利用单核细胞示踪模型研究组织巨噬细胞来源与更新

The origin and function of tissue-resident macrophages is the fundamental questions in the field. Recently, the long-held concept that adult tissue-resident macrophages are continuously replenished by blood monocytes arising from dedicated bone marrow (BM) derived progenitors has been overturned. Several studies have now shown that most of the tissue-resident macrophage populations are seeded by waves of embryonic hematopoiesis and self-maintain independently of BM contribution during adulthood, while others are constantly replaced by blood monocytes. However, there are still debates on the exact kinetics and extent of contribution of circulating monocytes to macrophages in adult tissues during homeostasis and most importantly during disease. To address this question, we identified Ms4a3 as a specific marker expressed by granulocyte-monocyte progenitors (GMPs) and subsequently generated Ms4a3Cre-RosaTdT fate mapper models to follow monocytes and their progenies. Our Ms4a3Cre-RosaTdT model traced efficiently blood monocytes (97%) but no tissue-resident macrophages. This is the first model that could distinguish monocytes derived macrophages from the embryonic macrophages and will help to answer several basic biological questions in the field, such as the origin and renewal of the tissue-resident macrophages and the differences between the macrophages with different origins. This research will also provide new ideas for myeloid cell-targeted clinical therapy.

组织巨噬细胞的来源和功能是该领域重要的基础性生物学问题。长期以来，组织巨噬细胞被认为是由血液中的单核细胞发育而来。但是，随着研究的进展，这一长久以来秉持的观念遭到了质疑。新的研究显示大多数组织巨噬细胞是在胚胎发育过程中产生并且能够自我更新和维持，单核细胞对巨噬细胞群体的贡献只限于一些特定的组织。但是，循环单核细胞对组织巨噬细胞的贡献程度和动态变化依然存在争议。更重要的是，在炎症状态下巨噬细胞的来源和命运有待阐明。在前期工作中，我们发现Ms4a3特异性地在骨髓单核细胞前体中表达，并且构建了Ms4a3Cre-RosaTdT小鼠单核细胞示踪模型，该模型是首个可以有效区分单核细胞和胚胎来源的组织巨噬细胞的示踪模型，有助于回答在生理和病理情况下组织巨噬细胞的来源、更新以及不同来源的巨噬细胞的差异等巨噬细胞相关的基础生物学问题。同时，该研究将对临床上靶向髓系细胞的治疗方案提供新的思路。

巨噬细胞是重要的固有免疫细胞，在组织稳态维持和免疫反应中起到重要作用，这些细胞的来源和功能是该领域重要的基础性生物学问题。长期以来，组织巨噬细胞被认为是由血液中的单核细胞发育而来。但是，随着研究的进展，这一长久以来秉持的观念遭到了质疑。新的研究显示大多数组织巨噬细胞是在胚胎发育过程中产生并且能够自我更新和维持，单核细胞对巨噬细胞群体的贡献只限于一些特定的组织。但是，循环单核细胞对组织巨噬细胞的贡献程度和动态变化依然存在争议。更重要的是，在炎症状态下巨噬细胞的来源和命运有待阐明。在该研究中，我们发现Ms4a3特异性地在骨髓单核细胞前体中表达，并且构建了Ms4a3TdT报告小鼠、Ms4a3Cre-RosaTdT示踪模型和Ms4a3CreERT2-RosaTdT诱导型单核细胞示踪模型，Ms4a3Cre-RosaTdT示踪模型特异性标记单核细胞和粒细胞而不标记胚胎来源的组织巨噬细胞和树突状细胞，是首个可以有效区分不同来源的组织巨噬细胞的示踪模型，利用该单核细胞示踪模型我们阐明了单核细胞对各种组织巨噬细胞的贡献，证明大多数组织（大脑、表皮和肝脏除外）中的巨噬细胞是一个随年龄变化的、由不同比例胚胎来源和单核细胞来源的细胞组成的群体。本研究将有助于阐明单核细胞的发育过程、理清单核细胞和组织巨噬细胞的关系，并对临床上靶向髓系细胞的治疗方案提供重要的指导。