Biomaterial-based 3D human lung models replicate pathological characteristics of early pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable lung disease characterized by tissue scarring that disrupts gas exchange. Epithelial cell dysfunction, fibroblast activation, and excessive extracellular matrix deposition drive this pathology that ultimately leads to respiratory failure. Mechanistic studies have shown that repeated injury to alveolar epithelial cells initiates an aberrant wound-healing response by surrounding fibroblasts through secretion of mediators like transforming growth factor beta (TGF- β), yet the precise biological pathways contributing to disease progression are not fully understood.

Hydrogel-embedded precision-cut lung slices support ex vivo culture of in vivo-induced premalignant lung lesions.

Lung cancer is the leading cause of global cancer death, and prevention strategies are key to reducing mortality. Medical prevention of premalignant lesion (PML) progression may have a larger impact than treatment on mortality by targeting high-risk populations and reducing their lung cancer risk. PMLs are difficult to study in humans but are easily accessible in murine preclinical carcinogenesis studies.

The MUC5B promoter variant results in proteomic changes in the nonfibrotic lung.

The gain-of-function MUC5B promoter variant is the dominant risk factor for the development of idiopathic pulmonary fibrosis (IPF). However, its impact on protein expression in both nonfibrotic control and IPF lung specimens has not been well characterized. Utilizing laser capture microdissection coupled to mass spectrometry, we investigated the proteomic profiles of airway and alveolar epithelium in nonfibrotic controls (n = 12) and IPF specimens (n = 12), stratified by the MUC5B promoter variant.

Female Fibroblast Activation Is Estrogen-Mediated in Sex-Specific 3D-Bioprinted Pulmonary Artery Adventitia Models.

Pulmonary arterial hypertension (PAH) is a form of pulmonary vascular disease characterized by scarring of the small blood vessels that results in reduced blood flow and increased blood pressure in the lungs. Over time, this increase in blood pressure causes damage to the heart. Idiopathic (IPAH) impacts male and female patients differently, with female patients showing a higher disease susceptibility (4:1 female-to-male ratio) but experiencing longer survival rates postdiagnosis compared to male patients.

Biomaterial-based 3D human lung models replicate pathological characteristics of early pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable lung disease characterized by tissue scarring that disrupts gas exchange. Epithelial cell dysfunction, fibroblast activation, and excessive extracellular matrix deposition drive this pathology that ultimately leads to respiratory failure. Mechanistic studies have shown that repeated injury to alveolar epithelial cells initiates an aberrant wound-healing response in surrounding fibroblasts through secretion of mediators like transforming growth factor-β, yet the precise biological pathways contributing to disease progression are not fully understood.

Female fibroblast activation is estrogen-mediated in sex-specific 3D-bioprinted pulmonary artery adventitia models.

Pulmonary arterial hypertension (PAH) impacts male and female patients in different ways. Female patients exhibit a greater susceptibility to disease (4:1 female-to-male ratio) but live longer after diagnosis than male patients. This complex sexual dimorphism is known as the estrogen paradox.

Engineered hydrogel biomaterials facilitate lung progenitor cell differentiation from induced pluripotent stem cells.

Lung progenitor (LP) cells identified by the expression of transcription factor NK2 homeobox 1 (NKX2.1) are essential for the development of all lung epithelial cell types and hold tremendous potential for pulmonary research and translational regenerative medicine applications. Here, we present engineered hydrogels as a promising alternative to the naturally derived materials that are often used to differentiate human-induced pluripotent stem cells (iPSCs) into LP cells.

Hydrogel-embedded precision-cut lung slices support culture of -induced premalignant lung lesions.

Lung cancer is the leading cause of global cancer death and prevention strategies are key to reducing mortality. Medical prevention may have a larger impact than treatment on mortality by targeting high-risk populations and reducing their lung cancer risk. Premalignant lesions (PMLs) that can be intercepted by prevention agents are difficult to study in humans but easily accessible in murine preclinical carcinogenesis studies.

