The human body is remarkably dynamic, reshaping itself from the inside out as we age. Take the blood system, which is made up of stem cells — specifically, hematopoietic stem cells (HSCs), immature cells that develop into blood cells. As we age, these cells exhibit a dog-eat-dog mentality, competing with neighboring blood cells. The stronger cells gradually clone themselves, taking over blood production and minimizing diversity in the blood system. A new study in the journal Nature examines this process, exploring how reduced stem cell diversity during aging can prompt the unbridled creation of potentially harmful myeloid cells.
Clonal Behavior in the Human Blood System
The study was performed at the Centre for Genomic Regulation (CRG) in Barcelona. The published material focuses on “barcodes” written into human DNA, which helped the CRG team evaluate the clonal properties of stem cells in the blood system.
Dr. Lars Velten, the co-corresponding author of the study, wrote that “blood stem cells compete for survival.” He went on to explain, “In youth, this competition produces a rich, diverse ecosystem while in old age, some drop out entirely. A few stem cells take over, and these work extra hard to compensate. This reduces diversity, which is bad for the blood system’s resilience.” In other words, the blood system changes as we age, becoming dominated by clones of certain stem cells. Velten’s team observed that during aging, those stem cells frequently show a preference for producing myeloid cells, immune cells that are linked to chronic inflammation. To make this discovery, the team had to get creative.
Genetically Engineering the Blood System
Per the CRG release, the scientists “had to solve a long-standing technical challenge to make their discovery.” To evaluate how certain stem cells take over blood production in the process of aging, the team had to track each individual blood cell back to its original stem cell. In theory, this process would require genetically modifying human DNA, an unethical and logistically impossible task. Instead, the team turned to epimutations, which are epigenetic changes in the methylation marks attached to DNA. The release explains: “When a stem cell divides, methylation marks are copied to its daughter cells, leaving behind a permanent, natural ‘barcode’ that researchers can ‘scan’ or read to chart each cell’s position in the family tree.” To read these barcodes, researchers had to develop a proprietary technique.
The Epi-Clone Technique and Clonal Expansion
Ultimately, the team developed a new technique called EPI-Clone to read the methylation barcodes. They used an existing single-cell sequencing platform to reconstruct the history of blood production in both mice and human subjects. This allowed the team to trace which stem cells were competitive enough to create blood cells over the long term.
The results were fascinating. Studying older mice, the team found that up to 70 percent of blood stem cells belonged to just a few dozen large clones. Studying humans, the team found that larger clones begin to take over the blood system around age 50.
In both humans and mice, many of the larger clones, defined as clones that individually made up at least 1 percent of total HSCs, exhibited a preference for producing myeloid cells, which are linked to chronic inflammation. Could scientists find a way to remove myeloid-biased stem cells in humans? The research is still in its early stages. However, the Epi-Clone technique could leverage the naturally occurring “barcodes” to find a solution.
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While the Epi-Clone technique is still new, future findings could pave the way for preventive care in older adults. For example, a clinician could monitor a patient’s blood stem cell pool for a rapid expansion of risky stem cell clones. This could provide more positive outcomes for aging individuals predisposed to chronic illness.
Scantox Neuro offers several in vitro and in vivo models of aging, including SAMP8 mice, and corresponding biomarker measurements, such as DNA methylation, β-galactosidase activity, mitochondria and reactive oxygen species (ROS), inflammation, cognitive deficits, and motor impairments.
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