Abstract: PO1274
Deposition of an Abnormal Extracellular Matrix as an Initiating Event in Cyst Formation
Session Information
- Cystic Kidney Disease - II
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Schumacher, Valerie A., Boston Children's Hospital, Boston, Massachusetts, United States
- Taglienti, Mary E., Boston Children's Hospital, Boston, Massachusetts, United States
- Kreidberg, Jordan A., Boston Children's Hospital, Boston, Massachusetts, United States
Background
Extracellular matrix (ECM) refers to the proteins and other macromolecules outside of cells that provide a scaffolding to maintain tissue architecture. The distinct ECMs to which these cells are attached, epithelial cells to a laminin-rich basement membrane vs. interstitial cells to a collagen/fibronectin (FN) ECM, has profound implications for cell behavior and tissue architecture. These differences in cell behavior are mediated through a family of receptors known as integrins, used by cells to attach to the ECM. Here we provide evidence that cyst formation in ADPKD is a manifestation of abnormal cell behavior in response to an atypical extracellular matrix and changes in integrins.
Methods
To understand the pathological contribution of integrins and FN to ADPKD, we measured their expression and localization in vivo using a postnatal murine model of ADPKD and kidney samples from human ADPKD.
Results
We observed increased expression of FN in murine cystic kidneys and also in kidneys from humans with ADPKD. In mice, increased fibronectin expression preceded cyst formation. Moreover, laminin basement membrane underlying cyst lining cells was discontinuous and replaced in some sections by a FN-rich ECM. Some sections were conspicuous for expressing the FN receptor α5β1 integrin, and for cell morphology being cuboidal instead of flattened. In other areas of the FN rich ECM, αv-integrins, were present on flattened cyst lining cells. α3β1 integrin was more abundant on cyst lining cells than on non-cystic tubules. Interestingly, in situ hybridization revealed that Fn1 was not expressed in all cyst lining cells but in the specific subset of cells that had a cuboidal appearance.
Conclusion
Our studies presented here identify a distinct subset of cuboidal cyst lining cells that express Fn1. They also demonstrate distinct integrin repertoires among subsets of cyst lining cells. As FN deposition precedes cyst formation, these FN-expressing cuboidal cells may have a role in the initiation or early progression of cysts in ADPKD.
Funding
- NIDDK Support