Dynamic interplay between IL-1 and WNT pathways in regulating dermal adipocyte lineage cells during skin development and wound regeneration

• Published in: Cell reports (Cambridge) 2023-06, Vol.42 (6), p.112647-112647, Article 112647
• Main Authors: Sun, Lixiang, Zhang, Xiaowei, Wu, Shuai, Liu, Youxi, Guerrero-Juarez, Christian F., Liu, Wenjie, Huang, Jinwen, Yao, Qian, Yin, Meimei, Li, Jiacheng, Ramos, Raul, Liao, Yanhang, Wu, Rundong, Xia, Tian, Zhang, Xinyuan, Yang, Yichun, Li, Fengwu, Heng, Shujun, Zhang, Wenlu, Yang, Minggang, Tzeng, Chi-Meng, Ji, Chao, Plikus, Maksim V., Gallo, Richard L., Zhang, Ling-juan
• Format: Article
• Language: English
• Subjects: adipocyte progenitor; Adipocytes - metabolism; adipogenesis; Adipogenesis - genetics; Animals; beta Catenin - metabolism; Cell Differentiation - physiology; CP: Developmental biology; CP: Stem cell research; dermal adipocyte; Glycogen Synthase Kinase 3 - metabolism; Humans; IL-1; Interleukin-1 - metabolism; lipolysis; Mice; myofibroblast; NF-kappa B - metabolism; scRNA-seq; skin development; WNT; Wnt Signaling Pathway - physiology; wound regeneration
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112647

Dermal adipocyte lineage cells are highly plastic and can undergo reversible differentiation and dedifferentiation in response to various stimuli. Using single-cell RNA sequencing of developing or wounded mouse skin, we classify dermal fibroblasts (dFBs) into distinct non-adipogenic and adipogenic cell states. Cell differentiation trajectory analyses identify IL-1-NF-κB and WNT-β-catenin as top signaling pathways that positively and negatively associate with adipogenesis, respectively. Upon wounding, activation of adipocyte progenitors and wound-induced adipogenesis are mediated in part by neutrophils through the IL-1R-NF-κB-CREB signaling axis. In contrast, WNT activation, by WNT ligand and/or ablation of Gsk3, inhibits the adipogenic potential of dFBs but promotes lipolysis and dedifferentiation of mature adipocytes, contributing to myofibroblast formation. Finally, sustained WNT activation and inhibition of adipogenesis is seen in human keloids. These data reveal molecular mechanisms underlying the plasticity of dermal adipocyte lineage cells, defining potential therapeutic targets for defective wound healing and scar formation. [Display omitted] •Highly heterogeneous adipocyte lineage cells are defined in developing mouse skin•WNT and IL-1 are identified as key suppressing or activating signals for dermal adipogenesis•Wound-induced adipogenesis is triggered by neutrophils through IL-1R signaling•WNT activation in adipocytes promotes lipolysis and myofibroblast formation Dermal adipocyte lineage cells are highly plastic cells that expand or retract in response to stimuli. Zhang and colleagues define the heterogeneity of these cells in developing or wounded mouse skin and demonstrate that dermal adipogenesis and lipolysis are regulated by an antagonistic interplay between the IL-1-pCREB and the WNT-β catenin pathways.