Tissue Engineering Models of Polycystic Kidney Disease.
Ko, Wei-Che.
2017-04-18T13:58:18.373Z
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Abstract: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a life-threatening monogenic disorder where innumerable cysts develop in the kidney, leading to renal failure. There is no known cure, and animal studies, while beneficial, often yield mixed results when translated to the human condition. Thus, new opportunities present itself for the study of human ADPKD by utilizing tissue enginee... read morering principles of disease modeling. However, modeling cystic diseases in vitro presents a unique challenge as cyst morphogenesis, in addition to complex intercellular interactions, is also governed by synergistic spatial, mechanical and temporal effects. This thesis reports the development of kidney-like tissue structures for normal and diseased (cystic) states using commercially available human kidney cells. Gene silencing is used to simulate autosomal dominant polycystic kidney disease, as inactivating mutations in polycystins -1 and/or -2 are responsible for the disease in vivo. Our system utilizes extracellular-matrix molecules infused in slow degrading porous silk scaffolds, which provides a 3D microenvironment for proper cell polarization (ECM), while exhibiting structural robustness and tension (silk scaffold). Our results indicate development of cyst-like structures in a 3D environment, while also demonstrating the respective normal and altered phenotypes concurrent with normal tissue and patient-derived ADPKD tissue. The structural and functional features of kidney-like tissue structures were further characterized based on distribution of E-cadherin, N-cadherin, transport phenomena of 6-carboxyfluorescein, and cell-matrix interactions through integrin signaling. Importantly, this 3D in vitro model may be further extended via perfusion reactor for long term studies of ADPKD or other renal cystic diseases, and may have beneficial use as a therapeutic drug screening tool.
Thesis (M.S.)--Tufts University, 2012.
Submitted to the Dept. of Biomedical Engineering.
Advisor: David Kaplan.
Committee: Ronald Perrone, and Qiaobing Xu.
Keyword: Biomedical engineering.read less - ID:
- g445cr91r
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