Pharmacologic inhibition of JAK-STAT signaling promotes hair growth

Sivan Harel, Claire A Higgins, Jane E Cerise, Zhenpeng Dai, James C Chen, Raphael Clynes, Angela M Christiano, Sivan Harel, Claire A Higgins, Jane E Cerise, Zhenpeng Dai, James C Chen, Raphael Clynes, Angela M Christiano

Abstract

Several forms of hair loss in humans are characterized by the inability of hair follicles to enter the growth phase (anagen) of the hair cycle after being arrested in the resting phase (telogen). Current pharmacologic therapies have been largely unsuccessful in targeting pathways that can be selectively modulated to induce entry into anagen. We show that topical treatment of mouse and human skin with small-molecule inhibitors of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway results in rapid onset of anagen and subsequent hair growth. We show that JAK inhibition regulates the activation of key hair follicle populations such as the hair germ and improves the inductivity of cultured human dermal papilla cells by controlling a molecular signature enriched in intact, fully inductive dermal papillae. Our findings open new avenues for exploration of JAK-STAT inhibition for promotion of hair growth and highlight the role of this pathway in regulating the activation of hair follicle stem cells.

Keywords: Genetics; Hair; JAK-STAT; Regeneration; Stem cells.

Figures

Fig. 1. Inhibition of JAK-STAT signaling restarts…
Fig. 1. Inhibition of JAK-STAT signaling restarts anagen in wild-type mice.
(A) Seven-week-old wild-type mice were shaved and treated daily with either a topical application of vehicle control, sonic hedgehog agonist (SAG), 3% ruxolitinib (JAK1/2 inhibitor), or tofacitinib (JAK3 inhibitor). Skin was harvested at the indicated time points and stained with hematoxylin and eosin (H&E). Images of mice were taken at D21 of treatment. (B) Mice (8.5 weeks old) were treated with ruxolitinib, tofacitinib, or vehicle control for 5 days and were monitored for the appearance of skin pigmentation, signaling the initiation of anagen. No hair growth (and no pigmentation) was assigned the arbitrary value of 0. Skin darkening was given a value from 0 to 100%, with the higher number indicating darker skin/visible hair growth. Five mice were used per condition. Nonparametric longitudinal data analysis was performed over days 8 to 18 after treatment to generate P = 7.6 × 10−34 for control versus ruxolitinib and P = 1.5 × 10−10 for control versus tofacitinib. Double asterisks indicate high statistical significance.(C) Whole skin from mice treated with vehicle control, ruxolitinib, and tofacitinib for 4 days was analyzed by microarrays. Expression data were used to identify genes that were differentially expressed between T0 and T5 in each of the three treatment groups. Three mice were used per condition and biopsied at two time points. (D) IPA was used to identify the molecular pathways and processes that were overrepresented in our lists of differentially expressed genes. Comparison of the differentially expressed gene lists revealed a subset of genes regulated by both ruxolitinib and tofacitinib. Red, genes up-regulated in drug-treated T5 versus T0; green, genes down-regulated in drug-treated T5 versus T0. (E) Mice (8.5 weeks old) were treated with ruxolitinib or tofacitinib on one side of their dorsal skin and with vehicle control on the other side. Four hours after treatment, Edu was injected into each mouse, and skin was harvested 1 hour later. Treatments were performed once, twice, and thrice, and skin was analyzed for the presence of Edu+ cells. DAPI, 4′,6-diamidino-2-phenylindole.
Fig. 2. The JAK-STAT pathway is dynamically…
Fig. 2. The JAK-STAT pathway is dynamically regulated during HF cycling.
(A) Eight-week-old Rag1−/− and Tcr β/δ−/− mice were treated daily with JAK inhibitors. Mice were treated for a week, and images were taken 7 days after cessation of daily treatments. Representative pictures of three mice per genotype are shown. (B) Whole skin was harvested from mice at postnatal day 17 (D17) (catagen), day 23 (telogen), day 29 (early anagen), and day 33 (mid-anagen). Changes in gene expression were analyzed using a JAK-STAT qPCR array that includes genes involved in the JAK-STAT pathway as well as normalizing controls (Qiagen). Three mice were used per time point, each hybridized to a separate qPCR plate. Log 2 fold changes in gene expression were used to generate GEDI self-organizing maps to visualize the dynamic changes in gene expression over the hair cycle. GEDI clusters transcripts into metagenes on the basis of their similar expression pattern over time and placed them on a 5 × 6 grid. Metagenes repressed in experimental samples (D23, D29, and D33, respectively) versus control samples (D17) are in green to blue, whereas metagenes overrepresented in experimental samples are in red. The upper and lower thresholds correspond to a twofold change. Changes larger/smaller than 2× are set to maximum color. (C) The gene content of the repressed metagenes highlighted in (A) (boxed pixels) is detailed in the table. The color of boxed pixels corresponds to the color of lines in the table. (D) Skin from wild-type mice in anagen (day 30), catagen (day 42), and telogen (D50) was harvested, fixed, and stained with anti–phospho-Stat3 (anti–p-Stat3) and anti–phospho-Stat5 (anti–p-Stat5), as well as with Krt15 (a bulge marker) and P-cadherin (hair germ marker). Phospho-Stat3 is expressed in extrafollicular cells during anagen, as well as in DP cells (white arrows). In catagen, phospho-Stat3 is expressed in the DP (red arrow) and the hair germ (orange arrow). In early telogen, phospho-Stat3 is present in the hair germ cells that are closest to the DP (green arrow). Phospho-Stat5 is strongly expressed in the DP throughout the hair cycle, with expression peaking during catagen (yellow arrows). Phospho-Stat5 can also be detected in the bulge of catagen follicles (magenta arrow). Images were taken with a Zeiss confocal microscope (×40 magnification).
