Summary Sweat glands are abundant glands of our body and essential for thermoregulation. Like mammary glands, they originate from epidermal progenitors. However, they display few signs of cellular turnover, and whether they have stem cells and tissue regenerative capacity remain largely unexplored. Here we address these issues. Using lineage-tracing, we identify multipotent progenitors in sweat duct that transition to unipotency after developing the sweat gland. In characterizing four adult stem cell populations of glandular skin, we show that they display distinct regenerative capabilities and remain unipotent when healing epidermal, myoepithelial-specific and luminal-specific injuries. We devise purification schemes, isolate and transcriptionally profile progenitors. Exploiting molecular differences between sweat and mammary glands, we show that only some progenitors regain multipotency to produce de novo ductal and glandular structures, but that these can retain their identity even within certain foreign microenvironments. Our findings provide new concepts about glandular stem cells and sweat gland biology.

Summary Tissue stem cells contribute to tissue regeneration and wound repair through cellular programs that can be hijacked by cancer cells. Here, we investigate such a phenomenon in skin, where during homeostasis, stem cells of epidermis and hair follicle fuel their respective tissues. We find that breakdown of stem cell lineage confinement - granting privileges associated with both fates - is not only hallmark, but also functional in cancer development. We show that lineage plasticity is critical in wound repair, where it operates transiently to redirect fates. Probing mechanism, we discover that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers become activated and override homeostatic enhancers that govern lineage specificity. In cancer, stress responsive transcription factor levels rise, causing lineage commanders to reach excess. When lineage and stress factors collaborate, they activate oncogenic enhancers that distinguish cancers from wounds.

SUMMARY Homeostasis and wound-healing rely on stem cells (SCs) whose activity and directed migration are often governed by Wnt signaling. In dissecting how this pathway integrates with the necessary downstream cytoskeletal dynamics, we discovered that GSK3β directly phosphorylates ACF7, a >500kd microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7’s GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. Phosphorylation-refractile ACF7 rescues overall microtubule architecture, but phosphorylation-constitutive mutants do not. Neither mutant rescues polarized movement, revealing that phospho-regulation must be dynamic. This circuitry is physiologically relevant, depending upon polarized GSK3β inhibition at the migrating front of SCs/progeny streaming from HFs during wound-repair. Moreover, only ACF7 and not GSKβ-refractile-ACF7 restore polarized microtubule-growth and SC-migration to ACF7-null skin. Our findings provide insights into how this conserved spectraplakin integrates signaling, cytoskeletal dynamics and polarized locomotion of somatic SCs.