Taking advantage of 3D humanized in vitro models to study pulmonary diseases

• Autor(a) principal: Piedade, Francisca Rodrigues da
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/31073
• topic: Lung fibrosis; Fibrotic diseases; Extracellular matrix; 3D lung models; Hydrogels; PLMA

Pulmonary fibrosis, characterized by progressive and irreversible lung tissue stiffening resulting in organ failure, is a growing health problem and belongs to the major causes of death worldwide. The pathological mechanisms of lung fibrosis are not fully understood; current pathogenic theories assume an impaired wound healing response to chronic lung injuries, in which the mechanical and chemical stimuli from the lung environment induces fibroblast activation. Currently, therapeutic options are severely limited, and lung transplantation remains the only effective treatment for patients in end-stage fibrotic diseases. Complex tridimensional (3D) lung platforms able to accurately recapitulate function, structure, and cell and matrix interactions found in fibrotic lung tissue, are therefore necessary to provide the means for understanding the pathological mechanisms and mediators involved in the fibrotic process. Of the vast array of biomaterials that have been used for Tissue Engineering (TE) applications, a major enthusiasm has been developed towards hydrogels: 3D water-swollen polymeric networks, that provide mechanical support to cells and allow for the diffusion of nutrients, waste, and oxygen. Hydrogels are particularly interesting to study lung diseases as they recapitulate the mechanical and viscoelastic properties found in load-bearing soft tissues like the lung. Natural-based hydrogels are appealing platforms as they are inherently biocompatible and bioactive. Platelet-rich plasma (PRP) and human platelet lysates (PL) provide interesting materials to create hydrogels as they are a source for human-derived growth factors (GF). However, they present poor mechanical properties and are easily degraded. Synthetic-derived hydrogels do not face these limitations, but they lack differentiative cues required for tissue development. Human methacryloyl platelet lysates (PLMA)- based hydrogels have been proposed as a biochemical and biomechanicalsuperior platform for cell culture purposes. These autologous, GF-rich, platforms are herein proposed as reliable 3D platforms to model the fibrotic lung. PLMA hydrogels recapitulated the pathological stiffness of the fibrotic lung and supported the viability of lung fibroblasts cells for at least 7 days in culture. Cells adopted different morphologies as matrix stiffness changed and were able to induce matrix deformations in PLMA hydrogels, suggesting the feasibility of this scaffold to induce a profibrotic phenotype in fibroblasts in 3D, therefore recapitulating the pathological remodeling of lung fibrosis.