SummaryHuman skin heals more slowly in aged vs. young adults, but the mechanism for this delay is unclear. In humans, eccrine sweat glands (ESGs) and hair follicles underlying wounds generate cohesive keratinocyte outgrowths that expand to form the new epidermis. Here, we compared the re‐epithelialization of partial‐thickness wounds created on the forearm of healthy young (< 40 yo) and aged (> 70 yo) adults. Our results confirm that the outgrowth of cells from ESGs is a major feature of repair in young skin. Strikingly, in aged skin, although ESG density is unaltered, less than 50% of the ESGs generate epithelial outgrowths during repair (vs. 100% in young). Surprisingly, aging does not alter the wound‐induced proliferation response in hair follicles or ESGs. Instead, there is an overall reduced cohesiveness of keratinocytes in aged skin. Reduced cell–cell cohesiveness was most obvious in ESG‐derived outgrowths that, when present, were surrounded by unconnected cells in the scab overlaying aged wounds. Reduced cell–cell contact persisted during the repair process, with increased intercellular spacing and reduced number of desmosomes. Together, reduced outgrowths of ESG (i) reduce the initial number of cells participating in epidermal repair, (ii) delay wound closure, and (iii) lead to a thinner repaired epidermis in aged vs. young skin. Failure to form cohesive ESG outgrowths may reflect impaired interactions of keratinocytes with the damaged ECM in aged skin. Our findings provide a framework to better understand the mediators of delayed re‐epithelialization in aging and further support the importance of ESGs for the repair of human wounds.

Although extensive Alopecia areata/AA has a large impact on patients' quality of life, its treatment options are limited. Oral immune-suppressants (Cyclosporine A and JAK inhibitors) have shown efficacy, but their side effects preclude long-term use. IL-12/23p40 was recently found to be highly elevated in AA lesions. We evaluated hair regrowth in 3 extensive AA patients treated with 90mg ustekinumab subcutaneously at 0, 4, and 16wks. The AA involvement ranged from alopecia universalis/AU (100%) to 40%. Patients were evaluated for clinical improvement using percent hair loss and for genomic modulation using gene-arrays performed on scalp biopsies taken at 0 and 20wks. At 20wks all 3 patients showed hair regrowth, ranging from 25% in the patient with the longest disease duration (15yrs) to 85% in the AU patient and 62.5% in the third patient. The AU patient continued to improve with 97% regrowth at week 49. Significant increases in inflammatory markers were observed in lesional AA (compared with non-lesional and normal scalp), with marked decreases after treatment (eg. MMP12, CD1B, CD4, IL-23A, CCL13, STAT1, PDE4). Hair-associated keratins were profoundly decreased in AA lesions at wk0 and increased post treatment. Overall, greater inflammation and larger suppression of hair keratins at baseline were associated with higher regrowth. The two patients with substantial clinical improvement also had normalization of immune (IL-12/23, IFN/Th1, Th2, PDE) and keratin gene-subsets. This is the first report of hair regrowth with specific cytokine antagonism coupled with suppression of inflammatory pathways, possibly opening the door for targeted treatments for extensive AA patients.