FK506 binding protein like, FKBPL, as a novel therapeutic target in 2D and 3D bioprinted, models of cardiac fibrosis

Q1 Computer Science
Michael Chhor , Shreya Barman , Fatemeh Heidari , Amy L. Bottomley , Tracy Robson , Kristine McGrath , Lana McClements
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引用次数: 0

Abstract

Background

Cardiac fibrosis characterised by increased collagen deposition and extracellular matrix (ECM) remodeling is one of the main causes of heart failure. Inflammation and hypoxia are key processes leading to cardiac fibrosis although the mechanisms are poorly understood. In this study, we developed an innovative 3D bioprinted model of cardiac fibrosis using tunable matrices. The role of an anti-angiogenic protein, FK506 binding protein like (FKBPL) was then elucidated, for the first time, using both 2D and 3D bioprinted, models of cardiac fibrosis.

Methods

3D bioprinted model of cardiac fibrosis was developed using fetal fibroblast cells (HFF08), customised ECM cardiac components and pro-fibrotic/hypoxic factors (TGF-β, 10 ng/ml, DMOG, 1 mM) ± FKBPL mimetic (AD-01, 100 mM). In parallel, 2D in vitro models were also employed.

Results

In the 3D bioprinted model, fibroblasts formed networks spontaneously, which were stimulated by all treatments (p < 0.05–0.0001). This was in conjunction with a trend towards reduced FKBPL expression, particularly in the presence of DMOG/AD-01 treatment. In 2D cell culture, AD-01 potentiated TGF-β-induced col1a1 (p < 0.0001) and mmp2 mRNA (p < 0.05) expression whereas DMOG or reduced FKBPL expression with AD-01 abrogated this (p < 0.05–0.001). Following siRNA FKBPL transfection, α-SMA was reduced (p < 0.05).

Conclusion

This 3D bioprinted model of cardiac fibrosis in conjunction with 2D cell models could be used for biomarker and drug therapy screening towards accelerating the development of treatments for this hard-to-treat condition. Low FKBPL expression could be protective in cardiac fibrosis through the reduction in collagen production and α-SMA expression, or TGF-β/HIF-1α-mediated effects. Therapeutic strategies that inhibit FKBPL should be explored to abrogate cardiac fibrosis.
FK506结合蛋白样,FKBPL,在2D和3D生物打印心脏纤维化模型中作为新的治疗靶点
以胶原沉积增加和细胞外基质(ECM)重塑为特征的心脏纤维化是心力衰竭的主要原因之一。炎症和缺氧是导致心脏纤维化的关键过程,尽管其机制尚不清楚。在这项研究中,我们开发了一种使用可调基质的创新型3D生物打印心脏纤维化模型。随后,利用2D和3D生物打印的心脏纤维化模型,首次阐明了抗血管生成蛋白FK506结合蛋白样(FKBPL)的作用。方法采用胎儿成纤维细胞(HFF08)、定制ECM心脏成分和促纤维化/缺氧因子(TGF-β, 10 ng/ml, DMOG, 1 mM)±FKBPL模拟物(AD-01, 100 mM)建立生物3d打印心脏纤维化模型。同时,还采用了2D体外模型。结果在生物3D打印模型中,成纤维细胞自发形成网络,所有处理均刺激成纤维细胞形成网络(p <;0.05 - -0.0001)。这与FKBPL表达降低的趋势相结合,特别是在DMOG/AD-01治疗的情况下。在2D细胞培养中,AD-01增强TGF-β诱导的col1a1 (p <;0.0001)和mmp2 mRNA (p <;而DMOG或AD-01降低FKBPL表达则消除了这一点(p <;0.05 - -0.001)。转染siRNA FKBPL后,α-SMA减少(p <;0.05)。结论:该3D生物打印心脏纤维化模型与2D细胞模型相结合,可用于生物标志物和药物治疗筛选,以加速这种难以治疗的疾病的治疗开发。低FKBPL表达可能通过减少胶原生成和α-SMA表达,或TGF-β/ hif -1α介导的作用,对心脏纤维化具有保护作用。应探索抑制FKBPL的治疗策略,以消除心脏纤维化。
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来源期刊
Bioprinting
Bioprinting Computer Science-Computer Science Applications
CiteScore
11.50
自引率
0.00%
发文量
72
审稿时长
68 days
期刊介绍: Bioprinting is a broad-spectrum, multidisciplinary journal that covers all aspects of 3D fabrication technology involving biological tissues, organs and cells for medical and biotechnology applications. Topics covered include nanomaterials, biomaterials, scaffolds, 3D printing technology, imaging and CAD/CAM software and hardware, post-printing bioreactor maturation, cell and biological factor patterning, biofabrication, tissue engineering and other applications of 3D bioprinting technology. Bioprinting publishes research reports describing novel results with high clinical significance in all areas of 3D bioprinting research. Bioprinting issues contain a wide variety of review and analysis articles covering topics relevant to 3D bioprinting ranging from basic biological, material and technical advances to pre-clinical and clinical applications of 3D bioprinting.
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