Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease
| Autor: | York Pei, Laura S. Finn, Jonathan Himmelfarb, Ramila E. Gulieva, Nelly M. Cruz, Benjamin S. Freedman, Angela J. Churchill, Yong Kyun Kim, Hongxia Fu, Linh M. Tran, Xuewen Song, Marco A. Diaz, Kosuke Winston, Stefan Czerniecki |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pluripotent Stem Cells TRPP Cation Channels Biology Models Biological Article Cell Line 03 medical and health sciences chemistry.chemical_compound Stroma Genetic model Cyclic AMP medicine Polycystic kidney disease Organoid Humans General Materials Science Cyclic adenosine monophosphate Induced pluripotent stem cell Regulation of gene expression Kidney Polycystic Kidney Diseases Mechanical Engineering General Chemistry Condensed Matter Physics medicine.disease musculoskeletal system Cell biology Organoids 030104 developmental biology medicine.anatomical_structure Cellular Microenvironment Gene Expression Regulation chemistry Mechanics of Materials cardiovascular system |
| Zdroj: | Nature materials |
| ISSN: | 1476-1122 |
| Popis: | Tissue mimics are of great interest in understanding diseases. Here, organoids were developed that resemble polycystic kidney disease cysts and it was demonstrated how material environment and adhesion can affect cystogenesis and disease progression. Polycystic kidney disease (PKD) is a life-threatening disorder, commonly caused by defects in polycystin-1 (PC1) or polycystin-2 (PC2), in which tubular epithelia form fluid-filled cysts1,2. A major barrier to understanding PKD is the absence of human cellular models that accurately and efficiently recapitulate cystogenesis3,4. Previously, we have generated a genetic model of PKD using human pluripotent stem cells and derived kidney organoids5,6. Here we show that systematic substitution of physical components can dramatically increase or decrease cyst formation, unveiling a critical role for microenvironment in PKD. Removal of adherent cues increases cystogenesis 10-fold, producing cysts phenotypically resembling PKD that expand massively to 1-centimetre diameters. Removal of stroma enables outgrowth of PKD cell lines, which exhibit defects in PC1 expression and collagen compaction. Cyclic adenosine monophosphate (cAMP), when added, induces cysts in both PKD organoids and controls. These biomaterials establish a highly efficient model of PKD cystogenesis that directly implicates the microenvironment at the earliest stages of the disease. |
| Databáze: | OpenAIRE |
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