Biomimetic Topological Micropattern Arrays Regulate the Heterogeneity of Cellular Fates in Lung Fibroblasts between Fibrosis and Invasion

被引：0

作者：

Zhu, Xinglong ^{[1
,2
]}

Mao, Shengqiang ^{[1
]}

Yang, Ying ^{[1
]}

Liu, Xinmei ^{[2
]}

Liu, Qin ^{[3
]}

Zhang, Ning ^{[4
]}

Yang, Yongfeng ^{[1
]}

Li, Yanan ^{[4
]}

Gao, Mengyu ^{[2
]}

Bao, Ji ^{[2
]}

Li, Weimin ^{[1
]}

Li, Yi ^{[1
]}

机构：

[1] Sichuan Univ, West China Hosp, Inst Resp Hlth, Frontiers Sci Ctr Dis Related Mol Network,Dept Res, Chengdu 610041, Sichuan, Peoples R China

[2] Sichuan Univ, West China Hosp, Inst Clin Pathol, Key Lab Transplant Engn & Immunol,Dept Pathol, Chengdu 610041, Sichuan, Peoples R China

[3] Sichuan Univ, West China Hosp, Core Facil, Chengdu 610041, Sichuan, Peoples R China

[4] Sichuan Univ, West China Hosp, Dept Pediat Surg, Div Oncol, Chengdu 610041, Sichuan, Peoples R China

来源：

ACS NANO | 2025年 / 19卷 / 01期

基金：

中国国家自然科学基金;

关键词：

topology; cellular isotropy; fibroblast tomyofibroblast transition; pulmonary fibrosis; invasion; drug screening; GROWTH-FACTOR; EXPRESSION; PD-L1; ANISOTROPY; MIGRATION; CELLS; BETA;

D O I：

10.1021/acsnano.4c11113

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Idiopathic pulmonary fibrosis (IPF) is characterized by persistent tissue injury, dysregulated wound healing, and extracellular matrix (ECM) deposition by myofibroblasts (MFs) through the fibroblast-to-myofibroblast transition (FMT). Implicit in the FMT process are changes in the ECM and cellular topology, but their relationship with the lung fibroblast phenotype has not been explored. We engineered topological mimetics of alignment cues (anisotropy/isotropy) using lung decellularized ECM micropattern arrays and investigated the effects of cellular topology on cellular fates in MRC-5 lung fibroblasts. We found that isotropic MRC-5 cells presented changes of the cytoskeleton, increased cell-cell adhesions and a multicellular architecture with increased overlap, changes in actin-myosin development, and enhanced focal adhesion and cell junction with random alignment. Besides, anisotropic fibroblasts were activated into a regular phenotype with an ECM remodeling profile. In contrast, isotropic fibroblasts developed a highly invasive phenotype expressing molecules, including CD274/programmed death-ligand 1 (PD-L1), cellular communication network factor 2 (CCN2)/connective tissue growth factor (CTGF), hyaluronan synthase 2 (HAS2), and semaphorin 7A (SEMA7A), but with downregulated matrix genes. Moreover, isotropic fibroblasts also showed higher expressions of Ki-67 and cyclin D1 (CCND1), resistance to apoptosis/senescence, and decreased autophagy. The topology regulated the cellular heterogeneity and resulted in positive feedback between changes in the cellular phenotype and the ECM structure, which may aggravate fibrosis and lead to a priming of malignant microenvironment during carcinogenesis. Using the versatile platform of micropattern array, we can not only visualize the interaction mechanism between cells and the ECM but also select potential clinical targets for diagnosis and therapeutics.

引用

页码：580 / 599

页数：20