Dendritic cells maintain dermal adipose–derived stromal cells in skin fibrosis
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
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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Research Article Dermatology Immunology

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 4

DCs maintain ADSC survival and skin function in BLM-induced fibrosis.

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DCs maintain ADSC survival and skin function in BLM-induced fibrosis. (A...
(A–D) WT→WT chimeras (WT) or zDCDTR/+→WT chimeras (zDCDTR/+) were treated s.c. with BLM over 35 days, with i.p. PBS or DT over the final 14 days before skin analysis. (A) DC numbers per punch. (B) ADSC numbers. Left: absolute numbers per punch; right: normalized to PBS group. (C) Representative H&E-stained sections. For comparison, left panel shows a zDCDTR/+ chimera treated with PBS s.c. for 35 days. Scale bars: 100 μm. (D) Dermal and DWAT thicknesses. (E–G) zDCDTR/+ chimeras were treated with BLM over 22 days, with PBS or DT for the final 2 days before analysis. (E) DC numbers per punch. (F) ADSC numbers. Left: absolute numbers per punch; right: normalized. (G) TUNEL+ ADSCs. Left: percentage of ADSCs that are TUNEL+; right: normalized. (A–G) n = 6–8 chimeras per condition over 3–6 experiments. (H) zDCDTR/+ chimeras were treated as in A–D. Relative mRNA expression of indicated genes using NanoString or, for Adipoq, quantitative PCR for first 2 BLM samples. Each column represents 1 mouse; n = 4–5 per condition over 3 experiments. Statistical significance of differences between the PBS s.c. and the BLM s.c. plus PBS i.p. groups is shown at left, and of differences between the BLM s.c. plus PBS i.p. and the BLM s.c. plus DT i.p. groups at right. (I and J) zDCDTR/+ chimeras were treated with BLM for 22 days, receiving PBS i.p. or DT i.p. from day 20 onward. Full-thickness wounds were inflicted the day after BLM cessation and analysis performed 14 days later (see Supplemental Figure 4R). n = 8 wounds in 4 mice per condition over 2 experiments. (I) Representative wounds. Scale bars: 1 mm. (J) Percentage open at day 14 relative to wound size at day 0. *P < 0.05, **P < 0.01, ***P < 0.001 using 2-tailed unpaired Student’s t test. Error bars depict the SEM.