Researchers Rejuvenate Aged Mouse Blood Stem Cells

Key Points: 

• After two weeks of treatment with Netrin-1, the bone marrow niche of old mice is restored to its youthful state.
• This Netrin-1 supplementation also revitalizes the efficiency and regenerative potential of aged blood stem cells.
• The therapeutic effects of Netrin-1 may improve healthspan and lifespan as well as accelerated recovery and increased survival during chemotherapy.

Researchers from the University of Florida Health Cancer Center, Hackensack University Medical Center, and Weill Cornell Medicine identified a developmental molecule called Netrin-1 as a critical regulator of bone marrow cell aging. Co-lead authors Ramalingam, Gutkin, and Poulos demonstrate that supplementation of aged mice with Netrin-1 rejuvenates aged bone marrow and restores the competitive fitness of aged blood stem cells to youthful levels. The research, published in Nature Communications, has therapeutic implications for the treatment of aging-related blood disorders like hematologic malignancies (blood cancers), such as lymphoma, myeloma, and leukemia.

Keeping Blood Stem Cells Young

All of our blood cells, including white blood cells, red blood cells, and platelets, are developed from blood stem cells that reside in our bone marrow. The production and function of various blood and immune cells can be disrupted by certain mutations in these blood stem cells, which can eventually lead to cancer. We may be born with these variations, or they may develop over the course of our lives. Having a strong immune system at a young age can prevent cancer from developing, but stopping it before it poses a significant threat to health and longevity is much more likely at a later age.

Hematopoietic stem cell transplantation (HSCT) is a treatment option for blood cancers that involves replacing damaged or diseased blood cells with healthy ones. Patients undergoing this therapy must first undergo conditioning, a procedure that destroys their existing blood stem cells in the bone marrow so that the transplanted cells can survive and engraft there to generate an effective immune response. However, the regenerative ability of the blood system to recover from the toxic effects of conditioning decreases with age, increasing the risk of HSCT failure in elderly patients.

Netrin-1 Restores Regenerative Capacity of Aged Blood Stem Cells

Co-led by Pradeep Ramalingam, Michael Gutkin, and Michael Poulos, this Nature Communications article explored the possibility that revitalizing bone marrow niches (networks of thin-walled, porous blood vessels whose integrity is maintained and supported by surrounding blood stem cells) could revive the functionality of aged blood stem cells. To find factors that can boost niche function and blood stem cell fitness as the body ages, researchers analyzed gene activity data from a recently described murine model that exhibits premature aging of the blood system.

Based on their findings, it appears that Netrin-1 has some responsibility for controlling how the bone marrow niche ages. Netrin-1 is a well-known guidance cue that has recently been shown to regulate various processes, such as the formation of new nerves, blood vessels, and bones and the maintenance of blood stem cell dormancy in young mice. According to studies conducted by Ramalingam, Gutkin, and Poulos, Netrin-1 is essential for cells in the bone marrow niche and blood stem cells to keep their DNA damage response going strong, prevent further DNA damage, and keep functioning normally even as they age. They also showed that adding Netrin-1 to blood stem cells and niche cells revived the sluggish DNA damage response and repaired the accumulated damage.

These results suggest that downregulation of the DNA damage response may be the basis for a fundamentally conserved property of tissue-specific stem cells and the microenvironments that sustain them. The research team shows that treating old mice with lab-made Netrin-1 is enough to fix some of the problems that come with old bone marrow niches. This includes fixing broken blood vessels in the bone marrow and stopping the buildup of unhealthy fat in the bone marrow that comes with getting older. The team also shows that the self-renewal capacity of aged blood stem cells is restored to youthful levels following niche rejuvenation mediated by Netrin-1. 

Netrin-1 Improves Survival From Chemotherapy During Aging

The positive effects of Netrin-1 on hematopoietic regeneration were of interest to Ramalingam, Gutkin, and Poulos, and they were curious if these effects carried over to chemotherapy. The researchers put this theory to the test by administering a chemotherapeutic to old mice every 35 days and monitoring their survival for 140 days. Following the first injection of the chemotherapeutic, aged mice were treated with either saline or Netrin-1 every other day for a total of 5 injections and did not receive additional Netrin-1 treatment following subsequent chemotherapeutic doses.

Consistent with what is already known about the decline in the ability of blood stem cells to self-renew and regenerate with age, 75% of the PBS-treated aged mice died of hematopoietic failure after only two doses of chemotherapy, and only 1 out of 18 mice survived all four doses. In contrast, Netrin-1 treatment resulted in a hundred percent survival rate in aged mice. These findings suggest that treatment with Netrin-1 can protect the hematopoietic system from the progressive loss of stem cell reserves and preserve body weight; toxicities commonly associated with chemotherapy in older patients, while also preserving the self-renewal and regenerative capacity of aged blood stem cells. 

Rejuvenating old blood stem cells may be a good way to slow down the aging process in general, as the hematopoietic system transports many factors involved in rejuvenation. Other systemic aging parameters may have been affected by Netrin-1 infusion, but these were not studied in this study. Further investigation into the effect of Netrin-1 on extending healthspan and life expectancy is warranted because the DNA damage response is so important across a wide range of processes, including neurodegenerative disorders and the aging of the entire body’s systems.