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J Biol Chem. 2018 Jan 12;293(2):567-578. doi: 10.1074/jbc.RA117.000148. Epub 2017 Nov 28.

Hyaluronan content governs tissue stiffness in pancreatic islet inflammation.

Author information

1
From the Department of Medicine, Division of Infectious Diseases, nnagy@stanford.edu.
2
the Department of Materials Science and Engineering.
3
From the Department of Medicine, Division of Infectious Diseases.
4
the Matrix Biology Program, Benaroya Research Institute, Seattle, Washington 98101.
5
Stanford Biophysics.
6
the Department of Medicine, Division of Endocrinology, and.
7
the Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, Stanford University, Stanford, California 94305 and.

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.

KEYWORDS:

atomic force microscopy (AFM); autoimmune disease; diabetes; extracellular matrix;; hyaluronan; hydrogels; tissue stiffness

PMID:
29183997
PMCID:
PMC5767862
[Available on 2019-01-12]
DOI:
10.1074/jbc.RA117.000148
[Indexed for MEDLINE]

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