Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

Tsuchiya, Haruka; M, Ota; Sumitomo, Shuji; Ishigaki, Kazuyoshi; Suzuki, Akari; Sakata, Toyonori; Tsuchida, Yoshiaki; Inui, Hiroshi; Hirose, Jun; Kochi, Yuta; Kadono, Yuho; Shirahige, Katsuhiko; Tanaka, Sakae; Yamamoto, Kazuhiko; Fujio, Keishi

doi:10.1101/861781

Cited by 5 publications

(4 citation statements)

References 52 publications

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“…In some reports, transcriptomic data proved useful for patient stratification. In RA, synovial fibroblasts (SFs) play important roles in joint inflammation [ 28 ] and show a dynamic response to inflammation at the epigenomic and transcriptomic levels [ 29 ]. Lewis et al .…”

Section: Introductionmentioning

confidence: 99%

Multi-omics approach to precision medicine for immune-mediated diseases

Fujio

2021

Inflamm Regener

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Recent innovation in high-throughput sequencing technologies has drastically empowered the scientific research. Consequently, now, it is possible to capture comprehensive profiles of samples at multiple levels including genome, epigenome, and transcriptome at a time. Applying these kinds of rich information to clinical settings is of great social significance. For some traits such as cardiovascular diseases, attempts to apply omics datasets in clinical practice for the prediction of the disease risk have already shown promising results, although still under way for immune-mediated diseases. Multiple studies have tried to predict treatment response in immune-mediated diseases using genomic, transcriptomic, or clinical information, showing various possible indicators. For better prediction of treatment response or disease outcome in immune-mediated diseases, combining multi-layer information together may increase the power. In addition, in order to efficiently pick up meaningful information from the massive data, high-quality annotation of genomic functions is also crucial. In this review, we discuss the achievement so far and the future direction of multi-omics approach to immune-mediated diseases.

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Section: Introductionmentioning

confidence: 99%

Multi-omics approach to precision medicine for immune-mediated diseases

Fujio

2021

Inflamm Regener

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“…Moreover, they also expressed several proteinases such as ADAMTSs and MMPs [66]. Tsuchiya et al showed that the responses of OA-SFs to the stimulation of in ammatory cytokines were shared in RA-SFs, indicating the common potential for proin ammation in expanded cells derived from OA, RA [67], and probably healthy synovium. Furthermore, other groups demonstrated that hSSCs either from healthy subjects or OA patients could induce osteoclastogenesis from PBMCs in vitro [68].…”

Section: Discussionmentioning

confidence: 99%

In vivo cartilage-formation potency of somatic stem cells is associated with responsiveness to TGFβ stimulation in vitro

Chijimatsu¹,

Miwa²,

Okamura³

et al. 2021

Preprint

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Background: Somatic stem cell transplantation has been performed for cartilage injury, but the reparative mechanisms are still conflicting. The chondrogenic potential of stem cells are thought as promising features for cartilage therapy, however the correlation between their potential for chondrogenesis in vitro and in vivo remains undefined. The purpose of this study was to investigate the intrinsic chondrogenic condition depends on cell types and explore an indicator to select useful stem cells for cartilage regeneration.Methods: The chondrogenic potential of two different stem cell types derived from adipose tissue (ASCs) and synovium (SSCs) of mice and humans was assessed using bone morphogenic protein-2 (BMP2) and transforming growth factor-β1 (TGFβ1). Their reparative potential was also validated through transplantation into a mouse osteochondral defect model.Results: All cell types showed apparent chondrogenesis under the combination of BMP2 and TGFβ1 in vitro, as assessed by the formation of proteoglycan- and type 2 collagen (COL2)-rich tissues. However, our results vastly differed with those observed following single stimulation among species and cell types; apparent chondrogenesis of mouse ASCs, mouse SSCs, and human SSCs was observed with supplementation of BMP2, either BMP2 and TGFβ1, and BMP2, respectively. Human ASCs showed no chondrogenesis following single stimulation. Among human SSCs, two of six donors formed partially COL2-positive tissues in response to TGFβ1. However, unlike mouse cells, human cells showed fibrous components (COL1/3) with all treatments. Mouse SSCs formed hyaline-like cartilage (proteoglycan+/COL2+/COL1-/COL3-) in the transplanted site in vivo, but other cell types mainly formed COL1/3-positive fibrous tissues. Remarkably, only donors that showed chondrogenic response to TGFβ1 in vitro formed partially COL2-positive tissues in vivo. However, the area was mainly composed of COL1/3, indicating fibrous cartilage-like tissues.Conclusion: The chondrogenic response to TGFβ1 may represent the fate of stem cells when locally transplanted into cartilage defects.

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“…In this sense, a complex multidimensional study in RA fibroblast-like synoviocytes (FLS), an aggressive phenotype of fibroblasts in RA, was performed with the objective of establishing a high-resolution epigenomic landscape in RA. This study included histone modifications, open chromatin, RNA expression and DNA methylation analysis in RA FLS [ 68 ]. The effect of variants on histone regions is relevant, as seen in SLE.…”

Section: Epigenomics Studiesmentioning

confidence: 99%

Approaching Shared Pathophysiology in Immune-Mediated Diseases through Functional Genomics

González‐Serna

Martín

Acosta‐Herrera

et al. 2020

Genes

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Immune-mediated diseases (IMDs) are complex pathologies that are strongly influenced by environmental and genetic factors. Associations between genetic loci and susceptibility to these diseases have been widely studied, and hundreds of risk variants have emerged during the last two decades, with researchers observing a shared genetic pattern among them. Nevertheless, the pathological mechanism behind these associations remains a challenge that has just started to be understood thanks to functional genomic approaches. Transcriptomics, regulatory elements, chromatin interactome, as well as the experimental characterization of genomic findings, constitute key elements in the emerging understandings of how genetics affects the etiopathogenesis of IMDs. In this review, we will focus on the latest advances in the field of functional genomics, centering our attention on systemic rheumatic IMDs.

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Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

Cited by 5 publications

References 52 publications

Multi-omics approach to precision medicine for immune-mediated diseases

Multi-omics approach to precision medicine for immune-mediated diseases

In vivo cartilage-formation potency of somatic stem cells is associated with responsiveness to TGFβ stimulation in vitro

Approaching Shared Pathophysiology in Immune-Mediated Diseases through Functional Genomics

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