Biomechanical Modeling of Cell Chirality and Symmetry Breaking of Biological Systems.

Accumulating evidence strongly suggests that cell chirality plays a pivotal role in driving left-right (LR) symmetry breaking, a widespread phenomenon in living organisms. Whole embryos and excised organs have historically been employed to investigate LR symmetry breaking and have yielded exciting findings. In recent years, in vitro engineered platforms have emerged as powerful tools to reveal cellular chiral biases and led to uncovering molecular and biophysical insights into chiral morphogenesis, including the significant role of the actin cytoskeleton. Establishing a link between observed in vivo tissue chiral morphogenesis and the determined chiral bias of cells in vitro has become increasingly important. In this regard, computational mathematical models hold immense value as they can explain and predict tissue morphogenic behavior based on the chiral biases of individual cells. Here, we present the formulations and discoveries achieved using various computational models spanning different biological scales, from the molecular and cellular levels to tissue and organ levels. Furthermore, we offer insights into future directions and the role of such models in advancing the study of asymmetric cellular mechanobiology.

Helical vasculogenesis driven by cell chirality.

The cellular helical structure is well known for its crucial role in development and disease. Nevertheless, the underlying mechanism governing this phenomenon remains largely unexplored, particularly in recapitulating it in well-controlled engineering systems. Leveraging advanced microfluidics, we present compelling evidence of the spontaneous emergence of helical endothelial tubes exhibiting robust right-handedness governed by inherent cell chirality. To strengthen our findings, we identify a consistent bias toward the same chirality in mouse vascular tissues. Manipulating endothelial cell chirality using small-molecule drugs produces a dose-dependent reversal of the handedness in engineered vessels, accompanied by non-monotonic changes in vascular permeability. Moreover, our three-dimensional cell vertex model provides biomechanical insights into the chiral morphogenesis process, highlighting the role of cellular torque and tissue fluidity in its regulation. Our study unravels an intriguing mechanism underlying vascular chiral morphogenesis, shedding light on the broader implications and distinctive perspectives of tubulogenesis within biological systems.

Cell jamming regulates epithelial chiral morphogenesis.

Internal organs such as the heart demonstrate apparent left-right (LR) asymmetric morphology and positioning. Cellular chirality and associated LR biased mechanical behavior such as cell migration have been attributed to LR symmetry breaking during embryonic development. Mathematical models have shown that chiral directional migration can be driven by cellular intrinsic torque. Tissue jamming state (i.e., solid-like vs fluid-like state) strongly regulates collective migratory behavior, but how it might affect chiral morphogenesis is still unknown. Here, we develop a cell vertex model to study the role of tissue rigidity or jamming state on chiral morphogenesis of the cells on a patterned ring-shaped tissue, simulating a previously reported experimental setup for measuring cell chirality. We simulate chirality as torsional forces acting on cell vertices. As expected, the cells undergo bidirectional migration at the opposing (inner and outer) boundaries of the ring-shaped tissue. We discover that more fluid-like tissues (unjammed) demonstrate a stronger chiral cell alignment and elongation than more solid-like (jammed) tissues and maintain a bigger difference in migration velocity between opposing tissue boundaries. Finally, we find that fluid-like tissues undergo more cell-neighbor exchange events. This study reveals that chiral torque is sufficient to achieve a biased cellular alignment as seen in vitro. It further sheds light on the mechanical regulation of chiral morphogenesis of tissues and reveals a role of cell density-independent tissue rigidity in this process.

Cell chirality in cardiovascular development and disease.

The cardiovascular system demonstrates left-right (LR) asymmetry: most notably, the LR asymmetric looping of the bilaterally symmetric linear heart tube. Similarly, the orientation of the aortic arch is asymmetric as well. Perturbations to the asymmetry have been associated with several congenital heart malformations and vascular disorders. The source of the asymmetry, however, is not clear. Cell chirality, a recently discovered and intrinsic LR asymmetric cellular morphological property, has been implicated in the heart looping and vascular barrier function. In this paper, we summarize recent advances in the field of cell chirality and describe various approaches developed for studying cell chirality at multi- and single-cell levels. We also examine research progress in asymmetric cardiovascular development and associated malformations. Finally, we review evidence connecting cell chirality to cardiac looping and vascular permeability and provide thoughts on future research directions for cell chirality in the context of cardiovascular development and disease.

Cell organelle-based analysis of cell chirality.

The maintenance of tight endothelial junctions requires the establishment of proper cell polarity, which includes not only the apicobasal and front-rear polarity but also the left-right (L-R) polarity. The cell possesses an intrinsic mechanism of orienting the L-R axis with respect to the other axes, following a left-hand or right-hand rule, termed cell chirality. We have previously reported that endothelial cells exhibit a clockwise or rightward bias on ring-shaped micropatterns. Now we further characterize the chirality of individual endothelial cells on micropatterns by analyzing the L-R positioning of the cell centroid relative to the nucleus-centrosome axis. Our results show that the centroids of endothelial cells preferably polarized towards the right side of the nucleus-centrosome axis. This bias is consistent with cell chirality characterized by other methods. These results suggest that the positioning of cell organelles is intrinsically L-R biased inside individual cells. This L-R bias provides an opportunity for determining cell chirality in situ, even in vivo, without the limitations of using isolated cells in in vitro engineered platforms.

Germline cytoskeletal and extra-cellular matrix-related single nucleotide variations associated with distinct cancer survival rates.

BACKGROUND: Human mutagenesis has a large stochastic component. Thus, large coding regions, especially cytoskeletal and extra-cellular matrix protein (CECMP) coding regions are particularly vulnerable to mutations. Recent results have verified a high level of somatic mutations in the CECMP coding regions in the cancer genome atlas (TCGA), and a relatively common occurrence of germline, deleterious mutations in the TCGA breast cancer dataset. METHODS: The objective of this study was to determine the correlations of CECMP coding region, germline nucleotide variations with both overall survival (OS) and disease-free survival (DFS). TCGA, tumor and blood variant calling files (VCFs) were intersected to identify germline SNVs. SNVs were then annotated to determine potential consequences for amino acid (AA) residue biochemistry. RESULTS: Germline SNVs were matched against somatic tumor SNVs (i.e., tumor mutations) over twenty TCGA datasets to identify 23 germline-somatic matched, deleterious AA substitutions in coding regions for FLG, TTN, MUC4, and MUC17. CONCLUSIONS: The germline-somatic matched SNVs, in particular for MUC4, extensively implicated in cancer development, represented highly, statistically significant effects on OS and DFS survival rates. The above results contribute to the establishment of what is potentially a new class of inherited cancer-facilitating genes, namely dominant negative tumor suppressor proteins.