Martin Karen E, García Andrés J
Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Acta Biomater. 2021 Oct 1;133:4-16. doi: 10.1016/j.actbio.2021.03.038. Epub 2021 Mar 26.
Macrophages are a highly heterogeneous and plastic population of cells that are crucial for tissue repair and regeneration. This has made macrophages a particularly attractive target for biomaterial-directed regenerative medicine strategies. However, macrophages also contribute to adverse inflammatory and fibrotic responses to implanted biomaterials, typically related to the foreign body response (FBR). The traditional model in the field asserts that the M2 macrophage phenotype is pro-regenerative and associated with positive wound healing outcomes, whereas the M1 phenotype is pro-inflammatory and associated with pathogenesis. However, recent studies indicate that both M1 and M2 macrophages play different, but equally vital, roles in promoting tissue repair. Furthermore, recent technological developments such as single-cell RNA sequencing have allowed for unprecedented insights into the heterogeneity within the myeloid compartment, related to activation state, niche, and ontogenetic origin. A better understanding of the phenotypic and functional characteristics of macrophages critical to tissue repair and FBR processes will allow for rational design of biomaterials to promote biomaterial-tissue integration and regeneration. In this review, we discuss the role of temporal and ontogenetic macrophage heterogeneity on tissue repair processes and the FBR and the potential implications for biomaterial-directed regenerative medicine applications. STATEMENT OF SIGNIFICANCE: This review outlines the contributions of different macrophage phenotypes to different phases of wound healing and angiogenesis. Pathological outcomes, such as chronic inflammation, fibrosis, and the foreign body response, related to disruption of the macrophage inflammation-resolution process are also discussed. We summarize recent insights into the vast heterogeneity of myeloid cells related to their niche, especially the biomaterial microenvironment, and ontogenetic origin. Additionally, we present a discussion on novel tools that allow for resolution of cellular heterogeneity at the single-cell level and how these can be used to build a better understanding of macrophage heterogeneity in the biomaterial immune microenvironment to better inform immunomodulatory biomaterial design.
巨噬细胞是一类高度异质性且具有可塑性的细胞群体，对组织修复和再生至关重要。这使得巨噬细胞成为生物材料导向的再生医学策略中一个特别有吸引力的靶点。然而，巨噬细胞也会对植入的生物材料产生不良的炎症和纤维化反应，这通常与异物反应（FBR）有关。该领域的传统模型认为，M2巨噬细胞表型具有促再生作用，并与积极的伤口愈合结果相关，而M1表型具有促炎作用，并与发病机制相关。然而，最近的研究表明，M1和M2巨噬细胞在促进组织修复中都发挥着不同但同样重要的作用。此外，诸如单细胞RNA测序等最新技术发展，使我们对髓系细胞内与激活状态、生态位和个体发生起源相关的异质性有了前所未有的深入了解。更好地理解对组织修复和FBR过程至关重要的巨噬细胞的表型和功能特征，将有助于合理设计生物材料，以促进生物材料与组织的整合和再生。在这篇综述中，我们讨论了巨噬细胞在时间和个体发生上的异质性对组织修复过程和FBR的作用，以及对生物材料导向的再生医学应用的潜在影响。重要性声明：本综述概述了不同巨噬细胞表型对伤口愈合和血管生成不同阶段的贡献。还讨论了与巨噬细胞炎症消退过程破坏相关的病理结果，如慢性炎症、纤维化和异物反应。我们总结了最近对髓系细胞与其生态位，特别是生物材料微环境和个体发生起源相关的巨大异质性的见解。此外，我们讨论了能够在单细胞水平解析细胞异质性的新型工具，以及如何利用这些工具更好地理解生物材料免疫微环境中的巨噬细胞异质性，从而为免疫调节生物材料的设计提供更充分的信息。
