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.
View: Text | PDF
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

×

Figure 8

LTβR stimulation increases engraftment and therapeutic effect of injected ADSCs.

Options: View larger image (or click on image) Download as PowerPoint
LTβR stimulation increases engraftment and therapeutic effect of injecte...
(A) Experimental schematic for B–H. Mice were treated with BLM over 21 days, and either whole skin cells or ADSCs from mCherry reporter mice were injected into fibrotic lesions 2 days after BLM cessation. Isotype control or agonist anti-LTβR was given i.p. at the time of cell injection and then twice a week for 14 days before skin analysis (2 doses of 20 μg and then 2 doses of 10 μg). (B) mCherry+ ADSC numbers per 8-mm punch. (C) Host ADSC numbers per punch. (B and C) n = 5–6 mice per condition over 6 experiments. (D) Percentage of host ADSCs that are Ki67+. n = 3 mice per condition over 3 experiments. (E) Representative H&E-stained sections. Scale bars: 100 μm. (F) DWAT and dermal thicknesses. (G) Collagen content normalized to whole skin plus isotype condition. (E–G) n = 4–5 mice per condition over 5 experiments. (H) Relative mRNA expression of indicated genes using NanoString. n = 3 mice per condition over 3 experiments. Asterisks denote statistical significance of differences between the whole skin plus isotype and the ADSC plus anti-LTβR conditions. †Genes that changed with BLM treatment in Figure 4H. Underlined genes change in the direction opposite that seen with BLM treatment. See Supplemental Table 1 for additional analysis. (I) Mice were treated as in A–H before full-thickness wounding, with no further treatment over 14 days before skin analysis. n = 11–12 wounds in 6 mice per condition over 6 experiments. *P < 0.05, **P < 0.01, ***P < 0.001 using 2-tailed unpaired Student’s t test. Error bars depict the SEM.