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 Article has an altmetric score of 95

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

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 1

Characterization of DWAT ADSCs.

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Characterization of DWAT ADSCs. (A) Representative H&E stain of norm...
(A) Representative H&E stain of normal skin. Dashed line indicates the division between the epidermal/dermal and DWAT fractions. n = at least 3 mice. (B and C) Skin was left unfractionated or separated into epidermal/dermal and DWAT fractions and prepared for flow cytometric analysis. n = 5–7 mice per condition over 3 to 4 experiments. (B) Gating of epidermal and mesenchymal cell populations. (C) Cell numbers of each population in indicated fraction. Numbers are reported per 8-mm punch. (D) Adipocyte differentiation of isolated EpCAM–PDPN– cells, inguinal fat pad ADSCs, or isolated DWAT ADSCs. Left: Representative Oil Red O–stained (ORO-stained) culture. Arrowheads point to undifferentiated cells. Right: Adipogenic efficiency. (E) Osteogenic differentiation of inguinal fat pad ADSCs or isolated DWAT ADSCs. Left: Representative Alizarin Red–stained culture. Right: Osteogenic efficiency. (F) Chondrogenic differentiation of inguinal fat pad ADSCs or isolated DWAT ADSCs. Left: Representative chondro-nodule in Alcian blue–stained culture. Right: Chondrogenic efficiency. (D–F) Symbols represent independent experiments. n = 3–5. Scale bars: 50 μm. *P < 0.05, **P < 0.01, ***P < 0.001 using 2-tailed unpaired Student’s t test. Error bars depict the SEM.