The journey started with an enigma in the zebrafish embryo: some endothelial cells, actively involved in the initial stages of the development of the earliest blood vessels, were dividing in an unconventional manner. Rather than dividing while rounding up into perfect balls, as often seen in the division of other cells, these cells maintained their rod shape, leading to the creation of offspring cells that differed in shape and possibly in function. This process, called isomorphic division, is a challenge to decades-long cell biology assumptions.
In most metazoan cells, rounding in mitosis is a protective mechanism. By reorganizing the actin cortex, they increase cortical pressure, which enables a geometric configuration so precise that it facilitates correct segregation of chromosomes and an equivalent share of cytoplasmic material. Symmetry is, however, a critical aspect of cell division since it enables both newly formed cells to be equivalent in function. In contrast, in the case of cells responsible for creating a new vasculature in angiogenesis, it seems, despite morphogenesis requirements, cells must stretch along with forming blood vessels, and in this way, even in mitosis, they retain interphase shape, thus directly conveying information to their descendants.
Live cell imaging in the zebrafish has played a crucial role in witnessing this act firsthand. Live cell imaging in the zebrafish has played a crucial role. Live cell imaging in the zebrafish has played a crucial role in noting this act. In the zebrafish live cell imaging, a crucial role has been played. In unizoned mitoses, the daughters were found to be asymmetric. Live cell imaging in the zebafish has played a crucial role in seeing this act. Live cell imaging in the zebrafish has played a crucial role. Live cell imaging in the zebrafish has played a crucial role in noting this act.
To investigate the causative aspect of this theory, a micropatterning approach, which is a very accurate method of UV laser etching to transfer adhesive protein spots of specific geometry on a non-stick surface, was used. The cells deposited on the protein spots took the geometrical forms of these spots; hence, cells of specific geometry were obtained in laboratory conditions to reverse the morphology of cells prior to division. The findings were very convincing: elongated cells translated into cells undergoing isomorphic division much more frequently; compact cells reverted to classical rounding division.
Mechanobiology gives insights into why shape is important. Pre-mitotic elongation changes the distribution of cortical tension and the orientation of the mitotic spindle, which impacts the division of fate factors, including recycling endosomes labeled by Rab4. In isomorphic division, these components and their contents remain asymetrically localized, meaning that one daughter cell inherits the signaling molecules to maintain the stem-like phenotype, and the other is set on the pathway to differentiation, much in the same way stem cell niches partition organelles, including lysosomes and the endoplasmic reticulum, to dictate cell fate decisions.
But the implications do not stop at development. Asymmetric divisions have long been established as a mechanism underlying cellular diversity, whereas in cancer, this process could also contribute to heterogeneity and metastasis. A similar ability to switch between symmetrical and asymmetric cell divisions exists for cancer stem cells (CSCs) utilizing Notch, Wnt/β-catenin, and/or p53 signaling pathways. If cancer cells are able to sustain interphase characteristics during cell divisions, they could potentially keep those characteristics beneficial for survival under stressful tumor environments, such as a hypoxic tumor core and/or following radiation therapy.
Recent developments in high resolution and time-lapse imaging are making it feasible to quantify these shape-driven behaviors in vivo. In zebrafish vasculatures, for instance, cell divisions, Ca²⁺ oscillations, filopodia, and extracellular matric remodeling are being studied, and how the mechanical and chemical cues are integrated to morphogenetic processes is being deciphered. This kind of integrated information will make it feasible to understand the “shape-signal-fate” connection in vivo, not just in normative processes but also in some pathological processes.
The discovery defies the dogma that mitotic rounding is an animal cell characteristic and proposes that cells have the capability to change their division mechanics to retain their structural information and essentially hardwire a morphological memory into their development. Readers who are enthusiastic about science will remember that even the most basic processes, such as cell division, retain secrets that could potentially be harnessed in order to control regeneration and arrest disease development at its roots.
