A quantitative study of myocardial motion and deformation during early mouse morphogenesis

• Autores: Morena Raiola
• Directores de la Tesis: Andres Santos Lleo (codir. tes.), Miguel Torres Sánchez (codir. tes.)
• Lectura: En la Universidad Politécnica de Madrid ( España ) en 2023
• Idioma: inglés
• Tribunal Calificador de la Tesis: María Jesús Ledesma Carbayo (presid.), Daniel Jiménez Carretero (secret.), Robert Kelly (voc.), Oscar Camara Rey (voc.), Juan Enrique Ortuño Fisac (voc.)
• Programa de doctorado: Programa de Doctorado en Ingeniería Biomédica por la Universidad Politécnica de Madrid
• Calificación: Sobresaliente Cum Laude
• Materias:
  • Física
    • Óptica
  • Ciencias de la vida
    • Biología animal (zoología)
      • Desarrollo animal
• Enlaces
  • Tesis en acceso abierto en: Archivo Digital UPM
• Resumen

  • Morphogenesis of the heart is a fascinating process in which few cells transform into a fully functioning pumping organ. This intricate process involves multiple stages of development, during which the cell population proliferates and rearranges while the heart shape gradually takes form. Such complexity arises from genetic, biochemical, and morphological changes that interact in a highly organized manner across different spatio-temporal scales. Despite cardiogenesis occurs in a robust and reproducible way, it gives rise to a variable heart shape when comparing different specimens. Thanks to recent advances in the physics of microscopy and the development of fluorescent proteins that report spatial gene expression patterns, we are now able to observe heart development in vivo. This imaging process generates high spatio-temporal resolution 3D+t data that provide a digital representation of heart morphologenesis. However, these data requires novel image processing and data analysis techniques to extract information. The quantification of deformation and dynamics involved in the process of heart shaping is one of the most relevant and challenging areas of developmental biology. However, due to the complexity of the process and the limitations in live imaging of heart development with enough penetration into the tissue and during the entire process, there is a gap in knowledge regarding the underlying heart tissue deformation during early morphogenesis. This PhD thesis addresses this challenge by proposing a systematic methodology to quantify and compare tissue deformation patterns, through the integration of motion profiles estimated from multiple 3D-live fluorescent microscopy images. The proposed framework focuses on the quantification of motion kinematics, specifically deformation and strains, without considering the forces that cause such motion. This is achieved through a non-invasive analysis made directly on the individual live images. To align the individual motion profiles of multiple specimens over time, the framework incorporates a staging system that syn chronizes 3D-live images with a previously described pseudodynamic ATLAS of tissue geometry during heart morphogenesis[1]. To validate this approach, we compared manually tracked cell motions with tracks predicted by the model implemented. The results obtained validated this strategy for description of cell trajectories and tissue deformation at cellular level. To address the issue of heart shape variability and facilitate comparison of deformation patterns, the framework includes a registration process that projects each individual specimen onto the synchronous ATLAS shape, which serves as a spatial reference. This framework maps a temporal profile of deformation during different stages of development, including both instantaneous events and cumulative deformation history. The maps generated allow as well in silico fate map analysis at the cellular or regional level. The results obtained indicate a sharp compartmentalization of tissue expansion/compression and deformation anisotropy. Therefore, although cardiomyocytes of the early cardiac primordium appear homogeneous, in fact they show a highly heterogeneous behaviour that is regionally regulated. In summary, this PhD thesis presents a comprehensive framework for the quantitative analysis and comparison of tissue deformation in developing hearts. The results of this study reveal a remarkable compartmentalization of heart tissue, which includes distinct zones of anisotropy and expansion. Through the use of this framework, it becomes possible to identify and track morphological changes in developing heart tissue, providing inferred insights into the dynamics of heart cells during the development process. This characterization provides a crucial foundation for the development of mechanical models and, more importantly, offers a deeper understanding of the intricate complexities involved in heart development.