Key takeaways
Multipotent progenitors, a kind of "parent" blood cell, act as a buffer against the effects of aging that are well-documented in blood stem cells.
The results help confirm that it is safe to accept bone marrow transplants from older donors.
As people age, so too do their stem cells. Scientists have known for years that the stem cells that go on to become blood cells show significant signs of aging that sometimes lead to leukemia, excessive blood clotting and other diseases.
A new study from researchers at the University of California, Santa Cruz reveals that even as blood stem cells age, the cells they turn into are often remarkably unaffected. The scientists provide evidence that specific "parent" cells may act as a buffer to protect the blood from the effects of aging.
The researchers, led by Professor of Biomolecular Engineering Camilla Forsberg and Biochemistry Ph.D. graduate Jenna Myers, published their findings in the journal Stem Cell Reports. Their work provides fresh, surprising insights into how blood cells are produced, and has implications for the safety of bone marrow transplants.
MPPs as a buffer
Camilla Forsberg's lab at the Institute for the Biology of Stem Cells and the Baskin School of Engineering focuses on blood cell development and its implications for clotting and heart disease, cancers, infectious disease, and more.
Blood-forming stem cells, called hematopoietic stem cells, live in the bone marrow and have the unique ability to self-replicate to sustain the body with blood for life. Like all stem cells, they go through several stages as they differentiate into their final specialized form.
As the body ages, hematopoietic stem cells show significant signs of aging, but the resulting blood cells aren't always affected. To understand why, the researchers decided to look at multipotent progenitors (MPPs), a kind of "parent" blood cell that is created in the first stage in the differentiation process for many blood cells.
First, they transplanted young and old mouse MPPs into a new host to see if they could produce new cells in this setting. Transplantation is a gold-standard assessment of blood cell function and is a curative treatment for human patients with cancer and genetic abnormalities. Surprisingly, while hematopoietic stem cell function declines with age, they found that there was no functional difference between old and young MPPs.
"The preliminary data that we found was pretty exciting, that there were no changes in function upon transplantation with age—and then we dug a little deeper," Myers said.
To further explore these findings, they examined the old and young MPPs to look for changes in cell proliferation and mitochondrial function—how well cells produce energy. These are well-documented ways that hematopoietic stem cells show signs of aging, but once again, they found no significant changes to MPPs.
"When people talk about hematopoietic stem cell aging, they tend to look at these factors, and they see drastic changes with aging," Myers said. "We wanted to test MPPs in those same contexts, and excitingly, strikingly, we found that there were no significant changes."
When analyzing gene expression, the researchers found that while more than 600 genes changed significantly between young and old hematopoietic stem cells, there were only 126 differentially expressed genes between young and old MPPs. This finding was supported by the rigorous contributions of bioinformatics specialist Paloma Medina.
The researchers also examined these same changes in other progenitors—other types of parent cells further down in the differentiation process—and similarly saw no differences with age.
"We think the MPPs are the instigators of this buffering effect, but the other progenitors also don't have functional differences. I don't think people have really thought about that aspect before," Forsberg said.
Safe bone marrow transplants
These findings help confirm the safety of bone marrow transplants, a common treatment for blood cancers and other blood and immune system diseases. Knowing that hematopoietic stem cell aging is most often not passed down to other blood cells means that doctors can be more confident in accepting bone marrow from older donors, even in self (autologous) bone marrow transplants.
The researchers provide three hypotheses as to how these MPPs may act as a buffer, leaving this as an open question for other researchers. But for the Forsberg Lab, this paper serves to steer their ongoing research toward a focus on a type of blood progenitor cell that does not pass through the MPP stage, as those cells have been shown to cause increased risk for aberrant blood clots and cardiovascular disease with aging.
Additional contributors to this work include previous Forsberg Lab Ph.D. students Atesh Worthington and Donna Poscablo, current Ph.D. student Raana Mogharrab, and postdoctoral scholars Saran Chattopadhyaya and Marcel Rommel.
