YAP/TAZ drives Notch and angiogenesis mechanoregulation in silico.

Endothelial cells are key players in the cardiovascular system. Among other things, they are responsible for sprouting angiogenesis, the process of new blood vessel formation essential for both health and disease. Endothelial cells are strongly regulated by the juxtacrine signaling pathway Notch.

Computational analysis of heart valve growth and remodeling after the Ross procedure.

During the Ross procedure, an aortic heart valve is replaced by a patient's own pulmonary valve. The pulmonary autograft subsequently undergoes substantial growth and remodeling (G&R) due to its exposure to increased hemodynamic loads. In this study, we developed a homogenized constrained mixture model to understand the observed adaptation of the autograft leaflets in response to the changed hemodynamic environment.

A computational analysis of the role of integrins and Rho-GTPases in the emergence and disruption of apical-basal polarization in renal epithelial cells.

Apical-basal polarization in renal epithelial cells is crucial to renal function and an important trigger for tubule formation in kidney development. Loss of polarity can induce epithelial-to-mesenchymal transition (EMT), which can lead to kidney pathologies. Understanding the relative and combined roles of the involved proteins and their interactions that govern epithelial polarity may provide insights for controlling the process of polarization via chemical or mechanical manipulations in an in vitro or in vivo setting.

The Importance of Effective Ligand Concentration to Direct Epithelial Cell Polarity in Dynamic Hydrogels.

Epithelial cysts and organoids are multicellular hollow structures formed by correctly polarized epithelial cells. Important in steering these cysts from single cells is the dynamic regulation of extracellular matrix presented ligands, and matrix dynamics. Here, control over the effective ligand concentration is introduced, decoupled from bulk and local mechanical properties, in synthetic dynamic supramolecular hydrogels formed through noncovalent crosslinking of supramolecular fibers.

A multiscale computational model of arterial growth and remodeling including Notch signaling.

Blood vessels grow and remodel in response to mechanical stimuli. Many computational models capture this process phenomenologically, by assuming stress homeostasis, but this approach cannot unravel the underlying cellular mechanisms. Mechano-sensitive Notch signaling is well-known to be key in vascular development and homeostasis.

Engineering Strategies to Move from Understanding to Steering Renal Tubulogenesis.

Rebuilding the kidney in the context of tissue engineering offers a major challenge as the organ is structurally complex and has a high variety of specific functions. Recreation of kidney function is inherently connected to the formation of tubules since the functional subunit of the kidney, the nephron, is based on tubular structures. , tubulogenesis culminates in a perfectly shaped, patterned, and functional renal tubule via different morphogenic processes that depend on delicately orchestrated chemical, physical, and mechanical interactions between cells and between cells and their microenvironment.

Notch signaling regulates strain-mediated phenotypic switching of vascular smooth muscle cells.

Mechanical stimuli experienced by vascular smooth muscle cells (VSMCs) and mechanosensitive Notch signaling are important regulators of vascular growth and remodeling. However, the interplay between mechanical cues and Notch signaling, and its contribution to regulate the VSMC phenotype are still unclear. Here, we investigated the role of Notch signaling in regulating strain-mediated changes in VSMC phenotype.

Computer Model-Driven Design in Cardiovascular Regenerative Medicine.

Continuing advances in genomics, molecular and cellular mechanobiology and immunobiology, including transcriptomics and proteomics, and biomechanics increasingly reveal the complexity underlying native tissue and organ structure and function. Identifying methods to repair, regenerate, or replace vital tissues and organs remains one of the greatest challenges of modern biomedical engineering, one that deserves our very best effort. Notwithstanding the continuing need for improving standard methods of investigation, including cell, organoid, and tissue culture, biomaterials development and fabrication, animal models, and clinical research, it is increasingly evident that modern computational methods should play increasingly greater roles in advancing the basic science, bioengineering, and clinical application of regenerative medicine.

Computational analysis of the role of mechanosensitive Notch signaling in arterial adaptation to hypertension.

Arteries grow and remodel in response to mechanical stimuli. Hypertension, for example, results in arterial wall thickening. Cell-cell Notch signaling between vascular smooth muscle cells (VSMCs) is known to be involved in this process, but the underlying mechanisms are still unclear.

Implementing Computational Modeling in Tissue Engineering: Where Disciplines Meet.

In recent years, the mathematical and computational sciences have developed novel methodologies and insights that can aid in designing advanced bioreactors, microfluidic setups or organ-on-chip devices, in optimizing culture conditions, or predicting long-term behavior of engineered tissues . In this review, we introduce the concept of computational models and how they can be integrated in an interdisciplinary workflow for Tissue Engineering and Regenerative Medicine (TERM). We specifically aim this review of general concepts and examples at experimental scientists with little or no computational modeling experience.

Substrate Stiffness Determines the Establishment of Apical-Basal Polarization in Renal Epithelial Cells but Not in Tubuloid-Derived Cells.

Mechanical guidance of tissue morphogenesis is an emerging method of regenerative medicine that can be employed to steer functional kidney architecture for the purpose of bioartificial kidney design or renal tissue engineering strategies. In kidney morphogenesis, apical-basal polarization of renal epithelial cells is paramount for tubule formation and subsequent tissue functions like excretion and resorption. In kidney epithelium, polarization is initiated by integrin-mediated cell-matrix adhesion at the cell membrane.

Scaffold Geometry-Imposed Anisotropic Mechanical Loading Guides the Evolution of the Mechanical State of Engineered Cardiovascular Tissues .

