Embryonic myeloid cells orchestrate niche cell homeostasis critical for the establishment of the definitive HSC pool

The lifelong replenishment of blood cells relies on the function of definitive HSCs that migrate to the bone marrow during development. This process is tightly controlled by the bone marrow microenvironment. Embryonic macrophages emerge before the onset of definitive hematopoiesis, seed into discrete tissues and contribute to specialized resident macrophages throughout life. However, the functional impact of embryonic macrophages on HSCs or the niche remains unknown. Here, by taking advantage of a lineage tracer mouse tool we show that bone marrow macrophages consist of two ontogenetically distinct cell populations from embryonic and adult hematopoiesis. Mice lacking embryonic myeloid cells have decreased HSC numbers in the bone marrow accompanied by an increase of stem cells in the liver of neonate mice. The emergence of HSCs from embryonic sources is unperturbed because pre-HSC and HSC numbers are normal, suggesting a key role for embryo-derived myeloid cells in orchestrating HSC trafficking around birth. We show here that the establishment of a normal cellular niche space in the bone marrow critically depends on embryonic myeloid cells that are important for the development of mesenchymal stromal cells, but not other non-hematopoietic niche cells, providing evidence for a specific role for embryo-derived myeloid cells in the establishment of a normal niche environment pivotal for HSC homing. PolyA selected mRNA sequenced for 12 bone marrow samples from 8 weeks old mice in four groups: HSC derived macrophages (adult), embryonic progenitor derived macrophages (Rank positive linage traced, eYFP positive), Ly6Clo monocytes, Ly6Chi monocytes

血细胞的终身更新依赖于发育过程中迁移至骨髓的定型造血干细胞（definitive HSCs）的功能。该过程受骨髓微环境（bone marrow microenvironment）的严格调控。胚胎巨噬细胞（embryonic macrophages）在定型造血作用（definitive hematopoiesis）启动前便已产生，定植于各类离散组织并终身分化为特化的组织驻留巨噬细胞。然而，胚胎巨噬细胞对造血干细胞（HSCs）或造血龛的功能影响迄今仍不明确。
本研究借助谱系示踪小鼠工具（lineage tracer mouse tool）证实，骨髓巨噬细胞存在两个发育起源截然不同的细胞群，分别源自胚胎造血与成体造血。缺失胚胎髓系细胞（embryonic myeloid cells）的小鼠，其骨髓内造血干细胞数量减少，同时新生小鼠肝脏内干细胞数量增多。由于前造血干细胞（pre-HSCs）与造血干细胞的数量未出现异常，提示胚胎来源的髓系细胞在出生前后造血干细胞的转运过程中发挥关键作用。
本研究进一步表明，骨髓正常细胞龛微环境的建立，严格依赖胚胎髓系细胞：这类细胞对间充质基质细胞（mesenchymal stromal cells）的发育至关重要，但对其他非造血龛细胞无显著影响，从而证明胚胎来源的髓系细胞在构建利于造血干细胞归巢（HSC homing）的正常龛环境中具有特异性功能。
本研究对4组共12份8周龄小鼠的骨髓样本开展了聚腺苷酸化筛选mRNA（PolyA selected mRNA）测序，分组如下：造血干细胞来源的巨噬细胞（成体来源）、胚胎祖细胞来源的巨噬细胞（Rank阳性、谱系示踪阳性且eYFP阳性）、Ly6Clo单核细胞、Ly6Chi单核细胞。