Fibroblast senescence-associated extracellular matrix promotes heterogeneous lung niche.

IF 6.6 3区 医学 Q1 ENGINEERING, BIOMEDICAL APL Bioengineering Pub Date : 2024-06-05 eCollection Date: 2024-06-01 DOI:10.1063/5.0204393
Andrew M Howes, Nova C Dea, Deepraj Ghosh, Krishangi Krishna, Yihong Wang, Yanxi Li, Braxton Morrison, Kimani C Toussaint, Michelle R Dawson
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Abstract

Senescent cell accumulation in the pulmonary niche is associated with heightened susceptibility to age-related disease, tissue alterations, and ultimately a decline in lung function. Our current knowledge of senescent cell-extracellular matrix (ECM) dynamics is limited, and our understanding of how senescent cells influence spatial ECM architecture changes over time is incomplete. Herein is the design of an in vitro model of senescence-associated extracellular matrix (SA-ECM) remodeling using a senescent lung fibroblast-derived matrix that captures the spatiotemporal dynamics of an evolving senescent ECM architecture. Multiphoton second-harmonic generation microscopy was utilized to examine the spatial and temporal dynamics of fibroblast SA-ECM remodeling, which revealed a biphasic process that established a disordered and heterogeneous architecture. Additionally, we observed that inhibition of transforming growth factor-β signaling during SA-ECM remodeling led to improved local collagen fiber organization. Finally, we examined patient samples diagnosed with pulmonary fibrosis to further tie our results of the in vitro model to clinical outcomes. Moreover, we observed that the senescence marker p16 is correlated with local collagen fiber disorder. By elucidating the temporal dynamics of SA-ECM remodeling, we provide further insight on the role of senescent cells and their contributions to pathological ECM remodeling.

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成纤维细胞衰老相关细胞外基质促进了异质性肺龛。
肺部生态位中衰老细胞的积累与对老年相关疾病的易感性增加、组织改变以及最终的肺功能下降有关。我们目前对衰老细胞-细胞外基质(ECM)动态的了解有限,对衰老细胞如何随着时间的推移影响空间 ECM 结构变化的了解也不全面。本文利用衰老肺成纤维细胞衍生基质设计了一个衰老相关细胞外基质(SA-ECM)重塑的体外模型,该模型捕捉到了不断演变的衰老 ECM 结构的时空动态。我们利用多光子二次谐波发生显微镜研究了成纤维细胞 SA-ECM 重塑的空间和时间动态,发现了一个建立无序和异质结构的双相过程。此外,我们还观察到,在 SA-ECM 重塑过程中抑制转化生长因子-β 信号传导可改善局部胶原纤维组织。最后,我们研究了确诊为肺纤维化的患者样本,进一步将体外模型的结果与临床结果联系起来。此外,我们还观察到衰老标志物 p16 与局部胶原纤维紊乱有关。通过阐明 SA-ECM 重塑的时间动态,我们进一步了解了衰老细胞的作用及其对病理 ECM 重塑的贡献。
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来源期刊
APL Bioengineering
APL Bioengineering ENGINEERING, BIOMEDICAL-
CiteScore
9.30
自引率
6.70%
发文量
39
审稿时长
19 weeks
期刊介绍: APL Bioengineering is devoted to research at the intersection of biology, physics, and engineering. The journal publishes high-impact manuscripts specific to the understanding and advancement of physics and engineering of biological systems. APL Bioengineering is the new home for the bioengineering and biomedical research communities. APL Bioengineering publishes original research articles, reviews, and perspectives. Topical coverage includes: -Biofabrication and Bioprinting -Biomedical Materials, Sensors, and Imaging -Engineered Living Systems -Cell and Tissue Engineering -Regenerative Medicine -Molecular, Cell, and Tissue Biomechanics -Systems Biology and Computational Biology
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