Julius Wolff Institut, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany.
Julius Wolff Institut, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Oral and Maxillofacial Surgery, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
Acta Biomater. 2021 Oct 1;133:46-57. doi: 10.1016/j.actbio.2021.04.052. Epub 2021 May 8.
To present knowledge, macrophages are found in all tissues of the human body. They are a cell population with high plasticity which come with a multitude of functions which appear to be adapted to the respective tissue niche and micro-environment in which they reside. Bone harbors multiple macrophage subpopulations, with the osteoclasts as classical representative of a bone resorbing cells and osteomacs as a bone tissue resident macrophage first described by the expression of F4/80. Both subtypes are found throughout all phases in bone healing. In vivo data on bone regeneration have demonstrated their essential role in initiating the healing cascade (inflammatory phase) but also of the later phases of healing (e.g. endochondral and intramembranous bone formation). To participate in such diverse processes macrophages have to be highly plastic in their functionality. Thus, the widely used M1/M2 paradigm to distinguish macrophage subpopulations may not mirror the comprehensive role of the dynamics of macrophage plasticity. From a clinical perspective it is especially relevant to distinguish what drives macrophages in impaired healing scenarios, implant loosening or infections, where their specific role of a misbalanced inflammatory setting is so far only partially known. With this review we aim at illustrating current knowledge and gaps of knowledge on macrophage plasticity and function during the cascades of regeneration and reconstitution of bone tissue. We propose aspects of the known biological mechanisms of macrophages and their specific subsets that might serve as targets to control their function in impaired healing and eventually support a scar-free regeneration. STATEMENT OF SIGNIFICANCE: Macrophages are essential for successful regeneration. In scar-free healing such as in bone, a complete failure of healing was shown if macrophages were depleted; the M1/M2 switch appears to be key to the progression from pro-inflammation to regeneration. However, experimental data illustrate that the classical M1/M2 paradigm does not completely mirror the complexity of observed macrophage functions during bone healing and thus demands a broader perspective. Within this review we discuss the high degree of plasticity of macrophages and the relevant contribution of the different and more specific M2 subtypes (M2a-M2f) during (bone) regeneration. It summarizes the versatile roles of macrophages in skeletal regeneration and thereby highlights potential target points for immunomodulatory approaches to enable or even foster bone repair.
为了介绍目前的知识，巨噬细胞存在于人体的所有组织中。它们是一种具有高度可塑性的细胞群体，具有多种功能，这些功能似乎适应于它们所在的组织龛位和微环境。骨骼中存在多种巨噬细胞亚群，破骨细胞是经典的骨吸收细胞代表，而骨巨噬细胞则是最早由 F4/80 表达描述的骨组织驻留巨噬细胞。这两种亚型在骨愈合的所有阶段都有发现。关于骨再生的体内数据表明，它们在启动愈合级联反应（炎症期）以及愈合的后期阶段（例如软骨内和膜内骨形成）中都起着至关重要的作用。为了参与如此多样化的过程，巨噬细胞在功能上必须具有高度的可塑性。因此，广泛使用的 M1/M2 范式来区分巨噬细胞亚群可能无法反映巨噬细胞可塑性的全面作用。从临床角度来看，区分在受损愈合、植入物松动或感染情况下是什么驱动了巨噬细胞，以及它们在失衡炎症环境中的特定作用，目前还只是部分了解，这一点尤为重要。本文旨在阐述在骨骼组织再生和重建的级联反应中，巨噬细胞的可塑性和功能的当前知识和知识空白。我们提出了已知的巨噬细胞及其特定亚群的生物学机制的各个方面，这些方面可能作为控制其在受损愈合中的功能的靶点，并最终支持无疤痕的再生。
巨噬细胞对成功的再生至关重要。在无疤痕愈合中，如在骨骼中，如果耗尽巨噬细胞，则完全无法愈合；M1/M2 转换似乎是从炎症前到再生的进展的关键。然而，实验数据表明，经典的 M1/M2 范式并不能完全反映骨骼愈合过程中观察到的巨噬细胞功能的复杂性，因此需要更广泛的视角。在这篇综述中，我们讨论了巨噬细胞的高度可塑性以及不同且更特异的 M2 亚型（M2a-M2f）在（骨）再生过程中的相关贡献。它总结了巨噬细胞在骨骼再生中的多种作用，从而突出了免疫调节方法的潜在靶标，以实现甚至促进骨修复。
