Tbx3-dependent proliferation of transit-amplifying cells drives interfollicular epidermal expansion during pregnancy and regeneration

Abstract

The skin surface area varies flexibly in response to body shape changes. Despite the growing evidence implicating that the interfollicular epidermis (IFE) of adult skin consists of slow-cycling stem cells and short-lived transit-amplifying (TA) cells, little is known about the dynamicity of IFE stem and TA cells during physiological body shape changes. By tracing IFE stem cell division using the Wnt-responsive gene Axin in mice, here we show that in pregnant mother mice the abdominal IFE stem cells are predisposed to planar-oriented asymmetric or symmetric cell division into TA cells. Microarray and genetic deletion analysis show that transcription factor Tbx3 is expressed in TA cells in the abdominal IFE of pregnant mice to drive their proliferation, enabling rapid skin expansion to accommodate foetal growth. The IFE stem/TA cell dynamicity of pregnant mice is induced by the dermal-derived secreted frizzled-related protein 1 (Sfrp1) and insulin-like growth factor binding protein 2 (Igfbp2). On wounding, Tbx3 positive-TA cells play a pivotal role in tissue repair, which is reinforced by topical administration of Sfrp1 and Igfbp2 proteins. Our findings demonstrate a fine-tuned IFE stem/TA cell orchestration during pregnancy and implicate its application for regenerative medicine.