Regulation of valve interstitial cell homeostasis by mechanical deformation: implications for heart valve disease and surgical repair

Abstract

Mechanical stress is one of the major aetiological factors underlying soft-tissue remodelling, especially for the mitral valve (MV). It has been hypothesized that altered MV tissue stress states lead to deviations from cellular homeostasis, resulting in subsequent cellular activation and extracellular matrix (ECM) remodelling. However, a quantitative link between alterations in the organlevel in vivo state and in vitro-based mechanobiology studies has yet to be made. We thus developed an integrated experimental-computational approach to elucidate MV tissue and interstitial cell responses to varying tissue strain levels. Comprehensive results at different length scales revealed that normal responses are observed only within a defined range of tissue deformations, whereas deformations outside of this range lead to hypo-and hyper-synthetic responses, evidenced by changes in a-smooth muscle actin, type I collagen, and other ECM and cell adhesion molecule regulation. We identified MV interstitial cell deformation as a key player in leaflet tissue homeostatic regulation and, as such, used it as the metric that makes the critical link between in vitro responses to simulated equivalent in vivo behaviour. Results indicated that cell responses have a delimited range of in vivo deformations that maintain a homeostatic response, suggesting that deviations from this range may lead to deleterious tissue remodelling and failure.

A noninvasive method for the determination of in vivo mitral valve leaflet strains

“…The present study builds upon over a century of investigations into MV mechanics and owes much to recent achievements in the development of high‐fidelity computational models of the MV . Moreover, the overarching objective of devising noninvasive methods to estimate MV strains in vivo is motivated by an increasingly compelling body of evidence that supports hypotheses of bidirectional causal links between tissue‐level deformations and cell‐mediated growth and remodeling events . It is thus strongly believed that accounting for these interconnected phenomena is paramount to the accurate prediction of clinical events, such as post‐MI MV/ventricular remodeling and postsurgical MV repair outcomes .…”

“…The homeostatic maintenance of MV leaflet tissue composition and microstructure, primarily mediated by interstitial cell deformation, has been shown to depend on direction‐specific loading patterns . For a physiologically relevant interpretation of strains, it is thus necessary to examine each component of the strain tensor individually.…”

“…[14][15][16][17][18][19][20] In light of this, recent studies have begun to elucidate links between MV function at the organ level and the mechanobiological responses of the underlying MV interstitial cells, which ultimately drive remodeling. 19,[21][22][23][24][25][26] These investigations have uncovered and quantified detailed relationships between MV leaflet stretch and interstitial cell deformation. Furthermore, specific cellular deformation patterns have been associated with concurrent remodeling in the extracellular matrix of the MV leaflets, mainly via biosynthetic changes to the tissue's collagen and elastin networks.…”

“…Such alterations place the MV in a nonphysiological loading state, leading to valvular tissue growth and remodeling . In light of this, recent studies have begun to elucidate links between MV function at the organ level and the mechanobiological responses of the underlying MV interstitial cells, which ultimately drive remodeling . These investigations have uncovered and quantified detailed relationships between MV leaflet stretch and interstitial cell deformation.…”

“…These investigations have uncovered and quantified detailed relationships between MV leaflet stretch and interstitial cell deformation. Furthermore, specific cellular deformation patterns have been associated with concurrent remodeling in the extracellular matrix of the MV leaflets, mainly via biosynthetic changes to the tissue's collagen and elastin networks . These findings strongly suggest that significant MV remodeling occurs after MI and surgical repair, as both of these events result in substantial changes to the MV.…”