Particle physics experiments

Experiments show how sugar molecules can be used to track stem cells in the brain

Unlike most other cells, mannose residues (green) are abundant on the MSC cell membrane. Thanks to an MRI technique sensitive to the presence of mannose, monitoring of transplanted MSCs is now possible without the need to label them. Credit: Image courtesy of Shreyas Kuddannaya

A Johns Hopkins Medicine scientist who has spent 30 years figuring out how to put chemical markers into cells to track their movement through living tissue has discovered that some self-renewing stem cells have built-in tracers – made from sugars – that can do the job without added chemical “tags” when injected into the brains of mice. The discovery, made with stem cells widely integrated into experimental therapies for multiple sclerosis and other neurodegenerative diseases, was a pleasant surprise, according to the researchers.

“There’s a whole field of science dedicated to the chemical and genetic marking of cells, because otherwise we can’t see where specially and expensively designed therapeutic cells travel and whether they arrive at their intended place in a body to repair or replace the diseased tissue,” says Jeff Bulte, Ph.D., professor of radiology and radiologic sciences at Johns Hopkins University School of Medicine and director of cell imaging at the Johns Hopkins Institute for Cellular Engineering. .

If confirmed by further experiments, the new study should, according to Bulte, streamline and advance restorative research for diseases of the brain, an organ considered the most difficult to track therapies due to the sensitive nature of the brain and of its blood-brain barrier. .

In Bulte’s experience, he says, labeling therapeutic cells ready for human clinical trials in any organ is an expensive and difficult process, requiring extensive safety studies and allowing teams of scientists to focus on finding better ways to track therapeutic cells damaged by multiple sclerosis and other neurodegenerative diseases.

For such research, scientists have long used so-called mesenchymal stromal cells, a type of stem cell found in bone marrow that can develop into many cell types and also reduce inflammation.

In the new proof-of-principle study described today (February 7, 2022) in Nature Biomedical EngineeringBulte and his research team discovered that these mesenchymal stromal cells contain high levels of a sugar called mannose, which is similar to glucose and can be spotted easily and successfully with a standard imaging method based on CT imaging. magnetic resonance (MRI).

Bulte’s team came up with the idea of ​​using sugars as tracers after publishing another study in Nature Communication showing that some tumor cells lose large amounts of sugar molecules easily detectable by MRI machines. Yue Yuan, Ph.D., a researcher in Bulte’s lab, found that stem cells had an abundance of mannose – about two to three times the amount found in typical cells.

Because mammalian cells typically lack a high sugar content, Bulte and his team reasoned, stem cell injections that are naturally high in sugar would potentially be easy to spot against the background of brain tissue.

For their study, Bulte’s team injected four types of human cells into the brains of live mice, including mesenchymal stem cells. For each type of cell, the researchers injected 300,000 cells.

Next, the researchers used MRI to track where they found clusters of injected cells over a two-week period.

They found that the MRI signal from the mesenchymal stem cells was about 60% higher than that from the other three injected cell types and was easily visible on the MRI images for up to two weeks after injection. Interestingly, they say, only live cells produced an MRI signal, creating an opportunity to use the technique to determine survival of transplanted cells, as well as follow-up.

Bulte’s team plans further studies to determine if cellular sugar molecules can be used to detect the differentiation of stem cells into other cell types.

“It’s amazing to discover, 30 years after I started my cell-tagging research, that these brain mesenchymal stem cells don’t need to be chemically tagged for tracking purposes after all, and it there may be better and easier ways to track these cells in the brain,” says Bulte.

Reference: “In vivo monitoring of unlabeled mesenchymal stromal cells by mannose-weighted chemical exchange saturation transfer MRI” by Yue Yuan, Congxiao Wang, Shreyas Kuddannaya, Jia Zhang, Dian R. Arifin, Zheng Han, Piotr Walczak, Guanshu Liu and Jeff WM Bulte, February 7, 2022, Nature Biomedical Engineering.
DOI: 10.1038/s41551-021-00822-w

This research study was supported by the Pearl and Yueh-Heng Yang Foundation and the National Institutes of Health (R56 NS098520 and P41 EB024495).

In addition to Bulte and Yuan, scientists who have contributed research to Johns Hopkins include Congxiao Wang, Shreyas Kuddannaya, Jia Zhang, Dian R. Arifin, Zheng Han, Piotr Walczak, and Guanshu Liu.

Bulte is a paid consultant for NovaDip Biosciences SA, NanomediGene LLC and SuperBranche. These arrangements have been reviewed and approved by Johns Hopkins University in accordance with its Conflict of Interest policies.