Functional evaluation of the pathological significance of MEFV variants using induced pluripotent stem cell–derived macrophages

Shiba, Takeshi; Tanaka, Takayuki; Ida, Hiroaki; Watanabe, Misa; Nakaseko, Haruna; Osawa, Mitsujiro; Shibata, Hirofumi; Izawa, Kazushi; Yasumi, Takahiro; Kawasaki, Yoshihisa; Saito, Megumu K.; Takita, Junko; Heike, Toshio; Nishikomori, Ryuta

doi:10.1016/j.jaci.2019.07.039

Cited by 22 publications

(28 citation statements)

References 20 publications

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“…We previously demonstrated that such MLs can be used to model the proinflammatory phenotypes of various autoinflammatory disorders [14,[28][29][30]. Combined with the current study, which successfully identified candidate compounds, we concluded that this ML-based HTS system provides a versatile platform for screening candidate compounds for treating autoinflammatory disorders.…”

Section: Discussionsupporting

confidence: 64%

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

Kase

Terashima

Ohta

et al. 2020

Preprint

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Nakajo-Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)-derived NNS disease model that reproduces several inflammatory phenotypes including the overproduction of monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein-10 (IP-10). Here we performed high-throughput compound screening (HTS) using this PSC-derived NNS model to find potential therapeutic candidates and identified CUDC-907 as an effective inhibitor of the release of MCP-1 and IP-10.CUDC-907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post-transcriptional. These findings suggest that HTS with PSC-derived disease models is useful for finding drug candidates for autoinflammatory diseases. Significance statementIn this study, we identified a histone deacetylase inhibitor CUDC-907 as a potential effective compound for ameliorating overproduction of inflammatory chemokines in an autoinflammatory disease named Nakajo-Nishimura syndrome. We performed high-throughput screening using pluripotent stem cell-derived monocytic cell lines. Our data prove the validity of screening system as a versatile platform for seeking candidate compounds for the treatment of congenital immunological disorders associated with monocytic lineage cells.

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Section: Discussionsupporting

confidence: 64%

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

Kase

Terashima

Ohta

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…MLs can be used to model the pro-inflammatory phenotypes of various autoinflammatory disorders. 14,[29][30][31] Combined with the current study, which successfully identified candidate compounds, we concluded that this ML-based HTS system provides a versatile platform for screening candidate compounds for treating autoinflammatory disorders.…”

Section: Discussionsupporting

confidence: 55%

“…We used MLs established from PSCs for the HTS, because MLs are easy to propagate, freeze‐stock, and differentiate into functional macrophages or dendritic cells 15 . We previously demonstrated that such MLs can be used to model the pro‐inflammatory phenotypes of various autoinflammatory disorders 14,29‐31 . Combined with the current study, which successfully identified candidate compounds, we concluded that this ML‐based HTS system provides a versatile platform for screening candidate compounds for treating autoinflammatory disorders.…”

Section: Discussionmentioning

confidence: 55%

Pluripotent stem cell-based screening identifies CUDC-907 as an effective compound for restoring the in vitro phenotype of Nakajo-Nishimura syndrome

Kase

Terashima

Ohta

et al. 2020

Stem Cells Translational Medicine

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Nakajo-Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)-derived NNS disease model that reproduces several inflammatory phenotypes including the overproduction of monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein-10 (IP-10). Here we performed high-throughput compound screening (HTS) using this PSC-derived NNS model to find potential therapeutic candidates and identified CUDC-907 as an effective inhibitor of the release of MCP-1 and IP-10. Short-term treatment of CUDC-907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post-transcriptional. These findings suggest that HTS with PSC-derived disease models is useful for finding drug candidates for autoinflammatory diseases. K E Y W O R D S chemokines, hereditary autoinflammatory diseases, high-throughput screening assays, histone deacetylase inhibitors, LMP7 protein, pluripotent stem cells 1 | INTRODUCTION Proteasome-associated autoinflammatory syndromes (PRAAS) are a recently defined group of autoinflammatory disorders caused by the mutations of proteasome subunits or their assembly factors. 1 PRAAS include diseases such as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), 2 POMP-related auto-inflammation and immune dysregulation disease (PRAID), 3 and

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“…Two main approaches are used to create iMph-based disease models: (i) generating iMphs from patient-derived iPSCs and (ii) introducing disease-associated mutations to iPSCs derived from healthy donors followed by the generation of iPSC-derived iMphs. The first approach has successfully been used to model Gaucher disease, Tangier disease, familial Mediterranean fever, chronic granulomatous disease (CGD), early onset sarcoidosis, Alzheimer disease, Parkinson disease, and others ( Panicker et al, 2012 ; Brault et al, 2014 ; Zhang et al, 2015 ; Aflaki et al, 2016 ; Haenseler et al, 2017 ; Takata et al, 2017 ; Brownjohn et al, 2018 ; Takada et al, 2018 ; Shiba et al, 2019 ; Mukhopadhyay et al, 2020 ). In the second approach, the introduction of p47-ΔGT mutation allowed to model CGD ( Klatt et al, 2019 ), and iMphs bearing genetic KOs of IL-10RA, IL-10RB, STAT1, or STAT3 modeled the very-early onset bowel disease (VEOBD) ( Mukhopadhyay et al, 2020 ; Sens et al, 2020 ).…”

Section: Imph Applications and Prospectsmentioning

confidence: 99%

Macrophages Derived From Human Induced Pluripotent Stem Cells: The Diversity of Protocols, Future Prospects, and Outstanding Questions

Lyadova

Gerasimova

Nenasheva

2021

Front. Cell Dev. Biol.

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Macrophages (Mφ) derived from induced pluripotent stem cells (iMphs) represent a novel and promising model for studying human Mφ function and differentiation and developing new therapeutic strategies based on or oriented at Mφs. iMphs have several advantages over the traditionally used human Mφ models, such as immortalized cell lines and monocyte-derived Mφs. The advantages include the possibility of obtaining genetically identical and editable cells in a potentially scalable way. Various applications of iMphs are being developed, and their number is rapidly growing. However, the protocols of iMph differentiation that are currently used vary substantially, which may lead to differences in iMph differentiation trajectories and properties. Standardization of the protocols and identification of minimum required conditions that would allow obtaining iMphs in a large-scale, inexpensive, and clinically suitable mode are needed for future iMph applications. As a first step in this direction, the current review discusses the fundamental basis for the generation of human iMphs, performs a detailed analysis of the generalities and the differences between iMph differentiation protocols currently employed, and discusses the prospects of iMph applications.

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Functional evaluation of the pathological significance of MEFV variants using induced pluripotent stem cell–derived macrophages

Abstract: O. N. Atkas declares no relevant conflicts of interest.

Cited by 22 publications

References 20 publications

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

Pluripotent stem cell-based screening identifies CUDC-907 as an effective compound for restoring the in vitro phenotype of Nakajo-Nishimura syndrome

Macrophages Derived From Human Induced Pluripotent Stem Cells: The Diversity of Protocols, Future Prospects, and Outstanding Questions

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