Neogenin-1 marks myeloid-primed fetal hematopoietic stem cells that undergo progressive lineage-restriction with age

Aged hematopoietic stem cells (HSCs) exhibit a shift from balanced to myeloid-biased differentiation, resulting in reduced lymphoid output and impaired adaptive immunity. The question of whether this lineage bias is established in a subset of HSCs during early development or primarily emerges with aging warrants further investigation. Here, we investigate whether myeloid-biased HSCs (my-HSCs) are established at the fetal liver stage by specifically examining Neogenin-1 (NEO1), a previously defined marker of my-HSCs. We identify two distinct populations of Hoxb5 ⁺ HSCs in the fetal liver: NEO1 ⁺ and NEO1, with NEO1 ⁺ HSCs exhibiting transcriptional and functional characteristics consistent with my- HSCs. With age, my-HSC-associated transcriptional programs become increasingly reinforced across the Hoxb5 ⁺ pHSC compartment, with NEO1 ⁺ cells showing early enrichment of this program and both NEO1 ⁺ and NEO1 ⁻ cells acquiring broader myeloid-biased features in aging. These findings suggest that lineage programming can begin early in development and is further shaped by age-related changes, potentially contributing to the functional decline observed in the aging hematopoietic system.