nanofiber membranes greatly induced the hCAP18/LL-37 gene expression in monocytes, neutrophils, and keratinocytes in vitro. Moreover, the administration of 1,25(OH)2D3/VID400-coencapsulated nanofiber membranes dramatically promoted the hCAP18/LL-37 expression in dermal wounds created in both human CAMP transgenic mice and human skin tissues. The 1,25(OH)2D3- and VID400-coencapsulated nanofiber dressings enhanced innate immunity via the more effective induction of antimicrobial peptide than the free drug alone or 1,25(OH)2D3-loaded nanofibers. Together, 1,25(OH)2D3/VID400-embedded nanofiber dressings presented in this study show potential in preventing surgical site infections.

CTIP2 and lipid metabolism: regulation in skin development and associated diseases.

INTRODUCTION: COUP-TF INTERACTING PROTEIN 2 (CTIP2) is a crucial transcription factor exhibiting its control through coupled modulation of epigenetic modification and transcriptional regulation of key genes related to skin, immune, and nervous system development. Previous studies have validated the essential role of CTIP2 in skin development and maintenance, propagating its effects in epidermal permeability barrier (EPB) homeostasis, wound healing, inflammatory diseases, and epithelial cancers. Lipid metabolism dysregulation, on the other hand, has also established its independent emerging role over the years in normal skin development and various skin-associated ailments. This review focuses on the relatively unexplored connections between CTIP2-mediated control of lipid metabolism and alteration of EPB homeostasis, delayed wound healing, inflammatory diseases exacerbation, and cancer promotion and progression. AREAS COVERED: Here we have discussed the intricate interplay of various endogenous lipids and lipoproteins accompanying skin development and associated disease processes and the possible link to CTIP2-mediated regulation of lipid metabolism. EXPERT OPINION: Establishing the link between CTIP2 and lipid metabolism alterations in the context of skin morphogenesis and diverse types of skin diseases including cancer can help us identify novel targets for effective therapeutic intervention.

Healing of Full-Thickness Murine Skin Wounds Containing Nanofibers Using Splints for Efficient Reepithelialization and to Avoid Contracture.

Wound healing process is the outcome of a series of actions and combined with collaborative process involving concerted efforts of multiple cell types. The dynamic series of events constituting each of these overlapping rather than discrete stages of wound healing increases its complexity and the necessity to understand it. The contrasting mechanisms of wound healing employed by mouse (via wound contraction) and humans (via reepithelialization) puts forth the need of a model closely mimicking human wound-healing and hence comes the applicability of the mouse excisional wound splinting model. Use of silicone-based splints has demonstrated their effectiveness in aptly resembling the human reepithelialization mediated wound healing by preventing contraction during healing. The rising popularity of nanofiber-based treatments for wound healing through sustained release of factors/molecules promoting wound closure can be potentially implemented in association with this model to determine its efficacy in wound management in a more humanized way.

Transcriptional control and transcriptomic analysis of lipid metabolism in skin barrier formation and atopic dermatitis (AD).

Introduction: Atopic dermatitis (AD) is a multifactorial ailment associated with barrier breach and intense systemic inflammation. Several studies over the years have shown the complex interplay of a large number of factors in governing the progression and outcome of AD. In addition to the diverse types of AD resulting due to variation in the intrinsic mechanisms giving rise to AD such as single nucleotide polymorphisms (SNPs), epigenetic alterations or transcriptional changes, extrinsic factors such as age, ancestry, ethnicity, immunological background of the subject, the interactions of the subject with environmental stimuli and existing microbiome in the periphery surrounding the subject account for further heterogeneity in the clinical manifestations of the disease. Areas covered: Here we have selectively discussed transcriptional regulation of genes associated with skin lipid metabolism in the context of AD. Transcriptional control and transcriptomic changes are just one face of this multifaceted disease known to affect humans and a detailed study concerning those will enable us to develop targeted therapies to deal with the disease. Expert opinion: Large-scale integration of different omics approaches (genomics, epigenomics, transcriptomics, lipidomics, proteomics, metabolomics, effect of exposome) will help identify the potential candidate gene(s) associated with the development of various endotypes of AD.

Epidermal Lipids: Key Mediators of Atopic Dermatitis Pathogenesis.

The skin barrier keeps the 'inside in' and the 'outside out', forming a protective blanket against external insults. Epidermal lipids, such as ceramides, fatty acids (FAs), triglycerides, and cholesterol, are integral components driving the formation and maintenance of the epidermal permeability barrier (EPB). A breach in this lipid barrier sets the platform for the subsequent onset and progression of atopic dermatitis (AD). Such lipids are also important in the normal functioning of organisms, both plants and animals, and in diseases, including cancer. Given the doubling of the number of cases of AD in recent years and the chronic nature of this disorder, here we shed light on the multifaceted role of diverse types of lipid in mediating AD pathogenesis.