Using live imaging and cellular barcodes, researchers at Boston Children’s Hospital’s Stem Cell Program have glimpsed how new stem cells — in this case, blood stem cells — are quality checked shortly after birth. The study, which may have implications for cancer and regenerative medicine, was published Sept. 22 in the journal Science.
Led by Sam Wattrus, a Ph.D. candidate in the lab of Leonard Zon, MD, the researchers used a zebrafish model to observe the development of stem cells. When a stem cell is born, they found, it travels to a special location where immune cells known as macrophages come into intimate physical contact with each cell.
That’s when the vetting takes place: Cells showing signs of stress (with high levels of toxic molecules known as reactive oxygen species) were engulfed and eaten by the macrophages, the team found. In contrast, apparently healthy stem cells were allowed to remain alive and were selectively amplified.
“Whenever a macrophage interacts with cells, it takes in an enormous amount of biological information,” Wattrus says. “What we’re seeing is that high-stress cells are eliminated and low-stress cells selectively divide.”
Further investigating, Wattrus and colleagues showed that the stressed stem cells carried a specific marker on their surface, a protein known as calreticulin, which acts as an “eat me” signal. Stem cells without calreticulin, or with only small amounts, were not eaten and seemed to be encouraged to expand. The macrophages seemed to be removing some material from them and the stem cells started to multiply after the encounter.
“Using cellular barcoding, we can measure the number of clones (different cell populations) after the interaction has occurred,” explains Zon, who is also a member of the Department of Hematology/Oncology and a Howard Hughes Medical Institute investigator. “If a macrophage doesn’t ‘like’ a stem cell, that clone will not contribute to the stem cell pool.”
Potential implications for cancer, regenerative medicine
The team also observed similar macrophage-stem cell interactions in embryonic mice. Zon thinks this QA process could lead to new approaches to cancer and regenerative medicine, and is currently exploring both possibilities in his lab.
“You would basically teach the stem cells to be attractive or repulsive to small molecule macrophages or other targeted therapies,” he says.
It is well known in the cancer world that cancer cells can germinate “don’t eat me” signals to evade attacks from our immune system, and there is a lot of interest in blocking these signals with antibodies to outsmart the cancer. But Zon is more interested in the “eat me” signals and whether they can be introduced into precancerous or cancerous cells to encourage macrophages to destroy them.
Such approaches could potentially be used in precancerous conditions such as clonal hematopoiesis and myelodysplasia, characterized by blood stem cell rogue states, or in leukemia and other blood cancers.
“There may be a way to use a small molecule to tax the cell, leading to calreticulin on the surface that causes the offending clones to be eaten,” Zon speculates.
He envisions the opposite approach in tissue regeneration, where stem cell markers can be manipulated to encourage macrophages to optimize the stem cell pool for cell-based therapies. Although this research focused on blood stem cells, Zon considers it likely that other stem cell populations are exposed to a similar QA process.
If so, there could be major potential lifelong health implications. “Your stem cell pool is made for the most part during embryonic development,” notes Zon. “Interactions that take place here determine which stem cells will be used in adulthood.”
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Samuel J. Wattrus et al, Quality Assurance of Hematopoietic Stem Cells by Macrophages Determines Stem Cell Clonality, Science (2022). DOI: 10.1126/science.abo4837
Quote: Providing ‘Quality Assurance’ for New Stem Cells: Macrophages Do the Check (2022, September 28) Retrieved September 28, 2022 from https://phys.org/news/2022-09-quality-stem-cells-macrophages-vetting. html
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