Hydrogel-Embedded Precision-Cut Lung Slices Model Lung Cancer Premalignancy Ex Vivo.

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 is constrained to rodent models, which are time-consuming, expensive, and require large cohorts.

Engineering Dynamic 3D Models of Lung.

The lung parenchyma-consisting of gas-filled alveoli, vasculature, and connective tissue-is the site for gas exchange in the lung and plays a critical role in a number of chronic lung diseases. In vitro models of lung parenchyma can, therefore, provide valuable platforms for the study of lung biology in health and disease. Yet modeling such a complex tissue requires integrating multiple components, including biochemical cues from the extracellular environment, geometrically defined multicellular interactions, and dynamic mechanical inputs such as the cyclic stretch of breathing.

Tissue-engineered models of lung cancer premalignancy.

Lung cancer is the leading global cause of cancer-related deaths. Although smoking cessation is the best preventive action, nearly 50% of all lung cancer diagnoses occur in people who have already quit smoking. Research into treatment options for these high-risk patients has been constrained to rodent models of chemical carcinogenesis, which are time-consuming, expensive, and require large numbers of animals.

Chemical Modification of Human Decellularized Extracellular Matrix for Incorporation into Phototunable Hybrid-Hydrogel Models of Tissue Fibrosis.

Tissue fibrosis remains a serious health condition with high morbidity and mortality rates. There is a critical need to engineer model systems that better recapitulate the spatial and temporal changes in the fibrotic extracellular microenvironment and enable study of the cellular and molecular alterations that occur during pathogenesis. Here, we present a process for chemically modifying human decellularized extracellular matrix (dECM) and incorporating it into a dynamically tunable hybrid-hydrogel system containing a poly(ethylene glycol)-α methacrylate (PEGαMA) backbone.

Engineering Hybrid-Hydrogels Comprised of Healthy or Diseased Decellularized Extracellular Matrix to Study Pulmonary Fibrosis.

Unlabelled: Idiopathic pulmonary fibrosis is a chronic disease characterized by progressive lung scarring that inhibits gas exchange. Evidence suggests fibroblast-matrix interactions are a prominent driver of disease. However, available preclinical models limit our ability to study these interactions.

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

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 challenging due to the myriad of complex processes that contribute to fibrogenesis and the inherent difficulty in accurately recreating the human pulmonary environment . Here, we describe a poly(ethylene glycol) PEG hydrogel-based three-dimensional model for the co-culture of primary murine pulmonary fibroblasts and alveolar epithelial cells that reproduces the micro-architecture, cell placement, and mechanical properties of healthy and fibrotic lung tissue.

Fibroblast activation protein restrains adipogenic differentiation and regulates matrix-mediated mTOR signaling.

Obesity is a risk factor for multiple diseases, including diabetes, cardiovascular disease, and cancer. Within obese adipose tissue, multiple factors contribute to creating a disease-promoting environment, including metabolic dysfunction, inflammation, and fibrosis. Recent evidence points to fibrotic responses, particularly extracellular matrix remodeling, in playing a highly functional role in the pathogenesis of obesity.

Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics.

Fibroblast activation protein (FAP) is a cell-surface serine protease that acts on various hormones and extracellular matrix components. FAP is highly upregulated in a wide variety of cancers, and is often used as a marker for pro-tumorigenic stroma. It has also been proposed as a molecular target of cancer therapies, and, especially in recent years, a great deal of research has gone into design and testing of diverse FAP-targeted treatments.

Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinomas (PDAs) are desmoplastic and can undergo epithelial-to-mesenchymal transition to confer metastasis and chemoresistance. Studies have demonstrated that phenotypically and functionally distinct stromal cell populations exist in PDAs. Fibroblast activation protein-expressing (FAP-expressing) cells act to enhance PDA progression, while α-smooth muscle actin myofibroblasts can restrain PDA.