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Modeling cilipoathy phenotypes; Biomanufacturing human tissues | ATLAS-D2K Center


Modeling cilipoathy phenotypes; Biomanufacturing human tissues

May 12, 2022

Check out the latest publications from Benjamin Freedman’s and Jennifer Lewis’ labs:

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. Nature Biomedical Engineering . 6(4):463–475. April 2022.

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 signaling during organoid differentiation, and that they constitutively release extracellular vesicles containing signaling 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.

Biomanufacturing human tissues via organ building blocks

Wolf, Kayla J.; Weiss, Jonathan D.; Uzel, Sebastien G.M.; Skylar-Scott, Mark A.; Lewis, Jennifer A. Cell Stem Cell. 29(5):667–677. May 2022.

The construction of human organs on demand remains a tantalizing vision to solve the organ donor shortage. Yet, engineering tissues that recapitulate the cellular and architectural complexity of native organs is a grand challenge. The use of organ building blocks (OBBs) composed of multicellular spheroids, organoids, and assembloids offers an important pathway for creating organ-specific tissues with the desired cellular-to-tissue-level organization. Here, we review the differentiation, maturation, and 3D assembly of OBBs into functional human tissues and, ultimately, organs for therapeutic repair and replacement. We also highlight future challenges and areas of opportunity for this nascent field.

View the latest RBK publications here: