title: 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.forename: Jennifer J
authors.initials: JJ
authors.lastname: Chia
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Susan
authors.initials: S
authors.lastname: Chyou
authors.forename: Dragos C
authors.initials: DC
authors.lastname: Dasoveanu
authors.forename: Camila
authors.initials: C
authors.lastname: Carballo
authors.forename: Sha
authors.initials: S
authors.lastname: Tian
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Magro
authors.forename: Scott
authors.initials: S
authors.lastname: Rodeo
authors.forename: Robert F
authors.initials: RF
authors.lastname: Spiera
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Ruddle
authors.forename: Timothy E
authors.initials: TE
authors.lastname: McGraw
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Browning
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Gordon
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Lu
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology; D020405:Dermis / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D053308:Lymphotoxin-beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D045743:Scleroderma, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D050151:Subcutaneous Fat / Q000378:metabolism* / Q000473:pathology
chemical_list: D019012:Integrin beta1; C505887:Ltb protein, mouse; D053308:Lymphotoxin-beta