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Modelling ciliopathy phenotypes in human tissues derived from pluripotent stem cells with genetically ablated cilia.
Cruz, Nelly M; Reddy, Raghava; McFaline-Figueroa, José L; Tran, Christine; Fu, Hongxia; Freedman, Benjamin S.
Afiliação
  • Cruz NM; Division of Nephrology, University of Washington School of Medicine, Seattle, WA, USA.
  • Reddy R; Kidney Research Institute, Seattle, WA, USA.
  • McFaline-Figueroa JL; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA.
  • Tran C; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
  • Fu H; Division of Nephrology, University of Washington School of Medicine, Seattle, WA, USA.
  • Freedman BS; Kidney Research Institute, Seattle, WA, USA.
Nat Biomed Eng ; 6(4): 463-475, 2022 04.
Article em En | MEDLINE | ID: mdl-35478224
ABSTRACT
The functions of cilia-antenna-like organelles associated with a spectrum of disease states-are poorly understood, particularly in human cells. Here we show that human pluripotent stem cells (hPSCs) edited via CRISPR to knock out the kinesin-2 subunits KIF3A or KIF3B can be used to model ciliopathy phenotypes and to reveal ciliary functions at the tissue scale. KIF3A-/- and KIF3B-/- hPSCs lacked cilia, yet remained robustly self-renewing and pluripotent. Tissues and organoids derived from these hPSCs displayed phenotypes that recapitulated defective neurogenesis and nephrogenesis, polycystic kidney disease (PKD) and other features of the ciliopathy spectrum. We also show that human cilia mediate a critical switch in hedgehog signalling during organoid differentiation, and that they constitutively release extracellular vesicles containing signalling molecules associated with ciliopathy phenotypes. The capacity of KIF3A-/- and KIF3B-/- hPSCs to reveal endogenous mechanisms underlying complex ciliary phenotypes may facilitate the discovery of candidate therapeutics.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco Pluripotentes / Ciliopatias Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco Pluripotentes / Ciliopatias Idioma: En Ano de publicação: 2022 Tipo de documento: Article