Cell chirality based mathematical models for left-right asymmetric morphogenesis

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Rahman, Tasnif
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Electronic thesis
Biomedical engineering
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Left-Right (LR) asymmetry is ubiquitous in all bilateral animals, including humans. Proper LR asymmetric morphogenesis is crucial for the structure and function of several internal organs. Disruption of proper LR asymmetry is associated with sever, and often fatal, congenital defects of major asymmetric organs such as the heart. Several hypotheses for the origin of LR asymmetric development are being actively investigated – ranging from cytoskeletal asymmetries to global LR asymmetries in morphogen patterning. Recent evidence suggests that inherent asymmetries in the dynamics of actin polymerization leads to the generation of torque and rotation at the cellular level – termed cell chirality. Cell chirality has also been observed in the biased migration, and alignment of cells both in vitro and in vivo. However, how actin driven chiral rotation mechanically leads to the asymmetric migration of multicellular collectives, and subsequently to the asymmetric morphogenesis of organs, such as heart-looping, is poorly understood. This is due to the inherent difficulties of measuring forces generated by individual rotating cells and measuring the contributions of such to asymmetric morphogenesis. This dissertation attempts to fill this gap by using a cell vertex based biomechanical computational model (CVM).We propose a model of chiral tissues wherein polygonal cells within a gapless array rotate about their area centroid – and show that such a model accurately recapitulates the biased cell migrations observed within micropatterns, as well as the biased elongation and alignment of these cells relative to the micropattern boundaries. This chiral morphogenesis is shown to be regulated by geometric properties of the model which modulates the rigidity of the tissue – such that more fluid-like tissues undergo more drastic chiral morphogenesis. We reveal a novel potential role of chirality in tissue segregation using models of micropatterned tissues that contain clockwise (CW) and counterclockwise (CCW) cells in randomly distributed 50:50 racemic mixture – such that CW xiv and CCW cells separate. This process is also shown to be regulated by tissue fluidity, with more fluid tissues demonstrating stronger segregation behavior. The segregation is shown to be driven by the instability of heterogenous edges shared between CW and CCW cells. Finally, we show that CW rotating cells, within the ventral surface of a 2.5D cylindrical CVM of the embryonic heart-tube drives chiral heart-looping. This looping only requires chirality in the right-ventral myocardium, as observed in vivo. The looping direction is dependent on the direction of chiral rotations of the cells, and the strength of looping is dependent on the strength of the torque forces, and the ratio of CW:CCW cells within the ventral myocardium. The CVM also recapitulates the biased alignment of cardiac cells within the model myocardium, in the same direction as in vivo chick cardiomyocytes. This alignment is also mimicked by the colonies made up of a cell’s immediate neighbors. Overall, our efforts show for the first time that chiral rotation of individual cells, derived from chiral actin dynamics, is sufficient to recapitulate the chiral morphogenesis of tissues on micropatterns, and the chiral looping of the heart-tube. Additionally, we reveal a novel potential role of chiral rotation in the segregation of heterogenous racemic tissues. This work should inspire several theoretical and experimental investigations to reveal further mechanical and biological mechanisms of LR asymmetry breaking.
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Rensselaer Polytechnic Institute, Troy, NY
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