Abstract
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. We therefore hypothesize that establishing a native-like tissue organization is vital to overcome the limitations of current CVTE approaches. To achieve this aim, a better understanding of the growth and remodeling (G&R) mechanisms of cardiovascular tissues is necessary. Cells are the main mediators of tissue G&R, and their behavior is strongly influenced by both mechanical stimuli and cell–cell signaling. An increasing number of signaling pathways has also been identified as mechanosensitive. As such, they may have a key underlying role in regulating the G&R of tissues in response to mechanical stimuli. A more detailed understanding of mechano-regulated cell–cell signaling may thus be crucial to advance CVTE, as it could inspire new methods to control tissue G&R and improve the organization and functionality of engineered tissues, thereby accelerating clinical translation. In this review, we discuss the organization and biomechanics of native cardiovascular tissues; recent CVTE studies emphasizing the obtained engineered tissue organization; and the interplay between mechanical stimuli, cell behavior, and cell–cell signaling. In addition, we review past contributions of computational models in understanding and predicting mechano-regulated tissue G&R and cell–cell signaling to highlight their potential role in future CVTE strategies.
Highlights
Cardiovascular diseases are one of the leading causes of morbidity and mortality worldwide and represent a major economic and social burden to society due to healthcare expenditures and productivity losses (Timmis et al 2020; Virani et al 2020)
We focus on both blood vessels and heart valves because they are similar from a tissue engineering perspective, as they share many of the methods and techniques adopted in this field, as well as many of the limitations and challenges we still face
Given the strong effects of mechanical stimuli on cell–cell signaling pathways (Sects. 5.1, 5.2, and 5.3) and cellular behavior, we propose that mechano-regulation of cell–cell signaling is an important factor to consider in future tissue engineering
Summary
Cardiovascular diseases are one of the leading causes of morbidity and mortality worldwide and represent a major economic and social burden to society due to healthcare expenditures and productivity losses (Timmis et al 2020; Virani et al 2020). We will focus on the interplay between cellular behavior, mechanical cues, and cell–cell signaling to identify the potential role of mechano-regulation of signaling pathways in G&R of TEBVs and TEHVs. Throughout the review, we will emphasize the past and future contributions of computational models in advancing understanding and predicting tissue G&R, cell–cell signaling, and CVTE strategies. We will conclude with a description of the challenges that remain to be addressed in CVTE and present an outlook on future directions We focus on both blood vessels and heart valves because they are similar from a tissue engineering perspective, as they share many of the methods and techniques adopted in this field, as well as many of the limitations and challenges we still face. The G&R of both these tissues are affected by mechanical stimuli and cell–cell signaling pathways and the computational models we discuss can generally be applied to both tissues
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