Modelling ciliopathy phenotypes in human tissues derived from pluripotent stem cells with genetically ablated cilia.
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Pluripotentes
/
Ciliopatias
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article