Seeing blood stem cells where they live

February 5, 2020

Live imaging of blood stem cells reveals that location matters in the bone marrow

Video of blood stem cell under the microscope.
Blood stem cell (green) and blood vessels (red) in the bone marrow. Credit: Camargo and Lin Labs

 

The stem cells found in bone marrow have saved the lives of thousands of leukemia patients through transplantation, as they are capable of making any type of blood cell. Yet there are roadblocks to understanding these blood stem cells in detail, as it has not been possible to study them at their source.

Now, researchers at the Harvard Stem Cell Institute (HSCI) have found a way to observe blood stem cells at an unprecedented level of accuracy and detail in mice. Using their new imaging method, the team revealed how stem cells behave differently depending on where they are located in the bone marrow. The findings, published in Nature, give scientists a better understanding of how to manipulate blood stem cells, paving the way for new treatments.

“There has been controversy about exactly where blood stem cells are located within the bone marrow — exactly which neighborhood the cells are in, and the properties of that neighborhood,” said Fernando Camargo, Ph.D., professor of stem cell and regenerative biology at Harvard and principal faculty member of HSCI. “This is the first time that we can visualize native blood stem cells, which allows us to discover new and important properties.”

Better than transplantation

Previously, to observe how blood stem cells behave in a living system, researchers had to remove the cells, label them, and transplant them back into mice. But transplantation is a disruptive process, so these observations came with a big measure of uncertainty.

To overcome this problem, HSCI researchers developed a way to observe stem cells without transplantation. They engineered a mouse model with inherently labelled blood stem cells.

“We have been doing a lot of stem cell imaging over the past few years, and always had to transplant the cells in order to visualize them. This is first time we could do this type of study without transplantation,” said Charles Lin, Ph.D., associate professor at the Center for Systems Biology and Wellman Center for Photomedicine at Massachusetts General Hospital and an affiliate faculty member of HSCI.

Discovering new properties

Using their new method, the HSCI researchers were able to answer long-standing, fundamental questions about blood stem cell biology.

“Stem cells only multiply some of the time, so one basic question is, how do stem cells know when to multiply?” Lin said. “By visualizing stem cells in this system, we found that there are different locations within the bone marrow where the cells have different activities.”

Bone marrow, they discovered, is not uniform — it has pockets with different properties, such as bone remodeling and what type of cell immediately surrounds the blood stem cells.

“This study is a perfect example of interdisciplinary work,” Camargo said. “We brought experience in genetics and stem cell biology. The Lin lab brought expertise in microscopy and cell tracking. Now that we can obtain this information, we can think about new strategies for manipulating blood stem cells.”

The team’s new technology will now allow them and other researchers to study stem cell behavior in other conditions, such as infection, aging, and cancer.

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Source article: Christodoulou, C., Spencer, J. A., Yeh, S. C. A., et al. (2020). Live-animal imaging of native haematopoietic stem and progenitor cells. Nature. DOI: 10.1038/s41586-020-1971-z

Funding: This study was supported by the National Institutes of Health. Fernando Camargo is a Leukemia and Lymphoma Society Scholar and a Howard Hughes Medical Institute Scholar.