Dermal adipose tissue has high plasticity and undergoes reversible dedifferentiation in mice
Zhuzhen Zhang, … , Rana K. Gupta, Philipp E. Scherer
Zhuzhen Zhang, … , Rana K. Gupta, Philipp E. Scherer
Published September 10, 2019
Citation Information: J Clin Invest. 2019;129(12):5327-5342. https://doi.org/10.1172/JCI130239.
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Research Article Dermatology Metabolism

Dermal adipose tissue has high plasticity and undergoes reversible dedifferentiation in mice

Abstract

Dermal adipose tissue (also known as dermal white adipose tissue and herein referred to as dWAT) has been the focus of much discussion in recent years. However, dWAT remains poorly characterized. The fate of the mature dermal adipocytes and the origin of the rapidly reappearing dermal adipocytes at different stages remain unclear. Here, we isolated dermal adipocytes and characterized dermal fat at the cellular and molecular level. Together with dWAT’s dynamic responses to external stimuli, we established that dermal adipocytes are a distinct class of white adipocytes with high plasticity. By combining pulse-chase lineage tracing and single-cell RNA sequencing, we observed that mature dermal adipocytes undergo dedifferentiation and redifferentiation under physiological and pathophysiological conditions. Upon various challenges, the dedifferentiated cells proliferate and redifferentiate into adipocytes. In addition, manipulation of dWAT highlighted an important role for mature dermal adipocytes for hair cycling and wound healing. Altogether, these observations unravel a surprising plasticity of dermal adipocytes and provide an explanation for the dynamic changes in dWAT mass that occur under physiological and pathophysiological conditions, and highlight the important contributions of dWAT toward maintaining skin homeostasis.

Authors

Zhuzhen Zhang, Mengle Shao, Chelsea Hepler, Zhenzhen Zi, Shangang Zhao, Yu A. An, Yi Zhu, Alexandra L. Ghaben, May-yun Wang, Na Li, Toshiharu Onodera, Nolwenn Joffin, Clair Crewe, Qingzhang Zhu, Lavanya Vishvanath, Ashwani Kumar, Chao Xing, Qiong A. Wang, Laurent Gautron, Yingfeng Deng, Ruth Gordillo, Ilja Kruglikov, Christine M. Kusminski, Rana K. Gupta, Philipp E. Scherer

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Figure 5

Characterization of dedifferentiated dermal adipocytes by single-cell RNA-Seq.

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Characterization of dedifferentiated dermal adipocytes by single-cell RN...
(A) Schematic diagram of the dedifferentiation of dermal adipocytes in AdipoChaser-mTmG mice. In the presence of Dox, adipocytes were indelibly labeled with membrane-bound GFP. In the case of dedifferentiation of dermal adipocytes, the dedifferentiated cells will be GFP positive. (B) The gating strategy showed the presence of CD31–CD45–PDGFRα+GFP+ cells in skin of Dox-treated AdipoChaser-mTmG mice (n = 3 per group). Results were confirmed by 2 independent experiments. (C) Heatmap of the top 25 most differentially expressed genes between CD31–CD45–PDGFRα+GFP– and CD31–CD45–PDGFRα+GFP+ cells. (D) Gene expression pattern of fibroblast marker genes, common adipocyte marker genes, fibrosis and inflammation marker genes, and skin adipocyte progenitor/precursor marker genes as displayed by a t-distributed stochastic neighbor embedding (tSNE) plot. Transcript counts represent log2 of gene expression. Plots were made using the Loupe Cell Browser (10x Genomics). (E–G) RT-PCR measurements of mRNA levels of fibroblast marker genes, common adipocyte marker genes, and stem cell marker genes in purified CD31–CD45–PDGFRα+GFP– and CD31–CD45–PDGFRα+GFP+ cells. RT-PCR results were confirmed by 3 independent experiments. n = 5–6 mice. (H) Unbiased clustering of combined cells reflects 15 clusters. (I) Split view of the CD31–CD45–PDGFRα+GFP– and CD31–CD45–PDGFRα+GFP+ cells in H. (J) Quantification of the GFP– and GFP+ cells in each cluster. Data are shown as mean ± SD. P values were calculated with 2-way ANOVA with Dunnett’s test. A P value less than 0.05 is considered significant.