Predicting and understanding collagen remodeling in human native heart valves during early development

Abstract

The hemodynamic functionality of heart valves strongly depends on the distribution of collagen fibers, which are their main load-bearing constituents. It is known that collagen networks remodel in response to mechanical stimuli. Yet, the complex interplay between external load and collagen remodeling is poorly understood. In this study, we adopted a computational approach to simulate collagen remodeling occurring in native fetal and pediatric heart valves. The computational model accounted for several biological phenomena: cellular (re)orientation in response to both mechanical stimuli and topographical cues provided by collagen fibers; collagen deposition and traction forces along the main cellular direction; collagen degradation decreasing with stretch; and cell-mediated collagen prestretch. Importantly, the computational results were well in agreement with previous experimental data for all simulated heart valves. Simulations performed by varying some of the computational parameters suggest that cellular forces and (re)orientation in response to mechanical stimuli may be fundamental mechanisms for the emergence of the circumferential collagen alignment usually observed in native heart valves. On the other hand, the tendency of cells to coalign with collagen fibers is essential to maintain and reinforce that circumferential alignment during development. STATEMENT OF SIGNIFICANCE: The hemodynamic functionality of heart valves is strongly influenced by the alignment of load-bearing collagen fibers. Currently, the mechanisms that are responsible for the development of the circumferential collagen alignment in native heart valves are not fully understood. In the present study, cell-mediated remodeling of native human heart valves during early development was computationally simulated to understand the impact of individual mechanisms on collagen alignment. Our simulations successfully predicted the degree of collagen alignment observed in native fetal and pediatric semilunar valves. The computational results suggest that the circumferential collagen alignment arises from cell traction and cellular (re)orientation in response to mechanical stimuli, and with increasing age is reinforced by the tendency of cells to co-align with pre-existing collagen fibers.

Bio-inspired anisotropic polymeric heart valves exhibiting valve-like mechanical and hemodynamic behavior

“…A previous study also showed the decrease of peak stress from 1.42 MPa in the isotropic bovine pericardium valve model to 1.13 MPa in the anisotropic model through computational modeling [60]. Therefore, anisotropic PEGDA-ASF leaflets with layered fibrous structures can mimic the circumferential alignment of collagen fibers in native heart valves, as well as their response to mechanical stimuli [61], and attenuate the stress concentration under closing pressure gradient, which may improve the durability of the PHV prosthesis.…”

Mechano-regulated cell–cell signaling in the context of cardiovascular tissue engineering

“…Early phenomenological models hypothesized that collagen fibers align along or in between the directions of principal stress or strain, which enabled them to successfully predict the collagen organization in heart valves and arteries (Driessen et al 2003(Driessen et al , 2004(Driessen et al , 2005(Driessen et al , 2008Boerboom et al 2003;Baek et al 2006;Kuhl et al 2007;Hariton et al 2007). In more recent studies, models of collagen remodeling have been developed that accounted for the effects of cell behavior, such as contractility and cell alignment, to unravel the underlying biological mechanisms (Loerakker et al 2014(Loerakker et al , 2016Soares et al 2014;Ristori et al 2018a). These models suggest that collagen remodeling is driven by mechanical stimuli both directly, via the influence of strain, and indirectly, via mechanomediated cell behavior.…”

“…Additionally, it has been predicted that mechanical stimuli provided by hemodynamic loading dominate the cell-mediated collagen remodeling process in TEHVs implanted in the aortic position, whereas the influence of contractility was predicted to be more important for TEHVs implanted in the pulmonary position (Loerakker et al 2016). To simulate long-term collagen remodeling in heart valves, the influence of topographical stimuli was included in a more recent study as well (Ristori et al 2018a(Ristori et al , 2018b. Simulations with this model revealed that cell traction and reorientation in response to mechanical stimuli can potentially explain the emergence of an anisotropic collagen organization in fetal heart valves, while the coalignment of collagen fibers with cells seems vital for maintaining and reinforcing the adopted collagen organization over time (Ristori et al 2018a).…”

“…To simulate long-term collagen remodeling in heart valves, the influence of topographical stimuli was included in a more recent study as well (Ristori et al 2018a(Ristori et al , 2018b. Simulations with this model revealed that cell traction and reorientation in response to mechanical stimuli can potentially explain the emergence of an anisotropic collagen organization in fetal heart valves, while the coalignment of collagen fibers with cells seems vital for maintaining and reinforcing the adopted collagen organization over time (Ristori et al 2018a). Taken together, these modeling results suggest a clear and fundamental role for mechano-mediated cellular activity in the process of collagen remodeling in cardiovascular tissues.…”

Cardiovascular abnormalities and its correlation with genotypes of children with osteogenesis imperfecta

“…Abnormalities in the cardiovascular system are found to be common in OI patients, including valvular disease, atrial fibrillation and heart failure, and the more severe the OI phenotype, the higher the risk of cardiovascular abnormalities ( 9 , 10 ). As valves, tendinous cords, fibrous rings, and the cardiac septum of hearts are mainly composed of type I and III collagen, type I collagen contributes to the stiffer and rigid property of the myocardium ( 11 ). Therefore, a decrease of the collagen was associated with a more compliant ventricle, which results in increased LV diastolic internal diameters and volume ( 12 ).…”