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Cited by 140Genetic and Kidney Cyst Diseases3D Printing in Biomedical ResearchMicrofluidic and Capillary Electrophoresis Applications

Organoid-on-a-chip model of human ARPKD reveals mechanosensing pathomechanisms for drug discovery

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Hiratsuka, Ken, Miyoshi, Tomoya, Kroll, Katharina T., Gupta, Navin R., Valerius, M. Todd, Ferrante, Thomas, Yamashita, Michifumi, Lewis, Jennifer A. +1 more·2022·Science Advances
DOI 10.1126/sciadv.abq0866PMC PMC9491724
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Abstract

Organoids serve as a novel tool for disease modeling in three-dimensional multicellular contexts. Static organoids, however, lack the requisite biophysical microenvironment such as fluid flow, limiting their ability to faithfully recapitulate disease pathology. Here, we unite organoids with organ-on-a-chip technology to unravel disease pathology and develop therapies for autosomal recessive polycystic kidney disease. PKHD1 -mutant organoids-on-a-chip are subjected to flow that induces clinically relevant phenotypes of distal nephron dilatation. Transcriptomics discover 229 signal pathways that are not identified by static models. Mechanosensing molecules, RAC1 and FOS, are identified as potential therapeutic targets and validated by patient kidney samples. On the basis of this insight, we tested two U.S. Food and Drug Administration–approved and one investigational new drugs that target RAC1 and FOS in our organoid-on-a-chip model, which suppressed cyst formation. Our observations highlight the vast potential of organoid-on-a-chip models to elucidate complex disease mechanisms for therapeutic testing and discovery.

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  • The use of siRNA technology in 3D organoid cultures has been very limited.

    “The use of siRNA technology in 3D organoid cultures has been very limited [48,49,50], likely also due to the technical challenge of delivering siRNAs through the extracellular matrix to organoids in situ [49].”

    From Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers (2024) · cites this paper as [48]

    The Results section (“Mechanosensing signals are activated by fluid flow”; page unavailable) reports siRNA knockdown in kidney organoids, so this paper is an example of siRNA use in organoid culture. It does not assess how common that use is across 3D organoid research and therefore does not establish that it has been “very limited.” (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Authors
Hiratsuka, K., Miyoshi, T., Kroll, K. T., Gupta, N. R., Valerius, M. T., Ferrante, T., Yamashita, M., Lewis, J. A., & Morizane, R.
Affiliations
  • Brigham and Women's Hospital (US)
  • Harvard University (US)
  • Cedars-Sinai Medical Center (US)
Corresponding author
  • Hiratsuka, Ken
  • Miyoshi, Tomoya
  • Lewis, Jennifer A.
  • Morizane, Ryuji
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-09-23
Volume
8
Issue
38
Pages
eabq0866-eabq0866
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.abq0866
PMC
PMC9491724
OpenAlex
W4296564551
Cited by
140
References
76
Citations by year
2026: 34 · 2025: 35 · 2024: 38 · 2023: 29 · 2022: 3 · 2012: 1
FWCI
15.84
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (UH3TR002155)
  • National Institute of Diabetes and Digestive and Kidney Diseases (UC2DK126023, DP2DK133821, U01DK127587, R21DK129909)
  • National Institute of Biomedical Imaging and Bioengineering (U01EB028899)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Physical Sciences › Engineering › Biomedical Engineering › Microfluidic and Capillary Electrophoresis Applications
Keywords
autosomal recessive polycystic kidney disease, PKHD1, mechanosensing, fluid flow, Rac1, FOS, drug target identification, drug screening, kidney cyst formation, disease modeling
MeSH terms
Humans, Organoids, Drugs, Investigational, Polycystic Kidney, Autosomal Recessive, Drug Discovery, Lab-On-A-Chip Devices

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