Alveolar epithelial cells and microenvironmental stiffness synergistically drive fibroblast activation in three-dimensional hydrogel lung models

Caracena, Thomas; Blomberg, Rachel; Hewawasam, Rukshika S; Fry, Zoe E; Riches, David W. H.; Magin, Chelsea M.

doi:10.1039/d2bm00827k

Cited by 12 publications

(7 citation statements)

References 73 publications

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“…PEG-norbornene (PEG-NB) based microsphere gels (170 μm) recreate the microarchitecture and cellular organization, which facilitates the upregulation of fibrotic markers (Figure c). The study also demonstrated that the coculture of epithelial cells and fibroblasts on a stiffened matrix is necessary for myofibroblast differentiation and ECM deposition . Using vinyl sulfone-functionalized dextran , a heterogeneous fiber-entangled hydrogel was used to recapitulate the fibrous character of the interstitial matrix (Figure d).…”

Section: Three-dimensional Culture Systemsmentioning

confidence: 94%

Section: Three-dimensional Culture Systemsmentioning

confidence: 99%

“…The study also demonstrated that the coculture of epithelial cells and fibroblasts on a stiffened matrix is necessary for myofibroblast differentiation and ECM deposition. 104 Using vinyl sulfone-functionalized dextran, a heterogeneous fiberentangled hydrogel was used to recapitulate the fibrous character of the interstitial matrix (Figure 3d). High fiber density promoted fibroblast differentiation to myofibroblasts revealing that matrix architecture could be a strong fibrogenic trigger, but this pattern inversely correlates with stiffness.…”

Section: Three-dimensional Culture Systemsmentioning

confidence: 99%

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Advanced 3D In Vitro Lung Fibrosis Models: Contemporary Status, Clinical Uptake, and Prospective Outlooks

Jain,

Shashi Bhushan,

Natarajan

et al. 2024

ACS Biomater. Sci. Eng.

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Fibrosis has been characterized as a global health problem and ranks as one of the primary causes of organ dysfunction. Currently, there is no cure for pulmonary fibrosis, and limited therapeutic options are available due to an inadequate understanding of the disease pathogenesis. The absence of advanced in vitro models replicating dynamic temporal changes observed in the tissue with the progression of the disease is a significant impediment in the development of novel antifibrotic treatments, which has motivated research on tissue-mimetic three-dimensional (3D) models. In this review, we summarize emerging trends in preparing advanced lung models to recapitulate biochemical and biomechanical processes associated with lung fibrogenesis. We begin by describing the importance of in vivo studies and highlighting the often poor correlation between preclinical research and clinical outcomes and the limitations of conventional cell culture in accurately simulating the 3D tissue microenvironment. Rapid advancement in biomaterials, biofabrication, biomicrofluidics, and related bioengineering techniques are enabling the preparation of in vitro models to reproduce the epithelium structure and operate as reliable drug screening strategies for precise prediction. Improving and understanding these model systems is necessary to find the cross-talks between growing cells and the stage at which myofibroblasts differentiate. These advanced models allow us to utilize the knowledge and identify, characterize, and hand pick medicines beneficial to the human community. The challenges of the current approaches, along with the opportunities for further research with potential for translation in this field, are presented toward developing novel treatments for pulmonary fibrosis.

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Section: Three-dimensional Culture Systemsmentioning

confidence: 94%

Section: Three-dimensional Culture Systemsmentioning

confidence: 99%

Section: Three-dimensional Culture Systemsmentioning

confidence: 99%

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Advanced 3D In Vitro Lung Fibrosis Models: Contemporary Status, Clinical Uptake, and Prospective Outlooks

Jain,

Shashi Bhushan,

Natarajan

et al. 2024

ACS Biomater. Sci. Eng.

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“…PEG-Norbornene (PEG-NB) Synthesis: Eight-arm 10 kg mol −1 PEGhydroxyl (PEG-OH; JenKem Technology) was conjugated with norbornene as described previously. [82,83] Lyophilized PEG-OH (5 g) and 4dimethylaminopyridine (DMAP, 0.002 mol; Sigma-Aldrich) were dissolved in anhydrous dichloromethane (DCM; Sigma-Aldrich) and then pyridine (0.02 mol; Fisher Scientific) was injected into the mixture. In a separate reaction container, N,N'-dicyclohexylcarbodiimide (DCC, 0.02 mol; Fisher Scientific) was dissolved in DCM with norbornene-2-carboxylic acid (0.04 mol; Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Hydrogel‐Embedded Precision‐Cut Lung Slices Model Lung Cancer Premalignancy Ex Vivo

