Key result
Biomimetic PCL/polyDOPA/C1F scaffolds successfully replicated the morphological, mechanical (Young's modulus ~50 kPa), and chemical cues of native cardiac fibrotic tissue.
Why the study?
Traditional 2D cell cultures and animal models have limited predictivity for preclinical testing of therapies aimed at reversing adverse remodeling and post-myocardial infarction cardiac fibrosis.
The developed biomimetic electrospun scaffold successfully replicates the hallmarks of early-stage human cardiac fibrosis, providing a promising in vitro model for preclinical testing of antifibrotic therapies.
Provides platform for studying post-MI fibroblast phenotypes in vitro; leaves open clinical translation.
High Resolution Image Download MS PowerPoint Slide Adverse remodeling post-myocardial infarction is hallmarked by the phenotypic change of cardiac fibroblasts (CFs) into myofibroblasts (MyoFs) and over-deposition of the fibrotic extracellular matrix (ECM) mainly composed by fibronectin and collagens, with the loss of tissue anisotropy and tissue stiffening. Reversing cardiac fibrosis represents a key challenge in cardiac regenerative medicine. Reliable in vitro models of human cardiac fibrotic tissue could be useful for preclinical testing of new advanced therapies, addressing the limited predictivity of traditional 2D cell cultures and animal in vivo models. In this work, we engineered a biomimetic in vitro model, reproducing the morphological, mechanical, and chemical cues of native cardiac fibrotic tissue. Polycaprolactone (PCL)-based scaffolds with randomly oriented fibers were fabricated by solution electrospinning technique, showing homogeneous nanofibers with an average size of 131 ± 39 nm. PCL scaffolds were then surface-functionalized with human type I collagen (C1) and fibronectin (F) by dihydroxyphenylalanine (DOPA)-mediated mussel-inspired approach (PCL/polyDOPA/C1F), in order to mimic fibrotic cardiac tissue-like ECM composition and support human CF culture. BCA assay confirmed the successful deposition of the biomimetic coating and its stability during 5 days of incubation in phosphate-buffered saline. Immunostaining for C1 and F demonstrated their homogeneous distribution in the coating. AFM mechanical characterization showed that PCL/polyDOPA/C1F scaffolds, in wet conditions, resembled fibrotic tissue stiffness with an average Young’s modulus of about 50 kPa. PCL/polyDOPA/C1F membranes supported human CF (HCF) adhesion and proliferation. Immunostaining for α-SMA and quantification of α-SMA-positive cells showed HCF activation into MyoFs in the absence of a transforming growth factor β (TGF-β) profibrotic stimulus, suggesting the intrinsic ability of biomimetic PCL/polyDOPA/C1F scaffolds to sustain the development of cardiac fibrotic tissue. A proof-of-concept study making use of a commercially available antifibrotic drug confirmed the potentialities of the developed in vitro model for drug efficacy testing. In conclusion, the proposed model was able to replicate the main hallmarks of early-stage cardiac fibrosis, appearing as a promising tool for future preclinical testing of advanced regenerative therapies.
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Ruocco et al. (2023) studied Cardiac fibrosis. Biomimetic PCL/polyDOPA/C1F scaffolds was evaluated on Replication of morphological, mechanical, and chemical cues of native cardiac fibrotic tissue. Biomimetic PCL/polyDOPA/C1F scaffolds successfully replicated the morphological, mechanical (Young's modulus ~50 kPa), and chemical cues of native cardiac fibrotic tissue.
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