Tubuloid differentiation to model the human distal nephron and collecting duct in health and disease

Organoid technology is rapidly gaining ground for studies on organ (patho)physiology. Tubuloids are long-term expanding organoids grown from adult kidney tissue or urine. The progenitor state of expanding tubuloids comes at the expense of differentiation. Here, we differentiate tubuloids to model th...

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Published in:	Cell reports (Cambridge) Vol. 43; no. 1; p. 113614
Main Authors:	Yousef Yengej, Fjodor A., Pou Casellas, Carla, Ammerlaan, Carola M.E., Olde Hanhof, Charlotte J.A., Dilmen, Emre, Beumer, Joep, Begthel, Harry, Meeder, Elise M.G., Hoenderop, Joost G., Rookmaaker, Maarten B., Verhaar, Marianne C., Clevers, Hans
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 23-01-2024 Elsevier
Subjects:	CP: Stem cell research kidney organoid lithium loop of Henle nephron principal cells RNA sequencing stem cells tubuloid RNA sequencing nephron stem cells lithium CP: Stem cell research loop of Henle principal cells kidney organoid tubuloid
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Summary:	Organoid technology is rapidly gaining ground for studies on organ (patho)physiology. Tubuloids are long-term expanding organoids grown from adult kidney tissue or urine. The progenitor state of expanding tubuloids comes at the expense of differentiation. Here, we differentiate tubuloids to model the distal nephron and collecting ducts, essential functional parts of the kidney. Differentiation suppresses progenitor traits and upregulates genes required for function. A single-cell atlas reveals that differentiation predominantly generates thick ascending limb and principal cells. Differentiated human tubuloids express luminal NKCC2 and ENaC capable of diuretic-inhibitable electrolyte uptake and enable disease modeling as demonstrated by a lithium-induced tubulopathy model. Lithium causes hallmark AQP2 loss, induces proliferation, and upregulates inflammatory mediators, as seen in vivo. Lithium also suppresses electrolyte transport in multiple segments. In conclusion, this tubuloid model enables modeling of the human distal nephron and collecting duct in health and disease and provides opportunities to develop improved therapies. [Display omitted] •Human tubuloid differentiation introduces distal nephron and collecting duct cells•Differentiated tubuloids demonstrate electrolyte reabsorption, a key renal function•A single-cell atlas shows differentiated tubuloid cells resemble in vivo equivalents•Differentiated tubuloids enable modeling of human lithium tubulopathy in vitro Tubuloid differentiation introduces distal nephron and collecting duct cell types that resemble their counterparts in human in vivo kidney tissue. Differentiated tubuloids demonstrate electrolyte reabsorption, a key renal function, and enable modeling of diseases of the human distal nephron and collecting duct in vitro.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2023.113614