Finding Their Sense of Direction: Cell Movement Helps Tissues Establish Polarity | Newswise

Newswise — From the hairs on our arms to the microscopic sensory structures of the inner ear, many tissues in the body are built with a clear sense of direction. To build these structures throughout development, individual cells must establish which way they are facing—and coordinate that orientation with cells around them. If they get this wrong, tissues may fail to form, form improperly, or fail to function.

How tissues establish this collective sense of direction from an initially unorganized state has long been a question in developmental biology.

Now, researchers in the lab of Whitehead Institute Member Pulin Li have recreated this process in engineered epithelial cells, which form sheets that cover the body’s surfaces and line its organs. The researchers used these cells to watch planar polarity–or the coordinated orientation of cells within such a sheet–emerge in real time. Published in Proceedings of the National Academy of Sciences on October 15, their findings show that collective cell migration provides a cue that establishes coordinated polarity across many cells. The study, led by first author Leah Wallach, a graduate student in the Li lab, in collaboration with fellow graduate student Connor Thomas, also identifies the junctional protein CELSR as a key driver of polarity initiation.

The work focuses on planar cell polarity (PCP), the asymmetric or directional organization of protein complexes within the plane of a tissue. PCP enables cells to coordinate their orientation across tissues and is essential for processes that shape the developing body and its organs. For example, sound travels across the sensitive hairs in our ears in a directional wave; if the hairs do not all grow facing the same direction, then the wave cannot flow, and the ear cannot properly register sound. Disruption of PCP is associated with developmental disorders including spina bifida and craniorachischisis, as well as hearing loss and chronic lung disease.

Scientists have identified many of the proteins involved in PCP. But one fundamental mystery remains: What initially tells cells which direction to face?

Gradients of signaling molecules such as WNT proteins have been proposed as guidance signals, whereas mechanical forces can help maintain or redirect polarity in already polarized tissues. But what initiates PCP in the first place has remained unclear. Studying that step in animals is especially difficult because polarity develops as tissues develop, grow, move, and change shape, making it hard to catch the moment of initiation.

Li and her colleagues instead rebuilt the process from the bottom up in cells cultured on petri dishes.

Using engineered epithelial cells that initially lacked planar polarity, the researchers fluorescently labeled proteins involved in establishing PCP so they could track their movements over time. They accidentally discovered that when the cells are induced to migrate collectively, CELSR-containing junctions become enriched along their front-to-back axis. This molecular asymmetry aligned across neighboring cells and continuously propagated to cells behind, transforming an initially nonpolarized sheet into a tissue with coordinated planar polarity.

In developmental biology, the transition from a uniform state to one with a defined orientation is known as symmetry breaking. The experiments showed that collective migration itself could provide the symmetry-disrupting cue that starts this process.

“We’ve identified a cue, and we’ve also found what we think is the protein responsible for actually reading that signal,” said Wallach. “Being able to recreate this process in cell culture lets us separate pieces that are extremely difficult to separate in an animal and watch the pattern form in real time.”

The engineered system also enabled the researchers to distinguish between two competing ideas about how polarity becomes coordinated across a tissue. One possibility was that each cell directly senses the directional cue. Another was that a subset of cells senses it first and then relays the information to neighboring cells.

The researchers found that individual cells directly interpreted the migration cue and remained responsive to it, supporting the first model.

Their experiments also revealed an important role for CELSR, a protein that forms connections at junctions between neighboring cells. Core PCP involves CELSR and two other protein families, Frizzled (FZD) and Van Gogh-like (VANGL). Surprisingly, CELSR polarity emerged without the reciprocal VANGL-FZD interactions, identifying CELSR as a driver of polarity initiation.

“Coordinating the orientation of cells is essential for the function of tissues such as the airway and inner ear, yet remains difficult to achieve in engineered tissues,” says Li. “This work illustrates how a reductionist approach can uncover fundamental principles underlying complex developmental processes and provide tools to control cell behavior in engineered tissues.”

The work takes a synthetic developmental biology approach, reconstructing a complex developmental process in a controlled laboratory setting. Before this study, researchers lacked a cell culture model that could reproduce key features of PCP, including polarity initiation and coordinated alignment across many cells. The new system makes it possible to trigger polarity and follow the process as it unfolds.

The findings also suggest a wider principle about development. Cell and tissue movements are often viewed as outcomes of molecular patterning programs: cells receive spatial instructions and then move accordingly. This study shows that the relationship can also run in the opposite direction. A collective behavior — collective cell migration — can itself provide spatial information that generates a molecular pattern.

Eventually, those principles could inform efforts to engineer functional tissues. Producing the right cell types is not always enough; in many organs, cells must also be correctly oriented. For now, the researchers have created a way to start with an unpolarized tissue, trigger its sense of direction, and watch organization emerge from molecules to cells to tissue.

Original release: https://wi.mit.edu/news/finding-their-sense-direction-cell-movement-helps-tissues-establish-polarity