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

DOI Web Site 1 Citations
  • Ken Hiratsuka
    Nephrology Division, Massachusetts General Hospital, Boston, MA, USA.
  • Tomoya Miyoshi
    Division of Renal Medicine, Brigham and Women’s Hospital, Boston, MA, USA.
  • Katharina T. Kroll
    John A. Paulson School of Engineering and Applied Sciences and Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
  • Navin R. Gupta
    Nephrology Division, Massachusetts General Hospital, Boston, MA, USA.
  • M. Todd Valerius
    Harvard Medical School, Boston, MA, USA.
  • Thomas Ferrante
    John A. Paulson School of Engineering and Applied Sciences and Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
  • Michifumi Yamashita
    Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Jennifer A. Lewis
    John A. Paulson School of Engineering and Applied Sciences and Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
  • Ryuji Morizane
    Nephrology Division, Massachusetts General Hospital, Boston, MA, USA.

Description

<jats:p> 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. <jats:italic>PKHD1</jats:italic> -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. </jats:p>

Journal

  • Science Advances

    Science Advances 8 (38), eabq0866-, 2022-09-23

    American Association for the Advancement of Science (AAAS)

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