Taming inflammaging – semaphorin signals a way

As we age, one word that starts to come up increasingly often (that I personally dread, just ask my right knee) – is inflammation. Exaggerated inflammatory responsiveness and increased myeloid cell production by aged hematopoietic stem cells, or HSCs, sets the stage for even more inflammation, fueling a “self-charging” inflammatory engine. “Inflammaging”, as this engine is otherwise known, is responsible for an increase in inflammatory disorders, atherosclerosis and blood cancers in aged people – not something to look forward to!

While inflammaging is unavoidable, does nature have a way to slow it down and ensure that we can still make it to our 80s and 90s? A new study in Nature Aging lead by Dorsa Toghani and Sanika Gupte in Dr. Lev Silberstein’s lab in the Translational Science and Therapeutics Division discovered that can protect HSCs from the deleterious effects of ‘inflammaging’.

Speaking on their new work, Silberstein emphasized that, so far, “the field has focused mainly on the mechanisms which draw HSC into inflammatory response and as a result, inflict inflammation-induced HSC damage. We found a secreted molecule, Semaphorin 4A [Sema4a], which “numbs” HSC reaction to inflammatory stress and as a result, protects them and ensures that they are able to produce blood cells life-long.

Dating back to 1992, Sema4A was originally discovered as a member of the semaphorin (which means “signal-carrying” in Greek) protein family. Semaphorins regulate axon guidance in the developing limb bud of grasshoppers, and are more broadly shown to play a critical role in cell-cell interactions, adhesion and motility. However, whether Sema4A – or any of the other semaphorins - has a function in the bone marrow has not been previously known.

The Silberstein lab initially became interested in Sema4A while looking for extrinsic, so called “niche” factors in the bone marrow that maintain HSC in their native, quiescent state, and found that stromal cells in close proximity to HSCs were transcriptionally enriched for Sema4A. To investigate what niche-derived Sema4A might be doing in the bone marrow, the group asked what would happen when its absence, i.e. in Sema4A knock-out mice. To their surprise, they found that as these mice aged, they developed anemia and excess of neutrophils and platelets in the blood. These exact features also occur in aged mice and people but were considerably more prominent in Sema4A knock out mice, suggesting that the absence of Sema4A accelerates inflammaging, suggesting that normally, this molecule puts a firm break on this process. 

To get a deeper look on how Sema4A works, Toghani, Gupte, and Silberstein employed single-cell sequencing. They found that aged HSCs from Sema4A-null mice were enriched for several proinflammatory transcription factors in the AP-1 family that are known to drive myeloid differentiation, while expression of genes restricting HSC activation were decreased. Further transcriptional analysis showed that HSC from Sema4A knockout mice differentiated at a faster speed and aged prematurely.

So, when do these mice start to turn the clock forward in their HSCs? In younger mice, it appears that disrupted hematopoiesis resultant from Sema4A loss is already underway at 8-12 weeks with increased neutrophils and thrombocytes in the blood. Repeating the transplantation assay showed that HSCs derived from young donor Sema4A null mice (i.e., transplanting young cells into young mice instead of aged cells into young mice) had decreased self-renewal, indicating that young Sema4A knock out HSC are already functionally impaired. The authors hypothesized that this is most likely due to their inability of these HSCs to resist acute and chronic inflammation, and follow-up studies showed that this was indeed the case.

In the subsequent series of experiments to pinpoint the cells responsible for producing Sema4A, the authors unexpectedly found that these were bone marrow neutrophils. Intriguingly, neutrophils – which originate from HSCs -  markedly upregulated Sema4A with inflammation. Thus, neutrophils and HSCs appear to be engaged in a negative feedback loop which countered inflammation in HSC.  This phenomenon at first appears paradoxical since neutrophils are classically known to promote inflammation and drive tissue damage.  But actually, there is no paradox; this is just a very smart design by nature: if the HSCs are not protected, inflammaging will flourish and eventually kill HSCs so that no blood cells will be produced, including neutrophils themselves. So by secreting Sema4A, neutrophils show their “good side” and ensure HSC longevity so that their own production can continue as well.

Looking forward, Silberstein hopes that their work will have therapeutic applications: “As a hematologist, I wonder whether the very same protective effect that Sema4A has on normal HSCs during inflammaging can be hijacked by leukemia, making leukemic cells invincible to chemotherapy, and we have some data that this might be the case.  Sema4A is a secreted protein which makes it an “easy” target for pharmacological manipulation – via blocking Sema4A or its receptor on HSCs, Plexin D1. With the help of the Kuni Foundation and the Evergreen Fund, we are currently testing this approach with the aim of designing new agents to overcome chemotherapy resistance and prevent relapse.”

The spotlighted research was funded by the National Institute of Health, the New Development Fund from the Fred Hutchinson Cancer Center, and the Leukemia and Lymphoma Society.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Hans-Peter Kiem and Lev Silberstein contributed to this work.

Toghani D, Gupte S, Zeng S, Mahammadov E, Crosse EI, Seyedhassantehrani N, Burns C, Gravano D, Radtke S, Kiem H, Rodriguez S, Carlesso N, Pradeep A, Georgiades A, Lucas F, Wilson N, Kinston SJ, Göttgens B, Zong L, Beerman I, Park B, Janssens DH, Jones D, Toghani A, Nerlov C, Pietras EM, Mesnieres M, Maes C, Kumanogoh A, Worzfeld T, Cheong J, Josefowicz SZ, Kharchenko P, Scadden DT, Scialdone A, Spencer JA, Silberstein L. 2025. Niche-derived Semaphorin 4A safeguards functional identity of myeloid-biased hematopoietic stem cells. Nature Aging. DOI: 10.1038/s43587-024-00798-7.