BMT Other Organs.

Adaptation to existence outside the womb is a key event in the life of a mammal. The absence of macrophages in rats with a homozygous mutation in the colony-stimulating factor 1 receptor (Csf1r) gene (Csf1rko) severely compromises pre-weaning somatic growth and maturation of organ function. Transfer of wild-type bone marrow cells (BMT) at weaning rescues tissue macrophage populations permitting normal development and long-term survival. To dissect the phenotype and function of macrophages in postnatal development, we generated transcriptomic profiles of all major organs of wild-type and Csf1rko rats at weaning and in selected organs following rescue by BMT. The transcriptomic profiles revealed subtle effects of macrophage deficiency on development of all major organs. Network analysis revealed a common signature of CSF1R-dependent resident tissue macrophages that includes the components of complement C1Q (C1qa/b/c genes). Circulating C1Q was almost undetectable in Csf1rko rats and rapidly restored to normal levels following BMT. Tissue-specific macrophage signatures were also identified, notably including sinus macrophage populations in the lymph nodes. Their loss in Csf1rko rats was confirmed by immunohistochemical localisation of CD209B (SIGNR1). By 6-12 weeks, Csf1rko rats succumb to emphysema-like pathology associated with the selective loss of interstitial macrophages and granulocytosis. This pathology was reversed by BMT. Along with physiological rescue, BMT precisely regenerated the abundance and expression profiles of resident macrophages. The exception was the brain, where BM-derived microglia-like cells had a distinct expression profile compared to resident microglia. In addition, the transferred BM failed to restore blood monocyte or CSF1R-positive bone marrow progenitors. These studies provide a model for the pathology and treatment of CSF1R mutations in humans and the innate immune deficiency associated with prematurity.

对于哺乳动物而言，适应子宫外的生存环境是其生命历程中的关键事件。携带集落刺激因子1受体（colony-stimulating factor 1 receptor, Csf1r）基因纯合突变的Csf1rko大鼠体内缺乏巨噬细胞，其断奶前的躯体生长与器官功能成熟过程会受到严重损害。在断奶时进行野生型骨髓细胞移植（bone marrow transplantation, BMT），可挽救组织巨噬细胞群，使机体恢复正常发育并获得长期存活。为解析巨噬细胞在出生后发育过程中的表型与功能，我们对断奶时的野生型及Csf1rko大鼠的所有主要器官，以及经BMT挽救后的部分器官开展了转录组谱分析。结果显示，巨噬细胞缺乏对所有主要器官的发育存在细微影响。通过网络分析，我们鉴定出依赖CSF1R的组织驻留巨噬细胞的共同特征基因集，其中包含补体C1Q的编码基因（C1qa、C1qb、C1qc）。Csf1rko大鼠体内几乎无法检测到循环C1Q，而在接受BMT后，循环C1Q水平可快速恢复至正常范围。我们还识别出组织特异性的巨噬细胞特征基因集，其中尤以淋巴结内的窦巨噬细胞群最为典型。通过对CD209B（SIGNR1）进行免疫组织化学定位，证实了Csf1rko大鼠体内该类巨噬细胞的缺失。至6~12周龄时，Csf1rko大鼠会出现肺气肿样病理症状，该症状与间质巨噬细胞的选择性丢失以及粒细胞增多症密切相关。该病理变化可通过BMT得到逆转。除实现生理功能挽救外，BMT还可精准重建组织驻留巨噬细胞的数量与表达谱。唯一的例外是大脑：骨髓来源的小胶质细胞样细胞与内源性小胶质细胞的表达谱存在显著差异。此外，移植的骨髓无法重建血液单核细胞以及CSF1R阳性的骨髓祖细胞群。本研究为人类CSF1R突变相关疾病以及早产儿伴发的先天性免疫缺陷的病理机制研究与治疗方案开发提供了理想的动物模型。