879 Dynamic regulation of sebaceous gland stem cells during skin homeostasis and aging

Abstract

Proper skin function depends upon sebaceous glands (SGs), which are typically paired appendages that release lipids onto the skin’s surface. SGs are subjected to complex regulation by diverse factors; however, it remains unclear how these factors act concurrently to regulate SG stem cells. Here, we provide functional evidence that SGs harbor distinct stem cell populations that replenish the gland from its proximal tip. These SG tip cells can be minimally defined as Lrig1+;PPARg+ or Lrig1+;AR+, while sebocyte differentiation is associated with a distinct K14:K5 to K14:K79 keratin shift. Ablation studies further suggest that individual sebaceous lobes do not sense the loss of their partners or neighbors. Rather, Notch signaling exerts dual contradicting effects on SGs, directly promoting sebocyte differentiation while simultaneously inhibiting SGs from a distance. Suppressing Notch in SG progenitors traps them in a hybrid state where stem cell markers become intermingled with sebocyte differentiation features, including nascent lipid droplet accumulation and K79 expression. Loss of K79 causes SG deterioration and also eyelid meibomian gland collapse, leading to corneal ulceration. Finally, to mimic the mutational status of aged, sun-exposed skin, we performed highly targeted sporadic Notch1 deletion in the adult epidermis and observed gradual SG expansion over time. This suggests that a common skin mutation incurred within one stem cell compartment can indirectly affect another during aging.