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Systemic Sclerosis Dermal Fibroblasts Induce Cutaneous Fibrosis Through Lysyl Oxidase–like 4: New Evidence From Three‐Dimensional Skin‐like Tissues
Author(s) -
Huang Mengqi,
Cai Guoshuai,
Baugh Lauren M.,
Liu Zhiyi,
Smith Avi,
Watson Matthew,
Popovich Dillon,
Zhang Tianyue,
Stawski Lukasz S.,
Trojanowska Maria,
Georgakoudi Irene,
Black Lauren D.,
Pioli Patricia A.,
Whitfield Michael L.,
Garlick Jonathan
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41163
Subject(s) - lysyl oxidase , fibroblast , fibrosis , extracellular matrix , fibrillin , dermis , dermal fibroblast , stromal cell , wound healing , transforming growth factor , chemistry , microbiology and biotechnology , biology , immunology , pathology , biochemistry , anatomy , medicine , cancer research , in vitro
Objective Systemic sclerosis ( SS c) is a clinically heterogeneous disease characterized by increased collagen accumulation and skin stiffness. Our previous work has demonstrated that transforming growth factor β ( TGF β) induces extracellular matrix ( ECM ) modifications through lysyl oxidase – like 4 ( LOXL ‐4), a collagen crosslinking enzyme, in bioengineered human skin equivalents ( HSE s) and self‐assembled stromal tissues ( SAS ). We undertook this study to investigate cutaneous fibrosis and the role of LOXL ‐4 in SS c pathogenesis using HSE s and SAS . Methods SS c‐derived dermal fibroblasts ( SS c DF s; n = 8) and normal dermal fibroblasts ( NDF s; n = 6) were incorporated into HSE s and SAS . These 3‐dimensional skin‐like microenvironments were used to study the effects of dysregulated LOXL ‐4 on ECM remodeling, fibroblast activation, and response to TGF β stimulation. Results SS c DF ‐containing SAS showed increased stromal thickness, collagen deposition, and interleukin‐6 secretion compared to NDF ‐containing SAS ( P < 0.05). In HSE , SS c DF s altered collagen as seen by a more mature and aligned fibrillar structure ( P < 0.05). With SS c DF s, enhanced stromal rigidity with increased collagen crosslinking ( P < 0.05), up‐regulation of LOXL4 expression ( P < 0.01), and innate immune signaling genes were observed in both tissue models. Conversely, knockdown of LOXL 4 suppressed rigidity, contraction, and α‐smooth muscle actin expression in SS c DF s in HSE , and TGF β‐induced ECM aggregation and collagen crosslinking in SAS . Conclusion A limitation to the development of effective therapeutics in SS c is the lack of in vitro human model systems that replicate human skin. Our findings demonstrate that SAS and HSE can serve as complementary in vitro skin‐like models for investigation of the mechanisms and mediators that drive fibrosis in SS c and implicate a pivotal role for LOXL ‐4 in SS c pathogenesis.