Tubuloid differentiation to model the human distal nephron and collecting duct in health and disease
Fjodor A. Yousef Yengej,
Carla Pou Casellas,
Carola M.E. Ammerlaan,
Charlotte J.A. Olde Hanhof,
Emre Dilmen,
Joep Beumer,
Harry Begthel,
Elise M.G. Meeder,
Joost G. Hoenderop,
Maarten B. Rookmaaker,
Marianne C. Verhaar,
Hans Clevers
Affiliations
Fjodor A. Yousef Yengej
Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW & University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
Carla Pou Casellas
Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW & University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
Carola M.E. Ammerlaan
Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW & University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
Charlotte J.A. Olde Hanhof
Department of Medical BioSciences, Radboud Institute for Medical Innovation, 6525 GA Nijmegen, the Netherlands
Emre Dilmen
Department of Medical BioSciences, Radboud Institute for Medical Innovation, 6525 GA Nijmegen, the Netherlands
Joep Beumer
Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW, 3584 CT Utrecht, the Netherlands; Institute of Human Biology, Roche Pharma Research and Early Development, 4058 Basel, Switzerland
Harry Begthel
Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW, 3584 CT Utrecht, the Netherlands
Elise M.G. Meeder
Department of Psychiatry, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
Joost G. Hoenderop
Department of Medical BioSciences, Radboud Institute for Medical Innovation, 6525 GA Nijmegen, the Netherlands
Maarten B. Rookmaaker
Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
Marianne C. Verhaar
Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Corresponding author
Hans Clevers
Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW & University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Oncode Institute, Hubrecht Institute-KNAW, 3584 CT Utrecht, the Netherlands; Corresponding author
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.