Cardiovascular tissue engineering is a promising approach to develop grafts that, in contrast to current replacement grafts, have the capacity to grow and remodel like native tissues. This approach largely depends on cell-driven tissue growth and remodeling, which are highly complex processes that are difficult to control inside the scaffolds used for tissue engineering. For several tissue engineering approaches, adverse tissue growth and remodeling outcomes were reported, such as aneurysm formation in vascular grafts, and leaflet retraction in heart valve grafts.

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

Cardiovascular tissue engineering (CVTE) aims to create living tissues, with the ability to grow and remodel, as replacements for diseased blood vessels and heart valves. Despite promising results, the (long-term) functionality of these engineered tissues still needs improvement to reach broad clinical application. The functionality of native tissues is ensured by their specific mechanical properties directly arising from tissue organization.

Computational modeling for cardiovascular tissue engineering: the importance of including cell behavior in growth and remodeling algorithms.

Understanding cardiovascular growth and remodeling (G&R) is fundamental for designing robust cardiovascular tissue engineering strategies, which enable synthetic or biological scaffolds to transform into healthy living tissues after implantation. Computational modeling, particularly when integrated with experimental research, is key for advancing our understanding, predicting the evolution of engineered tissues, and efficiently optimizing scaffold designs. As cells are ultimately the drivers of G&R and known to change their behavior in response to mechanical cues, increasing efforts are currently undertaken to capture (mechano-mediated) cell behavior in computational models.

Geometry influences inflammatory host cell response and remodeling in tissue-engineered heart valves in-vivo.

Regenerative tissue-engineered matrix-based heart valves (TEM-based TEHVs) may become an alternative to currently-used bioprostheses for transcatheter valve replacement. We recently identified TEM-based TEHVs-geometry as one key-factor guiding their remodeling towards successful long-term performance or failure. While our first-generation TEHVs, with a simple, non-physiological valve-geometry, failed over time due to leaflet-wall fusion phenomena, our second-generation TEHVs, with a computational modeling-inspired design, showed native-like remodeling resulting in long-term performance.

Next-generation tissue-engineered heart valves with repair, remodelling and regeneration capacity.

Valvular heart disease is a major cause of morbidity and mortality worldwide. Surgical valve repair or replacement has been the standard of care for patients with valvular heart disease for many decades, but transcatheter heart valve therapy has revolutionized the field in the past 15 years. However, despite the tremendous technical evolution of transcatheter heart valves, to date, the clinically available heart valve prostheses for surgical and transcatheter replacement have considerable limitations.

Cellular Contact Guidance Emerges from Gap Avoidance.

In the presence of anisotropic biochemical or topographical patterns, cells tend to align in the direction of these cues-a widely reported phenomenon known as "contact guidance." To investigate the origins of contact guidance, here, we created substrates micropatterned with parallel lines of fibronectin with dimensions spanning multiple orders of magnitude. Quantitative morphometric analysis of our experimental data reveals two regimes of contact guidance governed by the length scale of the cues that cannot be explained by enforced alignment of focal adhesions.

Pressure-induced collagen degradation in arterial tissue as a potential mechanism for degenerative arterial disease progression.

Collagen fibre degradation is a strain-dependent process, whereby the magnitude of experienced strain dictates the rate of enzymatic cleavage. Studies have identified conflicting findings as to whether strain inhibits or enhances collagen degradation, which may be explained by the tissue type and tissue scale investigated, as well as the strain range considered. The aim of this study is to identify, for the first time, the strain-dependent degradation response of intact arterial vessels experiencing physiological pressures and apply these findings to a computational model to better understand degenerative arterial diseases, such as aneurysms.

Lateral induction limits the impact of cell connectivity on Notch signaling in arterial walls.

It is well known that arteries grow and remodel in response to mechanical stimuli. Vascular smooth muscle cells are the main mediators of this process, as they can switch phenotype from contractile to synthetic, and vice-versa, based on the surrounding bio-chemo-mechanical stimuli. A correct regulation of this phenotypic switch is fundamental to obtain and maintain arterial homeostasis.

Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress.

The intermediate filament (IF) cytoskeleton has been proposed to regulate morphogenic processes by integrating the cell fate signaling machinery with mechanical cues. Signaling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) through the Notch pathway regulates arterial remodeling in response to changes in blood flow. Here we show that the IF-protein vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic forces.

A computational model to predict cell traction-mediated prestretch in the mitral valve.

Prestretch is observed in many soft biological tissues, directly influencing the mechanical behavior of the tissue in question. The development of this prestretch occurs through complex growth and remodeling phenomena, which yet remain to be elucidated. In the present study it was investigated whether local cell-mediated traction forces can explain the development of global anisotropic tissue prestretch in the mitral valve.

Increased Cell Traction-Induced Prestress in Dynamically Cultured Microtissues.

Prestress is a phenomenon present in many cardiovascular tissues and has profound implications on their functionality. For instance, the mechanical properties are altered by the presence of prestress, and prestress also influences tissue growth and remodeling processes. The development of tissue prestress typically originates from complex growth and remodeling phenomena which yet remain to be elucidated.

Initial scaffold thickness affects the emergence of a geometrical and mechanical equilibrium in engineered cardiovascular tissues.

cardiovascular tissue-engineering can potentially address the shortcomings of the current replacement therapies, in particular, their inability to grow and remodel. In native tissues, it is widely accepted that physiological growth and remodelling occur to maintain a homeostatic mechanical state to conserve its function, regardless of changes in the mechanical environment. A similar homeostatic state should be reached for tissue-engineered (TE) prostheses to ensure proper functioning.