Project P1

Novel human in vitro model systems for kidney diseases are urgently needed since data from rodent models is often not transferable to humans. Furthermore, in vitro platforms can be scaled-up toward true high-throughput and thus will advance target discovery and validation, as well as drug screening studies. In this project, we will develop novel in vitro model systems having three main goals in mind.

1) The development of a macroscopic model of a perfused human kidney tubule to model adult polycystic kidney disease.

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2) The design of a real resolution kidney system using rod shaped microgels with a scalable diameter of 8-200 µm for Anisogel alignment with the aim to develop a model of kidney fibrosis.

 

3) Our final aim is to move the system towards true high-throughput disease modeling and we will achieve this using automated pipetting and analysis methods, including novel bioprinting techniques.

 

Therefore, we will design synthetic polyethylene glycol (PEG)-based bioinks, consisting of rod-shaped, magneto-responsive microgels, to model the human tubulo-interstitium. We will compare these in vitro platforms with human kidney disease specimen and donor biopsies using scRNA-sequencing with the goal to have a model that reflects human disease.

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Jansen J, Reimer KC, Nagai JS, Varghese FS, Overheul GJ, de Beer M, Roverts R, Daviran D, Fremiin LAS, Willeemsen B, Beukenboom M, Djudja S, von Stillfried S, van Eijk LE, Mastik M, Bulthuis M, den Dunnen W, van Goor H, Hilledbrands JL, Triana Sh, Alexandrov T, Timm MC, van den Berge BT, van den Broek M, Nlandu Q, Heijner J, Bindels MJ, Hoogenboezem RM, Mooren F, Kuppe C, Miesen P, Grünberg K, Ijzermans T, Steenbergen EJ, Czogalla J, Schreuder MF, Sommerdijk N, Akiva A, Boor P, Puelles VG, Floege J, Huber TB. the COVID Moonshot consortium, van Rij RP, Costa IG, Schneider RK, Smeets B, Kramann R. SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids. Cell Stem Cell 2022 29(2):217-231

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Kuppe C, Ibrahim MM, Kranz J, Zhang X, Ziegler S, Perales-Patón J, Jansen J, Reimer KC, Smith JR, Dobie R, Wilson-Kanamari JR, Halder M, Xu Y, Kabgani N, Kaesler N, Klaus M, Gernhold L, Puelles VG, Huber TB, Boor P, Menzel S, Hoogenboezem RM, Bindels EMJ, Steffens J, Floege J, Schneider RK, Saez-Rodriguez J, Henderson NC, Kramann R. Decoding myofibroblast origins in human kidney fibrosis. Nature 2021 589(7841):281-286

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Kramann R#, Schneider RK, DiRocco DP, Machado F, Fleig S, Bondzie FP, Henderson JM, Ebert BL, Humphreys BD. Perivascular Gli1+ Progenitors Are Key Contributors to Injury-Induced Organ Fibrosis. Cell Stem Cell 2015,16(1):51-66 #Corresponding author

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Licht CJ, Rose CJ, Omidinia-Anarkoli A, Blondel D, Roccio M, Haraszti T, Hubbell JA, Lutolf M, De Laporte L. Synthetic 3D PEG-Anisogels tailored with fibronectin fragments induce aligned nerve extension. Biomacromolecules 2019, 20: 4075-87.

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Rommel D, Mork M, Vedaraman S, Bastard C, Guerzoni LPB, Kayku Y, Vinokur R, Born N, Haraszti T, De Laporte L. Functionalized microgel rods crosslinked into soft macroporous structures for 3D cell culture. Advanced Sciences 2022, e2103554.

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