Preprint: Bone marrow support cells from older people reduced young blood stem cell engraftment in mouse “mini-bones”, while old stem cells alongside them disappeared in 5 of 6 bones
Preprint: Bone marrow support cells from older people reduced young blood stem cell engraftment in mouse “mini-bones”, while old stem cells alongside them disappeared in 5 of 6 bones
On 28 October, Anja Grigoryan’s group at Ulm University and researchers at Lund University posted a preprint (a paper that has yet to undergo peer review) on bioRxiv. They grew a “mini-bone” containing bone marrow under the skin of immunodeficient mice, populated it with human support cells from donors younger than 40 or older than 65, and added human blood stem cells.
Blood stem cells replenish the blood throughout life. They live in a bone marrow “niche”, an environment made up of support cells and blood vessels. Their function declines with age: in a Japanese registry of bone marrow transplants for aplastic anaemia (a condition in which the bone marrow stops producing blood cells), grafts from unrelated donors aged 40 or older failed to engraft in 9,7% of cases, compared with 5,0% for younger donors, and patient survival was lower. Ageing human stem cells tend to produce myeloid cells (neutrophils and macrophages); this tendency has been linked to myeloid cancers.
The contribution of the surrounding environment to human stem cell ageing has been studied far less than the contribution of changes within the cells themselves. A mouse study published in 2021 showed that the descendants of old skeletal stem cells (which give rise to bone and cartilage) shift blood cell production towards myeloid cells. Human stem cells transplanted into mice divide actively in mouse bone marrow, whereas they are mostly quiescent in human bone marrow. This difference is why a human niche is needed.
Growing a “mini-bone” entirely from older people’s cells is difficult: old support cells proliferate poorly and are less able to form the cartilage from which bone develops in this model. The researchers therefore grow cartilage from a human cell line and remove the cells, leaving an identical scaffold for all groups. Under the mouse’s skin, this scaffold develops into bone over four weeks. Donor support cells are then injected into it: young cells come from the pelvic bones of healthy people, and old cells come from the sternum or femoral neck of patients undergoing surgery. In this niche, only the injected support cells are human; the blood vessels and other cells are mouse cells. The authors therefore attribute the difference between the “young” and “old” niches to the age of the support cells.
The first experiment tested whether an old niche impairs young stem cells. Cells from young donors were divided into two groups and placed alongside either old or young support cells. After 16 weeks, the proportion of human cells among blood cells in bones with an old niche was approximately half that in bones with a young niche. The proportion of myeloid cells among human cells increased, while the proportion of stem cells among the earliest blood cell populations decreased. The proportion of myeloid cells in the blood was also higher in 14 people aged 72–78 than in 16 people aged 20–40.
The second experiment reversed the comparison to test whether a young niche could maintain old stem cells. These cells were also divided into two groups and placed alongside either young or old support cells. Engraftment and the composition of their progeny did not differ, but cells with stem cell characteristics disappeared entirely in 5 of 6 “mini-bones” with an old niche and persisted in bones with a young niche. The authors conclude that, in mice exposed to a sublethal dose of radiation, an old niche is less able to maintain both young and old stem cells. They describe the clinical implications as follows:
“This finding has important clinical implications and may help explain the variability in haematopoietic stem cell transplantation outcomes, which may be influenced by both donor age and the condition of the recipient’s bone marrow niche.”