Periostin promotes liver fibrogenesis by activating lysyl oxidase in hepatic stellate cells

Kumar, Pradeep; Smith, T. Lynn; Raeman, Reben; Chopyk, Daniel M.; Brink, Hannah; Liu, Yuying; Sulchek, Todd; Anania, Frank A.

doi:10.1074/jbc.ra117.001601

Cited by 59 publications

(51 citation statements)

References 56 publications

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“…To this aim, we first generated inert poly(ethylene glycol) (PEG) hydrogels enzymatically crosslinked by the activated transglutaminase factor XIIIa (FXIIIa) 14 . To mimic the mechanical properties of the mouse liver, we tuned the stiffness of PEG gels to physiological values (»1.3 kPa) 15,16 . Key ECM proteins found in the native liver 17 , such as laminin-111, collagen IV and fibronectin, were then incorporated in the PEG network, and soluble factors found in the hepatic niche, such as hepatocyte growth factor (HGF) 18 , the Wnt agonist R-Spondin 2,19 and fibroblast growth factor 10 (FGF10) 20 , were added to the culture medium, referred to as expansion medium (EM) 2 .…”

Section: Resultsmentioning

confidence: 99%

“…Despite the recent progress in establishing novel 3D liver model systems 2,3,5 , relatively little is known about the role of mechanics in regulating hepatic stem cell biology. To test whether matrix mechanics affect liver organoid growth, we grew organoids in hydrogel of variable stiffness, ranging from values below the normal mouse liver stiffness (0.3 kPa) to those reaching physiological stiffness (1.3 kPa) 15,16 . Organoid formation efficiency was profoundly affected by the mechanical properties of the matrix, with values mimicking physiological liver stiffness (between 1.3 and 1.7 kPa) being optimal (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…We reasoned that liver organoids grown in defined hydrogels recapitulating the stiffness of fibrotic liver could serve as physiologically relevant 3D model to investigate how stem cells translate aberrant mechanical inputs into disease-relevant phenotypes. To this aim, we generated fibrosis-mimicking hydrogels with a stiffness of 4 kPa 15,16 . Strikingly, these hydrogels led to a significant impairment of organoid formation (Figs.…”

Section: Resultsmentioning

confidence: 99%

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Mechano-modulatory synthetic niches for liver organoid derivation

Sorrentino

Rezakhani

Yildiz

et al. 2019

Preprint

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The recent demonstration that primary cells from the liver can be expanded in vitro as organoids holds enormous promise for regenerative medicine and disease modeling 1-5 . The use of threedimensional (3D) cultures based on ill-defined and potentially immunogenic matrices, however, hampers the translation of liver organoid technology into real-life applications 6 . We here used chemically defined hydrogels for the efficient derivation of both mouse and human hepatic organoids.Organoid growth was found to be highly stiffness-sensitive and dependent on yes-associated protein 1 (YAP) activity. However, in contrast to intestinal organoids 7 , YAP-mediated stiffness sensitivity was independent of acto-myosin contractility, requiring instead activation of the Src family of kinases (SFKs). Aberrant matrix stiffness on the other hand led to a shift in the progenitor phenotype, resulting in compromised proliferative capacity. Finally, we demonstrate the unprecedented establishment of biopsy-derived human liver organoids without the use of animal components at any step of the process. Our approach thus opens up exciting perspectives for the establishment of protocols for liver organoid-based regenerative medicine.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Mechano-modulatory synthetic niches for liver organoid derivation

Sorrentino

Rezakhani

Yildiz

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Moreover, inflammation has also been suggested in migratory failure and subsequent deposition of aberrant proteinaceous materials in affected tissues in conjunction with other molecular actors. 71,[103][104][105][106][107][108] Finally, our comorbidity analysis in the BioVU EHR indicated XFS association with several chronic inflammatory dermatological, musculo-skeletal, respiratory and infectious conditions. Moreover, extracellular matrix dysregulation is also suggested by our PheWAS results indicating XFS comorbidity with Vitamin D deficiency.…”

