Research from JAMA Dermatology — In Vivo Stimulation of De Novo Collagen Production Caused by Cross-linked Hyaluronic Acid Dermal Filler Injections in Photodamaged Human Skin

The sphingomyelin derivative ceramide is a signaling molecule implicated in numerous physiological events. Recently published reports indicate that ceramide levels are elevated in insulin-responsive tissues of diabetic animals and that agents which trigger ceramide production inhibit insulin signaling. In the present series of studies, the short-chain ceramide analog C₂-ceramide inhibited insulin-stimulated glucose transport by ∼50% in 3T3-L1 adipocytes, with similar reductions in hormone-stimulated translocation of the insulin-responsive glucose transporter (GLUT4) and insulin-responsive aminopeptidase. C₂-ceramide also inhibited phosphorylation and activation of Akt, a molecule proposed to mediate multiple insulin-stimulated metabolic events. C₂-ceramide, at concentrations which antagonized activation of both glucose uptake and Akt, had no effect on the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) or the amounts of p85 protein and phosphatidylinositol kinase activity that immunoprecipitated with anti-IRS-1 or antiphosphotyrosine antibodies. Moreover, C₂-ceramide also inhibited stimulation of Akt by platelet-derived growth factor, an event that is IRS-1 independent. C₂-ceramide did not inhibit insulin-stimulated phosphorylation of mitogen-activated protein kinase or pp70 S6-kinase, and it actually stimulated phosphorylation of the latter in the absence of insulin. Various pharmacological agents, including the immunosuppressant rapamycin, the protein synthesis inhibitor cycloheximide, and several protein kinase C inhibitors, were without effect on ceramide’s inhibition of Akt. These studies demonstrate ceramide’s capacity to inhibit activation of Akt and imply that this is a mechanism of antagonism of insulin-dependent physiological events, such as the peripheral activation of glucose transport and the suppression of apoptosis.

Androgenetic alopecia (AGA), also known as common baldness, is characterized by a marked decrease in hair follicle size, which could be related to the loss of hair follicle stem or progenitor cells. To test this hypothesis, we analyzed bald and non-bald scalp from AGA individuals for the presence of hair follicle stem and progenitor cells. Cells expressing cytokeratin15 (KRT15), CD200, CD34, and integrin, α6 (ITGA6) were quantitated via flow cytometry. High levels of KRT15 expression correlated with stem cell properties of small cell size and quiescence. These KRT15^hi stem cells were maintained in bald scalp samples. However, CD200^hiITGA6^hi and CD34^hi cell populations — which both possessed a progenitor phenotype, in that they localized closely to the stem cell–rich bulge area but were larger and more proliferative than the KRT15^hi stem cells — were markedly diminished. In functional assays, analogous CD200^hiItga6^hi cells from murine hair follicles were multipotent and generated new hair follicles in skin reconstitution assays. These findings support the notion that a defect in conversion of hair follicle stem cells to progenitor cells plays a role in the pathogenesis of AGA.

Prostaglandin D ₂ inhibits hair growth through its receptor, GPR44, and this pathway could serve as a new target for developing treatments for male pattern baldness.

Lower-extremity wounds are a major complication of diabetes. Hemoglobin A1c (HbA1c) reflects glycemia over 2–3 months and is the standard measure used to monitor glycemia in diabetic patients, but results from studies have not shown a consistent association of HbA1c with wound healing. We hypothesized that elevated HbA1c would be most associated with poor wound healing. To test this hypothesis, we conducted a retrospective cohort study of 183 diabetic individuals treated at the Johns Hopkins Wound Center. Our primary outcome was wound-area healing rate (cm² per day). Calibrated tracings of digital images were used to measure wound area. We estimated coefficients for healing rate using a multiple linear regression model controlling for clustering of wounds within individuals and other common clinic variables. The study population was 45% female and 41% African American, with a mean age of 61 years. Mean HbA1c was 8.0%, and there were 2.3 wounds per individual (310 wounds total). Of all measures assessed, only HbA1c was significantly associated with wound-area healing rate. In particular, for each 1.0% point increase in HbA1c, the daily wound-area healing rate decreased by 0.028 <!----> cm² per day (95% confidence interval: 0.003, 0.0054, P=0.027). Our results suggest that glycemia, as assessed by HbA1c, may be an important biomarker in predicting wound-healing rate in diabetic patients. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://www.nature.com/jid/journalclub