Universität zu Köln

Ziegler, Wolfgang H. ORCID: 0000-0003-4529-1916, Luediger, Sarah, Hassan, Fatima, Georgiadis, Margarita E., Swolana, Kathrin, Khera, Amrit, Mertens, Arne, Franke, Doris, Wohlgemuth, Kai, Dahmer-Heath, Mareike ORCID: 0000-0002-1667-7820, Koenig, Jens, Dafinger, Claudia, Liebau, Max C., Cetiner, Metin, Bergmann, Carsten, Soetje, Birga ORCID: 0000-0002-6724-1314 and Haffner, Dieter (2022). Primary URECs: a source to better understand the pathology of renal tubular epithelia in pediatric hereditary cystic kidney diseases. Orphanet J. Rare Dis., 17 (1). LONDON: BMC. ISSN 1750-1172

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Abstract

Background In pediatric hereditary cystic kidney diseases, epithelial cell defects mostly result from rare, autosomal recessively inherited pathogenic variants in genes encoding proteins of the cilia-centrosome complex. Consequences of individual gene variants on epithelial function are often difficult to predict and can furthermore depend on the patient's genetic background. Here, we studied urine-derived renal tubular epithelial cells (URECs) from genetically determined, pediatric cohorts of different hereditary cystic kidney diseases, comprising autosomal recessive polycystic kidney disease, nephronophthisis (NPH) and the Bardet Biedl syndrome (BBS). UREC characteristics and behavior in epithelial function-related 3D cell culture were compared in order to identify gene and variant-specific properties and to determine aspects of epithelial (cell) dysfunction. Results UREC preparations from patients (19) and healthy controls (39) were studied in a qualitative and quantitative manner using primary cells cultured for up-to 21 days. In patients with biallelic pathogenic variants in PKHD1 or NPHP genes, we were able to receive satisfactory amounts of URECs of reproducible quality. In BBS patients, UREC yield was lower and more dependent on the individual genotype. In contrast, in UREC preparations derived from healthy controls, no predictable and satisfactory outcome could be established. Considering cell proliferation, tubular origin and epithelial properties in 2D/3D culture conditions, we observed distinct and reproducible epithelial properties of URECs. In particular, the cells from patients carrying PKHD1 variants were characterized by a high incidence of defective morphogenesis of monolayered spheroids-a property proposed to be suitable for corrective intervention. Furthermore, we explored different ways to generate reference cell lines for both-patients and healthy controls-in order to eliminate restrictions in cell number and availability of primary URECs. Conclusions Ex vivo 3D cell culture of primary URECs represents a valuable, non-invasive source to evaluate epithelial cell function in kidney diseases and as such helps to elucidate the functional consequences of rare genetic disorders. In combination with genetically defined control cell lines to be generated in the future, the cultivation of primary URECs could become a relevant tool for testing personalized treatment of epithelial dysfunction in patients with hereditary cystic kidney disease.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ziegler, Wolfgang H. UNSPECIFIED orcid.org/0000-0003-4529-1916 UNSPECIFIED Luediger, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Hassan, Fatima UNSPECIFIED UNSPECIFIED UNSPECIFIED Georgiadis, Margarita E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Swolana, Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Khera, Amrit UNSPECIFIED UNSPECIFIED UNSPECIFIED Mertens, Arne UNSPECIFIED UNSPECIFIED UNSPECIFIED Franke, Doris UNSPECIFIED UNSPECIFIED UNSPECIFIED Wohlgemuth, Kai UNSPECIFIED UNSPECIFIED UNSPECIFIED Dahmer-Heath, Mareike UNSPECIFIED orcid.org/0000-0002-1667-7820 UNSPECIFIED Koenig, Jens UNSPECIFIED UNSPECIFIED UNSPECIFIED Dafinger, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Liebau, Max C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cetiner, Metin UNSPECIFIED UNSPECIFIED UNSPECIFIED Bergmann, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Soetje, Birga UNSPECIFIED orcid.org/0000-0002-6724-1314 UNSPECIFIED Haffner, Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-687892
DOI:	10.1186/s13023-022-02265-1
Journal or Publication Title:	Orphanet J. Rare Dis.
Volume:	17
Number:	1
Date:	2022
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1750-1172
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CELLS; CYSTOGENESIS; MECHANISMS; EXPANSION; DEFECTS; REVEALS; ARPKD Multiple languages Genetics & Heredity; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68789