No abstract

Tissue fibrosis in many organs results from altered and excessive extracellular matrix (ECM) protein deposition 1. Concomitant with ECM expansion, resident lipid-filled cells including mature adipocytes are lost in human and mouse fibrosis2-5, yet the mechanisms that drive mature adipocyte lipid loss and their contribution to tissue fibrosis are unknown. Here, we identify an early, fibro-protective role of mature adipocyte lipolysis driven by Wnt signaling during fibrosis onset. Using chemical and genetic mouse models of skin fibrosis, we show that fibrotic stimuli induce and maintain lipolysis in mature dermal adipocytes. Loss of the lipolytic rate-limiting enzyme adipocyte triglyceride lipase (ATGL)6,7 in murine dermal adipocytes exacerbates bleomycin-induced fibrosis development. Adipocyte lipolysis is stimulated in the early stages of Wnt signaling-induced skin fibrosis and by Wnt agonists in vitro. Furthermore, deletion or inhibition of the Wnt target gene, CD26/Dipeptidyl peptidase 4 (DPP4) prevented Wnt-induced lipolysis and skin fibrosis in mice. Notably, DPP4 expression correlates with skin fibrosis severity in human patients. Thus, we propose that adipocyte-derived fatty acids and the Wnt-DPP4 axis act as essential regulators of ECM homeostasis within tissues and provide a therapeutic avenue to manipulate fibrosis.

No abstract

Human skin contains distinct spatial compartments that cooperate in functional barrier maintenance, including the interfollicular epidermis (IFE), dermis, and the pilosebaceous unit (PSU). Yet, cellular communication within and among these compartments is largely unexplored. To address this, we performed single-cell RNA-sequencing (scRNA-seq) of 10 adult patient hair-bearing normal skin tissues along with spatial transcriptomics on a subset of these. We obtained w21,000 single-cell transcriptomes and w13,000 spot transcriptomes and integrated these data with previously published scRNA-seq from human and mouse skin to deconvolve cell types and subpopulations. Cycling cell analysis suggested spinous keratinocytes (KCs) maintain proliferative capacity prior to terminal differentiation, in contrast to mouse IFE. Spinous KCs with proliferative potential displayed a transcriptional signature indicative of heavy metal processing, suggesting one pathway responsible for increased stratification of human skin. Ligand-receptor analyses mapped intercellular communication involved in epidermal homeostasis, including known mediators such as DLL1-NOTCH1 and AREG-EGFR and lesser studied pairs such as APOE-LDLR and EFNB1-EPHB6. To shed light on potential etiologies of dermatologic genetic disease, we identified cell type-specific expression of mutated genes, implicating specific cell types and their communication networks in pathogenesis. In inflammatory skin diseases with putative multicellular communication, such as hidradenitis suppurativa and generalized pustular psoriasis, we further nominate therapeutics to reverse these phenotypes, leveraging our crosstalk analyses and drug perturbation databases. This work provides a resource for advancing the study of human skin homeostasis and disease.