Nature Reviews Cardiology | Review
In conditions of prolonged stress valvular cells can contribute to valve disease progression. In this Review, Wang and colleagues describe how the biophysical and biochemical properties of the extracellular matrix... can regulate valve cell function in the context of calcific valvular diseases. The authors also describe how new cell culture approaches can be employed to better understand the pathophysiology of valve diseases.
Abstract
During every heartbeat, cardiac valves open and close coordinately to control the unidirectional flow of blood. In this dynamically challenging environment, resident valve cells actively maintain homeostasis, but the signalling between cells and their microenvironment is complex. When homeostasis is disrupted and the valve opening obstructed, haemodynamic profiles can be altered and lead to impaired cardiac function. Currently, late stages of cardiac valve diseases are treated surgically, because no drug therapies exist to reverse or halt disease progression. Consequently, investigators have sought to understand the molecular and cellular mechanisms of valvular diseases using in vitro cell culture systems and biomaterial scaffolds that can mimic the extracellular microenvironment. In this Review, we describe how signals in the extracellular matrix regulate valve cell function. We propose that the cellular context is a critical factor when studying the molecular basis of valvular diseases in vitro, and one should consider how the surrounding matrix might influence cell signalling and functional outcomes in the valve. Investigators need to build a systems-level understanding of the complex signalling network involved in valve regulation, to facilitate drug target identification and promote in situ or ex vivo heart valve regeneration.
Key points
- The interaction between valve cells and their microenvironment signals determine the functional output of cardiac valve tissues; cardiac valve diseases might be caused by a disruption of these interactions
- In vitro cell culture studies can help understand cardiac valve disease pathobiology, which is enhanced by culturing cells on biomaterials that mimic the native valve cell matrix environment
- Many biochemical signals regulate pathogenic phenotypes of cells in the valve; however, their effects are dependent on the matrix microenvironment
- Synthetic biomaterials can be used to understand valve cell regulation by biochemical, biophysical, and other matrix-associated signals, especially related to the development of valvular diseases
- Understanding the dynamic interplay between microenvironmental signals and valvular cell phenotypes will enable the identification of new therapies and the design of ex vivo tissue engineered valves
As the heart evolved from a single-chamber to a multiple-chamber structure, cardiac valves arose to control the unidirectional flow of blood during cardiac cycles. For example, aortic valves open in response to higher blood pressure in the left ventricle than in the aorta, and close when the pressure equilibrates. These valves function in a similar manner to valves in water dams or car engines, but cardiac valves are living tissue with the ability to repair and remodel in response to damage. During an average human life span, heart valves open and close approximately 3 billion times,1 withstanding various mechanical stresses, including fluid shear stresses and bending stretch.2, 3
The material composition and structure of cardiac valves confer their robustness and durability. In humans, cardiac valves are made of thin (~500 ÎĽm) pliable cusps, and only mitral and tricuspid valves have supporting chordae tendineae and papillary muscles.4 A close examination of the tissue architecture of an aortic valve reveals three distinct layers of extracellular matrix (ECM), rich in collagens, proteoglycans, or elastin (Figure 1a).4 These ECM proteins impart unique macroscopic mechanical properties to valves, enabling them to withstand tension when closed and flexure when open. For example, the elastin fibres on the flow side of the valves (known as ventricularis) are radially aligned and elastic, which extend when the valves open and recoil when valves close.5 Proteoglycans in the middle layer, or spongiosa, function as a cushion for absorbing tension and friction between the top and the bottom layers.4 Finally, the fibrosa layer contains circumferentially oriented collagen fibres, which confer stiffness and strength to the valves.4
, Young's modulus; PAVIC, porcine aortic valve interstitial cell; PEG, poly(ethylene glycol). Permission for panel b obtained from et al. Small peptide functionalized thiol-ene hydrogels as culture substrates for understanding valvular interstitial cell activation and de novo tissue deposition. Acta Biomaterialia, 8, 3201–3209 (2012). Permission for panel c obtained from et al. In situ elasticity modulation with dynamic substrates to direct cell phenotype.
Nice article...:)
ReplyDelete