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.
Highlights
We have identified a novel role for hyaluronan (HA), an extracellular matrix polymer, in governing the mechanical properties of inflamed tissues
We chose to evaluate the role of HA in tissue mechanics in autoimmune insulitis, a well-characterized and medically relevant form of inflammation that precedes type 1 diabetes (T1D), in which HA is known to be a prominent feature of the disease [16]
We found that prediabetic DO11.10 ؋ RIPmOVA (DORmO) mice at 8 weeks of age already had a significant decrease in the number of islets, compared with age-matched control mice (Fig. 1D)
Summary
Likely to drive edema at sites of injury. HA has been implicated in vascular permeability changes [7,8,9], as well as leukocyte adhesion and egress [10, 11]. We chose to evaluate the role of HA in tissue mechanics in autoimmune insulitis, a well-characterized and medically relevant form of inflammation that precedes type 1 diabetes (T1D), in which HA is known to be a prominent feature of the disease [16]. In this disease, the immune system attacks and destroys insulin-producing -cells that reside within pancreatic islets, thereby leaving the affected individual perilously dependent on exogenous insulin for survival [17]. We previously demonstrated that this treatment reduced HA levels in both the serum and islets of DORmO mice [19] Together, these tools allowed us to interrogate the role of HA in tissue stiffness during autoimmune insulitis. We test the hypothesis that increases in HA content during inflammation promote the softening of inflamed tissues, whereas reductions in HA promote a return to basal levels of stiffness
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