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 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. [ABSTRACT FROM AUTHOR]