• Wed. Feb 28th, 2024

Zooming in time and space simultaneously with super-resolution to understand how cells divide

Zooming in time and space simultaneously with super-resolution to understand how cells divide

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This hourglass depicts the process of super-resolution over time, where a protein at the bottom and a dividing cell at the top go from unresolved, on the left, to resolved, on the right. Credit: Somin Lee, CC BY-ND

cell division, or the process of how daughter cells arise from a mother cell, is fundamental to biology. Each cell inherits the same protein and DNA building blocks as the cell from which it originally arose. However, how these molecular building blocks organize themselves into new cells remains a mystery.

Studying cell division requires simultaneous observation of nanometer-scale macromolecules, such as proteins and DNA, as well as millimeter-scale populations of cells, on time scales ranging from seconds to weeks. Previous microscopes They were able to capture small objects in short time frames, usually just tens of seconds. There has never been a method that can probe a wide range of size and time scales simultaneously.

my group And I at the University of Michigan Bioplasmonics Group A was developed A new type of super-resolution imaging It reveals previously unknown features of how cells divide.

Super-resolution imaging in progress

Until recently, it was not possible to see cells at the molecular level 2014 Nobel Laureate The development of super-resolution.

Conventional light microscopes Blur very small objects They are close together in a sample because light spreads as it travels through space. With super-resolution, fluorescent probes attached to the sample can be turned on and off like twinkling stars on a clear night. By collecting and combining many images from these probes, a super-resolution image can bring very small objects into view. Super-resolution has opened up a new world in biology, revealing structures as small as 10 nanometers, the size of a protein molecule.

However, fluorescent probes that rely on this technique can wear out quickly. This limits its use in studying long-term processes such as cell division.

My research team and I have developed a solution we call Pine nanoscopy. Instead of absorbing light as traditional fluorescent probes do, the probes we use scatter light so they don’t break down with repeated light exposure.

To resolve very small objects in close proximity, we built filters made of thin layers of polymers and liquid crystals, which allow detection of scattered light, which triggers the probes to turn on and off. This allowed us to see nanometer-scale details of cells that would be obscured by conventional microscopes.

Remarkably, we found that these nanometer-scale details can be observed for very long periods of time—more than 250 hours. This detail is usually lost over time using traditional super-resolution methods.

This pine microscopy image shows cells dividing and their nuclei colored blue. Credit: Somin Lee/Nature Communications, CC BY

Shedding new light on cell division

We applied our method to study how molecular building blocks are organized during cell division.

We focused on A A protein called actin It helps maintain cell structure along with many other functions. Actin takes the form of branched filaments that span thousands of nanometers, each about 7 nanometers (millionths of a millimeter) in diameter. Using pine nanoscopy, we attached scattering probes to actin to visually follow dividing human cells.

We made three observations about how actin building blocks are organized during cell division. First, these molecular building blocks expand to increase their connections with their neighbors. Second, they become closer to their neighbors to increase their contact points. Third, the resulting networks contract when actin molecules are more interconnected and expand when they are not interconnected.

Based on these findings, we were able to Find new information About the process of cell division. We found that interactions between actin building blocks synchronize with the contraction and expansion of the whole cell during division. In other words, the behavior of actin molecules is related to the behavior of the cell: when actin expands, the cell contracts, and when actin contracts, it expands.

Super-resolution microscopy won the 2014 Nobel Prize in Chemistry.

Detecting disease with super resolution

We plan to use our method to study how other molecular building blocks are organized into tissues and organs. Like cells, tissues and organs Organized in a hierarchy It can be examined on a small and large scale. Examining the dynamic and complex process of how protein building blocks interact with each other to form larger structures could advance the creation of new replacement tissues and organs, such as skin grafts, in the future.

We also plan to use our imaging technique to study how protein building blocks become disordered in disease. Proteins are organized into cells, cells into tissues, and tissues into organelles. The building blocks can be modified very little Disturb this organization, with effects that cause diseases such as cancer. Our technique will help researchers better understand and visualize how molecular abnormalities in tissues and organs develop into disease.

More information:
Guangjie Cui et al., Phase intensity nanoscope (PINE) opens long-term probing windows of living organisms, Nature communication (2023). DOI: 10.1038/s41467-023-39624-w

Journal Information:
Nature communication

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