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Dendritic cells maintain dermal adipose–derived stromal cells in skin fibrosis
Jennifer J. Chia, … , Jessica K. Gordon, Theresa T. Lu
Jennifer J. Chia, … , Jessica K. Gordon, Theresa T. Lu
Published October 10, 2016
Citation Information: J Clin Invest. 2016;126(11):4331-4345. https://doi.org/10.1172/JCI85740.
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Research Article Dermatology Immunology

Dendritic cells maintain dermal adipose–derived stromal cells in skin fibrosis

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Abstract

Scleroderma is a group of skin-fibrosing diseases for which there are no effective treatments. A feature of the skin fibrosis typical of scleroderma is atrophy of the dermal white adipose tissue (DWAT). Adipose tissue contains adipose-derived mesenchymal stromal cells (ADSCs) that have regenerative and reparative functions; however, whether DWAT atrophy in fibrosis is accompanied by ADSC loss is poorly understood, as are the mechanisms that might maintain ADSC survival in fibrotic skin. Here, we have shown that DWAT ADSC numbers were reduced, likely because of cell death, in 2 murine models of scleroderma skin fibrosis. The remaining ADSCs showed a partial dependence on dendritic cells (DCs) for survival. Lymphotoxin β (LTβ) expression in DCs maintained ADSC survival in fibrotic skin by activating an LTβ receptor/β1 integrin (LTβR/β1 integrin) pathway on ADSCs. Stimulation of LTβR augmented the engraftment of therapeutically injected ADSCs, which was associated with reductions in skin fibrosis and improved skin function. These findings provide insight into the effects of skin fibrosis on DWAT ADSCs, identify a DC-ADSC survival axis in fibrotic skin, and suggest an approach for improving mesenchymal stromal cell therapy in scleroderma and other diseases.

Authors

Jennifer J. Chia, Tong Zhu, Susan Chyou, Dragos C. Dasoveanu, Camila Carballo, Sha Tian, Cynthia M. Magro, Scott Rodeo, Robert F. Spiera, Nancy H. Ruddle, Timothy E. McGraw, Jeffrey L. Browning, Robert Lafyatis, Jessica K. Gordon, Theresa T. Lu

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Figure 2

DWAT ADSC numbers are reduced upon fibrosis induction.

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DWAT ADSC numbers are reduced upon fibrosis induction.
Mice were injecte...
Mice were injected with PBS or BLM s.c. in back skin over 20 to 28 days unless otherwise indicated. n = 4–8 mice over 2 to 4 experiments. (A) Representative H&E stain. (B) Dermal and DWAT thicknesses. (C) Collagen content expressed as micrograms collagen per millimeter of tissue section length. (D) Relative Tgfb1 mRNA. (E–H) ADSCs were assessed by flow cytometry. (E) ADSC numbers per 8-mm punch. (F) Percentage of ADSCs that are TUNEL+. (G) Percentage of ADSCs that are Ki67+. (H) PDPN geometric mean fluorescence intensity (MFI) on ADSCs normalized to PBS group. Scale bars: 100 μm. *P < 0.05, **P < 0.01, ***P < 0.001 using 2-tailed unpaired Student’s t test. Error bars depict the SD in E–G and the SEM in the other graphs.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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