Fibroblast-seeded lung extracellular matrix (ecm)-derived hydrogels as an in vitro model for stromal bed in idiopathic pulmonary fibrosis (ipf)

Mehmet Nizamoglu, Marco Schlepütz, Irene Heijink, Kaj Blokland, Matthew J. Thomas, Barbro Melgert, Janette Burgess

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Abstract

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is characterized by aberrant extracellular matrix (ECM) deposition and remodeling, which orchestrates cellular responses to the fibrotic microenvironment[1]. Decellularized lung ECM‐derived hydrogels resemble the mechanical properties[2] of native decellularized tissues, potentially providing a 3D model mimicking native cell‐ECM interactions. We aimed to characterize this 3D human lung microenvironment model, with respect to stiffness and viscoelastic properties, in the presence and absence of primary human lung fibroblasts.

Materials & Methods: Lyophilized powders of decellularized IPF and control lung matrices (pool of 6 patients) were pepsin digested, and formed to hydrogels seeded with control primary lung fibroblasts (n = 4 donors), and cultured for 14 days. Stiffness and viscoelastic relaxation were measured by Low‐Load Compression Testing[2] (20% strain).

Results: IPF hydrogels were stiffer than controls (1.84 ± 0.33 kPA vs 1.37 ± 0.35 kPA), and became even more stiff when cell‐seeded (1.91 ± 0.37 kPA) in contrast to controls which became softer (1.09 ± 0.27 kPA). Time to reach 100% viscoelastic relaxation was shorter in cell‐seeded compared to native hydrogels for both IPF (19.14 ± 3.17 vs 41.6 ± 37.66 seconds) and control (11.44 ± 6.55 vs 22.21 ± 19.59 seconds).

Conclusion: The mechanical properties of the ECM hydrogels were modified by fibroblasts, while in turn the ECM microenvironment altered cellular responses. These data suggest that higher stiffnesses and altered relaxation patterns of the ECM could contribute to the fibrotic response in IPF by instructing the cells. Fibroblast‐seeded ECM‐derived hydrogels can provide more insight on cell‐ECM interactions in IPF.

References

[1] M. W. Parker et al., “Fibrotic extracellular matrix activates a profibrotic positive feedback loop,” J. Clin. Invest., vol. 124, no. 4, pp. 1622–1635, Apr. 2014.

[2] R. H. J. De Hilster et al., “Human lung extracellular matrix hydrogels resemble the stiffness and viscoelasticity of native lung tissue,” Am. J. Physiol. ‐ Lung Cell. Mol. Physiol., vol. 318, no. 4, pp. L698–L704, Apr. 2020.
Original languageEnglish
PagesS123-S123
Number of pages1
Publication statusPublished - 1-Apr-2022

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