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Hyaluronan content governs tissue stiffness in pancreatic islet inflammation.

Citation
Nagy, N., et al. “Hyaluronan Content Governs Tissue Stiffness In Pancreatic Islet Inflammation.”. The Journal Of Biological Chemistry, pp. 567-578.
Center Stanford University University of Washington
Multicenter
Multicenter
Author Nadine Nagy, Adi de la Zerda, Gernot Kaber, Pamela Y Johnson, Kenneth H Hu, Michael J Kratochvil, Koshika Yadava, Wenting Zhao, Yi Cui, Guadalupe Navarro, Justin P Annes, Thomas N Wight, Sarah C Heilshorn, Paul L Bollyky, Manish J Butte
Keywords atomic force microscopy (AFM), autoimmune disease, diabetes, extracellular matrix;, Hyaluronan, hydrogels, tissue stiffness
Abstract

We have identified a novel role for hyaluronan (HA), an extracellular matrix polymer, in governing the mechanical properties of inflamed tissues. We recently reported that insulitis in type 1 diabetes of mice and humans is preceded by intraislet accumulation of HA, a highly hygroscopic polymer. Using the double transgenic DO11.10 × RIPmOVA (DORmO) mouse model of type 1 diabetes, we asked whether autoimmune insulitis was associated with changes in the stiffness of islets. To measure islet stiffness, we used atomic force microscopy (AFM) and developed a novel "bed of nails"-like approach that uses quartz glass nanopillars to anchor islets, solving a long-standing problem of keeping tissue-scale objects immobilized while performing AFM. We measured stiffness via AFM nanoindentation with a spherical indenter and found that insulitis made islets mechanically soft compared with controls. Conversely, treatment with 4-methylumbelliferone, a small-molecule inhibitor of HA synthesis, reduced HA accumulation, diminished swelling, and restored basal tissue stiffness. These results indicate that HA content governs the mechanical properties of islets. In hydrogels with variable HA content, we confirmed that increased HA leads to mechanically softer hydrogels, consistent with our model. In light of recent reports that the insulin production of islets is mechanosensitive, these findings open up an exciting new avenue of research into the fundamental mechanisms by which inflammation impacts local cellular responses.

Year of Publication
2018
Journal
The Journal of biological chemistry
Volume
293
Issue
2
Number of Pages
567-578
Date Published
12/2018
ISSN Number
1083-351X
DOI
10.1074/jbc.RA117.000148
Alternate Journal
J. Biol. Chem.
PMID
29183997
PMCID
PMC5767862
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