Our cells are built from smaller structures that specialize in the key tasks of life, from cell division to cellular trash collection. And how those smaller parts fit together in three dimensions can affect the health of cells and of the body.
Researchers at Seattle’s Allen Institute for Cell Science and their colleagues have now developed a way to quantitatively map how these cellular components are arranged in space. Their approach, published in Nature, has the potential to be adapted broadly by scientists to investigate how cells operate.
The researchers analyzed more than 200,000 human stem cells at high resolution in three dimensions. They assessed the position of multiple internal structures, each visualized by a fluorescent label.
The data were used to make maps showing the average location of the internal structures, as in the video below.
The researchers found that some structures were always located in about the same place, whereas others showed more variability in their placement. They could measure how cellular organization shifted as cells entered cell division or otherwise changed state. And they could simulate cell transitions such as changes in the cytoskeleton that occur in cells at the edge of a cell colony.
When the researchers found they could simulate such transitions, that’s when they knew their approach was working as intended, said author Julie Theriot in a Nature summary linked to the study.
“Seeing the computer take a relatively small list of numbers and reproduce a completely convincing movie of how the cytoskeleton must adapt itself for cells exposed at the colony edge made me laugh out loud,” said Theriot, a University of Washington professor.
The researchers made their maps by first computationally representing the shape of the cell and then the components in it. Here’s roughly how that worked:
- They represented the shape of a cell using an eight-dimensional “shape space.” In the shape space, a single point represented the shape of each cell and its nucleus.
- Points that clustered together represented cells of a similar shape. The researchers could computationally “squish and stretch” cells in each cluster into a template shape.
- Templating the shapes facilitated the generation of a map providing the coordinates of the location of each cell structure.
“We’ve come up with a framework that allows us to measure a cell’s shape, and the moment you do that you can find cells that are similar shapes, and for those cells you can then look inside and see how everything is arranged,” said Allen Institute senior scientist Matheus Viana in an Allen Institute post. Viana led the study, which involved more than 80 researchers over seven years, with Allen Institute for Cell Science deputy director Susanne Rafelski.
The study examined only one type of cell, induced pluripotent stem cells derived from adult tissue. But the approach has the potential to be used on multiple cell types to analyze how cell interiors change during development or disease.
“This approach is generalizable to virtually any cell, and I expect that many others will adopt the same methodology,” said study author Wallace Marshall, a professor at the University of California, San Francisco and a member of the Allen Institute for Cell Science’s scientific advisory board.