Digital pathology with artificial intelligence analysis provides insight to the efficacy of anti-fibrotic compounds in human 3D MASH model

被引：2

作者：

Kostadinova, Radina ^{[2
]}

Stroebel, Simon ^{[2
]}

Chen, Li ^{[1
]}

Fiaschetti-Egli, Katia ^{[2
]}

Gadient, Jana ^{[2
]}

Pawlowska, Agnieszka ^{[2
]}

Petitjean, Louis ^{[1
]}

Bieri, Manuela ^{[2
]}

Thoma, Eva ^{[2
]}

Petitjean, Mathieu ^{[1
]}

机构：

[1] PharmaNest, Princeton, NJ USA

[2] InSphero AG, Wagistr 27A, Schlieren, Switzerland

来源：

SCIENTIFIC REPORTS | 2024年 / 14卷 / 01期

关键词：

HEPATIC STELLATE CELLS; NONALCOHOLIC STEATOHEPATITIS; MATRIX METALLOPROTEINASES; COLLAGEN; TRANSDIFFERENTIATION; FIBROSIS; NASH; PATHOGENESIS; EXPRESSION;

D O I：

10.1038/s41598-024-55438-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe liver disease characterized by lipid accumulation, inflammation and fibrosis. The development of MASH therapies has been hindered by the lack of human translational models and limitations of analysis techniques for fibrosis. The MASH three-dimensional (3D) InSight (TM) human liver microtissue (hLiMT) model recapitulates pathophysiological features of the disease. We established an algorithm for automated phenotypic quantification of fibrosis of Sirius Red stained histology sections of MASH hLiMTs model using a digital pathology quantitative single-fiber artificial intelligence (AI) FibroNest (TM) image analysis platform. The FibroNest (TM) algorithm for MASH hLiMTs was validated using anti-fibrotic reference compounds with different therapeutic modalities-ALK5i and anti-TGF-beta antibody. The phenotypic quantification of fibrosis demonstrated that both reference compounds decreased the deposition of fibrillated collagens in alignment with effects on the secretion of pro-collagen type I/III, tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-3 and pro-fibrotic gene expression. In contrast, clinical compounds, Firsocostat and Selonsertib, alone and in combination showed strong anti-fibrotic effects on the deposition of collagen fibers, however less pronounced on the secretion of pro-fibrotic biomarkers. In summary, the phenotypic quantification of fibrosis of MASH hLiMTs combined with secretion of pro-fibrotic biomarkers and transcriptomics represents a promising drug discovery tool for assessing anti-fibrotic compounds.

引用

页数：20