Fig. 3. Inhibition of JAK-STAT promotes hair…
Fig. 3. Inhibition of JAK-STAT promotes hair growth in human tissue.
(A) Human scalp skin was grafted onto SCID mice and topically treated with vehicle control, ruxolitinib (Ruxo), or tofacitinib (Tofa) for 4 weeks. Pictures of the grafts were taken every 3 to 5 days. To quantify differences between vehicle- and drug-treated sides, we used ImageJ to measure the intensity of pigmentation across the graft. The vertical line on each histogram corresponds to the boundary between the vehicle and drug treatments. (B) Individual HFs were dissected from adult human scalp tissue and placed in culture in the presence of vehicle control, ruxolitinib, and tofacitinib. Pictures of follicles were taken every 2 days for 10 days, and the length of each follicle was measured over time. (C) Quantification of the length of hair fibers over time. Treatment with tofacitinib and ruxolitinib significantly increased the length of hair fibers (P = 0.017 and P = 0.025, respectively). Experiment pictured was performed with follicles derived from a single donor with three to four follicles per condition. P values were obtained using nonparametric longitudinal data analysis. (D) DP spheres were grown in hanging drops in the presence of vehicle control, ruxolitinib, or tofacitinib and then combined with mouse neonatal keratinocytes and injected in vivo. Images of representative cysts are shown. (E) Graph of numbers of follicles induced after cysts were dissociated. Hair fibers were manually counted on a microscope. The difference between control and tofacitinib treatments is statistically significant (P = 0.00013). P values were calculated using a linear mixed-effect analysis, treating donor as a random effect. The graph represents three separate experiments with spheres generated from three individual donors. One injection of human DP spheres and mouse keratinocytes slurry was performed per DP donor per condition. N/S, not significant. Double asterisks, highly statistically significant.
Fig. 4. Tofacitinib enhances the inductive molecular…
Fig. 4. Tofacitinib enhances the inductive molecular signature.
(A) DP spheres treated with vehicle control, ruxolitinib, or tofacitinib were molecularly profiled using microarrays. Cells from three donors per condition. Log 2 fold changes in gene expression were used to generate GEDI plots visualizing the dynamic changes in gene expression over drug treatments (z axis and color scale). Clusters of transcripts, grouped into metagenes, were placed on an 18 × 19 grid (x and y axes). Three comparisons are shown: ruxolitinib versus control, tofacitinib versus control, and ruxolitinib versus tofacitinib. Four regions of interest are highlighted on the plots, reflecting genes repressed by tofacitinib treatment (regions 1 and 2) and genes up-regulated by tofacitinib treatment (regions 3 and 4). (B) Selected genes from regions 1 to 4 are presented in the table. (C) GSEA revealed that groups of genes previously shown to contribute to DP inductivity [genes within T2 and T4 as identified by Higgins et al. (31)] are significantly enriched by tofacitinib treatment (P = 1.3 × 10−5). The gray dotted line shows what a normal distribution (with no enrichment) looks like in this analysis. X axis describes the rank of all genes passing call in the array ranked from the most overexpressed to the most underexpressed comparing tofacitinib-treated to untreated cells. The y axis plots the enrichment score (ES) of the combined gene sets T2 and T4 at a given rank. The normalized ES (NES) reflects the Z-score probability of obtaining the observed ES distribution in randomized data, with the associated P value reported. Individual gene ranks for genes in T2 and T4 are represented as black hashes in the barcodes beneath the plot. (D) Summary of the results obtained in Figs. 3 and 4: Although intact DP is fully inductive, the potential to induce HF growth is lost when DP are cultured in vitro. We have previously shown that growing DP cells in spheroid cultures restores some of the inductive potential by regulating a subset of genes in the molecular signature associated with intact DP [territories 1 and 3 (T1 and T3)] (31). Treating DP spheres with tofacitinib increased the inductivity of cultured DP by targeting some of the pathways not previously altered by the 3D culture condition (T2 and T4). Blue, gene expression within territories corresponding on noninductive state; red, gene expression within territories corresponding to inductive state. Although tofacitinib restores genes within T2 and T4, restoration is incomplete compared to fully intact DP (territories in bright red).

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