Blomberg,

Sompel,

Hauer

et al. 2023

Adv Healthcare Materials

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Lung cancer is the leading global cause of cancer‐related deaths. Although smoking cessation is the best prevention, 50% of lung cancer diagnoses occur in people who have quit smoking. Research into treatment options for high‐risk patients has been constrained to rodent models, which are time‐consuming, expensive, and require large cohorts. Embedding precision‐cut lung slices (PCLS) within an engineered hydrogel and exposing this tissue to vinyl carbamate, a carcinogen from cigarette smoke, creates an in vitro model of lung cancer premalignancy. Hydrogel formulations are selected to promote early lung cancer cellular phenotypes and extend PCLS viability to six weeks. Hydrogel‐embedded PCLS are exposed to vinyl carbamate, which induces adenocarcinoma in mice. Analysis of proliferation, gene expression, histology, tissue stiffness, and cellular content after six weeks reveal that vinyl carbamate induces premalignant lesions with a mixed adenoma/squamous phenotype. Putative chemoprevention agents diffuse through the hydrogel and induce tissue‐level changes. The design parameters selected using murine tissue are validated with hydrogel‐embedded human PCLS and results show increased proliferation and premalignant lesion gene expression patterns. This tissue‐engineered model of human lung cancer premalignancy is the foundation for more sophisticated ex vivo models that enable study of carcinogenesis and chemoprevention strategies.This article is protected by copyright. All rights reserved

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“…Within the tissue engineering field much work has concentrated on the development of polymers from which soft or stiff hydrogels can be cast or 3D printed ( Tibbitt and Anseth, 2009 ; Melchels et al, 2012 ; Hospodiuk et al, 2017 ; Gungor-Ozkerim et al, 2018 ). These synthetic polymers [including polyacrylamide ( Marinkovic et al, 2013 ) and dextran ( Matera et al, 2020 )] offer many opportunities for tuning biomechanical and structural properties of the microenvironment but are generally inhospitable environments for cells, requiring the addition of cell binding epitopes, such as RGD motifs, to enable cellular attachment ( Lutolf and Hubbell, 2005 ; Reddy et al, 2021 ; Caracena et al, 2022 ). Alternatively, natural ECM components have also been used to generate single component hydrogels that readily support cell attachment, but are more limited in the possibilities for tuning their biomechanical properties.…”

Section: Introductionmentioning

confidence: 99%

Current possibilities and future opportunities provided by three-dimensional lung ECM-derived hydrogels

Nizamoglu

Burgess

2023

Front. Pharmacol.

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Disruption of the complex interplay between cells and extracellular matrix (ECM), the scaffold that provides support, biochemical and biomechanical cues, is emerging as a key element underlying lung diseases. We readily acknowledge that the lung is a flexible, relatively soft tissue that is three dimensional (3D) in structure, hence a need exists to develop in vitro model systems that reflect these properties. Lung ECM-derived hydrogels have recently emerged as a model system that mimics native lung physiology; they contain most of the plethora of biochemical components in native lung, as well as reflecting the biomechanics of native tissue. Research investigating the contribution of cell:matrix interactions to acute and chronic lung diseases has begun adopting these models but has yet to harness their full potential. This perspective article provides insight about the latest advances in the development, modification, characterization and utilization of lung ECM-derived hydrogels. We highlight some opportunities for expanding research incorporating lung ECM-derived hydrogels and potential improvements for the current approaches. Expanding the capabilities of investigations using lung ECM-derived hydrogels is positioned at a cross roads of disciplines, the path to new and innovative strategies for unravelling disease underlying mechanisms will benefit greatly from interdisciplinary approaches. While challenges need to be addressed before the maximum potential can be unlocked, with the rapid pace at which this field is evolving, we are close to a future where faster, more efficient and safer drug development targeting the disrupted 3D microenvironment is possible using lung ECM-derived hydrogels.

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Alveolar epithelial cells and microenvironmental stiffness synergistically drive fibroblast activation in three-dimensional hydrogel lung models

Abstract: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease that progressively and irreversibly alters the lung parenchyma, eventually leading to respiratory failure. The study of this disease has been historically...

Cited by 12 publications

References 73 publications

Advanced 3D In Vitro Lung Fibrosis Models: Contemporary Status, Clinical Uptake, and Prospective Outlooks

Advanced 3D In Vitro Lung Fibrosis Models: Contemporary Status, Clinical Uptake, and Prospective Outlooks

Hydrogel‐Embedded Precision‐Cut Lung Slices Model Lung Cancer Premalignancy Ex Vivo

Current possibilities and future opportunities provided by three-dimensional lung ECM-derived hydrogels

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