New research from the Howard Hughes Medical Institute (HHMI) utilized a shared-blood circulation mechanism in mice to provide support to the idea that stem cells from older organisms can adopt the capabilities of younger ones, when younger stem cells are introduced into an aging organism. The researchers, led by HHMI early career scientist Amy J. Wagers of Harvard Medical School, studied the hematopoietic stem cells in the blood of old mice that had been exposed for several weeks to the blood of young mice. The bone marrow stem cells in the old mice were reduced in number but became more effective at replenishing the blood system, which is characteristic of young stem cells.
To determine if exposure to young blood could reverse the effects of aging on stem cells, Wagners’ team surgically joined the bloodstreams of pairs of mice. The technique, called parabiosis, attached the circulatory systems of mice of different ages that were genetically similar, to enable the researchers to analyze the effects of one animal’s blood on the other animal. The researchers were able to differentiate between the blood of each animal using distinctive genetic markers.
“It’s the only model that really allows us to come close to mimicking an in vivo systemic environment,” Wagers said in a press release. “There is a constant exposure to any cell or soluble factor that circulates, at close to physiologic levels.”
Following exposure to the blood of the young mice, the researchers noticed a difference in the stem cells of the older mice. According to Wagers, old stem cells are characteristically less efficient at producing new cells, and are numerous because they build up over time. After several weeks, the researchers observed that the older stem cells had diminished in number, but those that still existed were producing new cells at a significantly higher efficiency, nearly recovering all of the cell-generation capacity of young stem cells. To test the old stem cells’ rejuvenated ability, the researchers transplanted the cells into mice whose own hematopoietic stem cells had been destroyed by radiation. The old stem cells repopulated the blood with cell types similar to those generated by young stem cells.
The researchers have not isolated the blood-borne factors that trigger this apparent switch from old to young, but they did form two conclusions about how these factors modify the stem cells. The team found that the unknown factors work through bone-forming cells called osteoblasts, which are known to help regulate hematopoietic stem cells in bone marrow. They determined this through a comparative analysis of the effects of exposing osteoblasts to young and old blood. The researchers also found that insulin-like growth factor 1(IGF-1) hormone is related to aging in osteoblasts. The researchers blocked IGF-1 activity in osteoblasts in culture and in bone marrow, and found that the osteoblasts began acting younger. Blocking IGF-1 activity in the blood did not produce the same effect, which signaled that the youthful ability was passed to the hematopoietic cells through the osteoblasts in the bone marrow.
“Our findings highlight the fact that IGF-1 signaling is complex and depends in part on the tissue involved,” said Wagers.
Wagers intends to focus subsequent studies on the signaling pathway to determine which factors circulate in the blood and trigger the rejuvenation activity in the bone marrow. “Knowing what these circulating factors are could enable the development of drugs to boost stem cell functions, for example, to restore a more youthful and healthy pattern of blood cell production in older individuals,” said Wagers.
According to Wagers, though the team has not yet determined the exact factor, the findings show the importance of understanding local cellular environments when studying stem cell activity. “If you’re thinking of transferring stem cells into a recipient to replace cells that have been lost to disease, you have to think a lot about the state of that recipient,” said Wagers. “In the wrong environment, even perfectly healthy young stem cells could lose much of their regenerative potential.”
The paper, “Systemic signals regulate ageing and rejuvenation of blood stem cell niches,” was published online Jan. 28 ahead of print at Nature.