Section: Discussionmentioning

confidence: 95%

“…50,51 LOXL1 has also been implicated in fibrosis in response to inflammation in human breast cancer, 52 in liver and lungs in model animals. [53][54][55] UBL7 encodes a member of the ubiquitin protein family, that is crucial in immune response and regulation of inflammatory response. [56][57][58] Genes that show significant association of predicted expression with XFS at nominal significance are enriched for genes associated with three inflammatory conditions: rheumatoid arthritis, Type 1 diabetes and vitiligo in the Jensen Diseases database, with genes associated with the former two conditions enriched even with HLA region excluded.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Genetically Determined Gene Expression Suggests Role of Inflammatory Processes in Etiology of Exfoliation Syndrome

Hirbo

Pasutto

Gamazon

et al. 2020

Preprint

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Exfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of abnormal extracellular material, with pathognomonic ocular manifestations. It is the most common cause of secondary glaucoma, resulting in widespread global blindness. We performed Transcriptomic Wide Association Studies using PrediXcan models trained in 48 GTEx tissues to identify genetically-determined gene expression changes associated with XFS risk, leveraging on results from a global GWAS that included 123,457 individuals from 24 countries. Twenty-eight genes in the chr15q22-25 region showed statistically significant associations in both single-tissue and multi-tissue analysis. Reduced models for these genes that excluded variants in LD with the known LOXL1 signal showed genome-wide significant association signals in nine genes, independently of LOXL1. Out of these ten genes, mRNA transcript levels for ARID3B, CD276, LOXL1, NEO1, SCAMP2, and UBL7 were significantly decreased in iris tissues from XFS patients compared to control samples. Genes with genetically determined expression changes in XFS were significantly enriched for genes associated with inflammatory conditions. We further explored the health consequences of high susceptibility to XFS using a large electronic health record and observed a higher incidence of XFS comorbidity with inflammatory and connective tissue diseases. Our results implicate a role for connective tissues and inflammation in the etiology of XFS. Targeting the inflammatory pathway may be a potential therapeutic option to reduce progression in XFS.

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Upgrading a Consumer Stereolithographic 3D Printer to Produce a Physiologically Relevant Model with Human Liver Cancer Organoids

Breideband

Wächtershäuser

Hafa

et al. 2022

Adv Materials Technologies

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A widespread application of 3D bioprinting in basic and translational research requires accessibility to affordable printers able to produce physiologically relevant tissue models. To facilitate the use of bioprinting as a standard technique in biology, an open‐source device based on a consumer‐grade 3D stereolithography apparatus (SLA) printer is developed. This SLA bioprinter can produce complex constructs that preserve cell viability and recapitulate the physiology of tissues. The detailed documentation of the modifications apported to the printer as well as a throughout performance analysis allow for a straightforward adoption of the device in other labs and its customization for specific applications. Given the low cost, several modified bioprinters could be simultaneously operated for a parallelized tissue production. To showcase the capability of the bioprinter, constructs consisting of patient‐derived cholangiocarcinoma organoids encapsulated in a gelatin methacrylate (GelMA)/polyethylene glycol diacrylate (PEGDA) hydrogel are produced. A thorough characterization of different GelMA/PEGDA ratios reveals that the mechanical properties of the bioprinted tumor model can be accurately fine‐tuned to mimic a specific tumor micro‐environment. Immunofluorescence and gene expression analyses of tumor markers confirm that the bioprinted synthetic hydrogel provides a flexible and adequate replacement of animal‐derived reconstituted extracellular matrix.

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Periostin promotes liver fibrogenesis by activating lysyl oxidase in hepatic stellate cells

Cited by 59 publications

References 56 publications

Mechano-modulatory synthetic niches for liver organoid derivation

Mechano-modulatory synthetic niches for liver organoid derivation

Analysis of Genetically Determined Gene Expression Suggests Role of Inflammatory Processes in Etiology of Exfoliation Syndrome

Upgrading a Consumer Stereolithographic 3D Printer to Produce a Physiologically Relevant Model with Human Liver Cancer Organoids

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