Dynamic interplay between IL-1 and WNT pathways in regulating dermal adipocyte lineage cells during skin development and wound regeneration
Lixiang Sun,
Xiaowei Zhang,
Shuai Wu,
Youxi Liu,
Christian F. Guerrero-Juarez,
Wenjie Liu,
Jinwen Huang,
Qian Yao,
Meimei Yin,
Jiacheng Li,
Raul Ramos,
Yanhang Liao,
Rundong Wu,
Tian Xia,
Xinyuan Zhang,
Yichun Yang,
Fengwu Li,
Shujun Heng,
Wenlu Zhang,
Minggang Yang,
Chi-Meng Tzeng,
Chao Ji,
Maksim V. Plikus,
Richard L. Gallo,
Ling-juan Zhang
Affiliations
Lixiang Sun
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Xiaowei Zhang
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Shuai Wu
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Youxi Liu
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Christian F. Guerrero-Juarez
Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
Wenjie Liu
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Jinwen Huang
Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
Qian Yao
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Meimei Yin
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Jiacheng Li
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Raul Ramos
Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA
Yanhang Liao
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Rundong Wu
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Tian Xia
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Xinyuan Zhang
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Yichun Yang
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Fengwu Li
Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA
Shujun Heng
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Wenlu Zhang
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Minggang Yang
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 350005, China
Chi-Meng Tzeng
Translation Medicine Research Center (TMRC), School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China
Chao Ji
Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
Maksim V. Plikus
Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA
Richard L. Gallo
Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA
Ling-juan Zhang
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian 361102, China; Corresponding author
Summary: 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.
