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Combination method peers into tissues to study early disease processes

Researchers combine tissue clearing with proteomics

by Laurel Oldach
December 27, 2022


One photo, labeled “Before extraction,” shows a fluorescence image of a transparent mouse head. The second, labeled “After extraction,” zooms in on a boxed region in the first photo and shows several circles where tissue has been removed.
Credit: Cell
Researchers extracted bone marrow immune cells from the cleared skull of a mouse (left) and used proteomics to study the molecular composition of small tissue regions (circled areas, right). Green shows all cells, blue shows cell nuclei, and magenta shows a marker for neutrophils, a type of immune cell.

The first method to combine tissue clearing and proteomics allows researchers to peer into tissues to find early markers of disease. By making tissues almost transparent, researchers can then reach in and pluck out particular areas to study their proteins. The study authors say the method will be useful for understanding processes such as plaque formation early in Alzheimer’s disease and how atherosclerotic deposits become lesions (Cell 2022, DOI: 10.1016/j.cell.2022.11.021).

Maladies such as cancer and neurodegeneration need to be treated earlier, Ali Ertürk of the Helmholtz Institute of Tissue Engineering and Regenerative Medicine says. “Otherwise, the chances [of success] are very low.” But it can be difficult for scientists to find the one small part of a mostly healthy organ that has begun to go wrong, something essential for understanding how diseases begin in model organisms and developing better interventions.

Ertürk and coauthor Matthias Mann of the Max Planck Institute for Biochemistry focus their research on tissue clearing and proteomics methods, respectively. Proteomics uses mass spectrometry to identify all the proteins present in a sample. Tissue clearing involves a group of chemical treatments that makes imaging easier by removing molecules that scatter light, while also immobilizing proteins and other large molecules.

After clearing tissues in mouse organs and even whole mice, the team labeled a small number of target proteins to visualize under a microscope. Then, using a purpose-built robot, they extracted small regions, such as the area around an early plaque buildup in the heart, and cataloged the proteins in those regions. Initially, Ertürk says, the two labs doubted that combining their methods would work; it came as a surprise that they could recover as much protein from cleared tissue as from fresh tissue.

Hiroki Ueda of the University of Tokyo, who works on cleared tissue imaging but was not involved in this study, says in an email that although imaging cleared tissues gives a large-scale view of cells in context, this new combined protocol allows researchers to zoom in on molecular changes. It remains to be seen whether tissue clearing can be combined with other “-omics” methods such as transcriptomics, which involves RNA sequencing.



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