Key Takeaways
- Brown University researchers discovered how human epithelial cells form multicellular spheroids and invade surrounding tissue.
- Sharply shaped spheroids guide where individual cells will migrate outward, indicating a cellular “memory” of shape.
- Environmental factors, such as osmotic pressure, significantly influence the invasion patterns of these cells, with implications for understanding tissue development and cancer spread.
Brown University engineers have unveiled critical insights into the movement and organization of cells as they form complex tissues. This research, published in Nature Physics, investigates how human epithelial cells interact as spherical aggregates confined within a collagen matrix. It highlights the intricate processes involved as these cells rotate collectively and ultimately invade their surroundings.
Cells must collaborate during tissue development, as they do not have predefined structures to guide them, yet their behavioral patterns are not fully understood. The study reveals that cells within a spheroid first rotate together before reshaping their environment to allow for outward movement. Specifically, the researchers found that the original shape of the spheroid—particularly when it deviates from a perfect sphere—predicts where cells will eventually begin to invade.
Jiwon Kim, the study’s lead author, emphasized that the spheroids are often slightly oval, which influences the dynamics of cellular invasion. “Cells invade from these sharper ends, as if they have a memory of the original shape,” she noted.
The research utilized the hanging droplet method to create multicellular spheroids by placing droplets of cell culture media in inverted Petri dish lids and allowing cells to aggregate into spheres. Once formed, the spheroids were embedded in collagen that mimics the extracellular matrix in the body. The setup allowed for real-time imaging and measurement of the forces exerted by the cells, using fluorescent proteins for tracking and red tracer particles to observe collagen deformation.
Within approximately five hours after being embedded, cells began rotating as a collective, an observation reminiscent of previous studies in other biological contexts. However, this research uniquely documented the subsequent migration behavior. Around twelve hours into the experiment, leader cells began to extend out of the spheroid, forming strands that pushed through the collagen matrix and facilitating further movement of additional cells.
Hyuntae Jeong, a co-author of the study, indicated that cells exert greater pulling forces at points where the initial culture deviates from a spherical shape, leading to reconfiguration of collagen fibers in a radial pattern that directs cells outward. This finding emphasizes the importance of the physical microenvironment on cellular behavior.
The researchers also explored how variations in osmotic pressure could alter invasion patterns. Higher osmotic pressure effectively immobilized cells within the original spheroid, halting their outward movement. Conversely, increased pressure during the invasion phase caused invading cells to retract, revealing significant implications for understanding how cellular dynamics affect tissue development and cancer metastasis.
This study underscores the necessity of examining the interactions between cells and their environments to further comprehend the complexities of tissue formation and cancer spread. As Ian Y. Wong, the study’s corresponding author, stated, understanding these cellular microenvironments is crucial, as cells receive signals not only from each other but also from their surroundings.
The research team included collaborators from various institutions, supported primarily by Brown University’s Hibbitt Engineering Fellowship, the National Institutes of Health, and the U.S. Army Research Office.
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