Unraveling the Roles of Macrophages in Vascularized Composite Allotransplantation

Abstract

The phenotypic heterogeneity and functional diversity of macrophages have been increasingly appreciated, particularly regarding their roles as innate immune cells in shaping transplantation outcomes. However, their functions in vascularized composite allotransplantation (VCA) remain underexplored. In this review, we first describe the development of macrophages and the heterogeneity of macrophage differentiation, then present current insights into macrophages' involvement across key stages of VCA, including ischemia-reperfusion injury at the peri-transplantation stage, and the outcomes following transplantation, including acute rejection, chronic rejection, and development of transplantation tolerance. The existing evidence supports that macrophages significantly influence both short- and long-term VCA graft survival. The presence of vascularized bone marrow within some VCA grafts further suggests the involvement of donor bone marrow-derived macrophage population and adds another layer of complexity to immune dynamics. Collectively, current understanding highlights the macrophage as a promising target for therapeutic intervention and warrants continued investigation into their diverse functions and potential for improving VCA outcomes.

Keywords: M1 macrophage; M2 macrophage; ischemia–reperfusion injury; macrophage; regulatory macrophage; transplantation rejection; transplantation tolerance; vascularized composite allotransplantation.

Figure 1

Origins and differentiation pathways of macrophages in the immune system. Macrophages originate from two primary sources: embryonic progenitors and bone marrow-derived HSCs. During embryogenesis, progenitors give rise to tissue-resident macrophages that persist into adulthood through self-renewal. In the adult, HSCs in the bone marrow differentiate into monocytes via intermediate progenitors, and subsequently into macrophages. These monocyte-derived macrophages infiltrate tissues and can adopt various phenotypes in response to local environmental cues. Solid arrows depict the dynamic phenotypic plasticity among macrophage subsets, including interconversion between M1 and M2, or among M2 subtypes. Dotted arrows represent that bone marrow-derived M1/M2 macrophages and TRMs can adopt each other’s phenotypic characteristics under certain conditions. ICs: immune complexes; TME: tumor microenvironment.

Figure 2

Macrophage heterogeneity in the bone marrow-containing VCA recipients. Within the VCA tissue, both donor- and recipient-derived bone marrow monocytes infiltrate and differentiate into diverse macrophage subtypes, including proinflammatory M1, anti-inflammatory M2, and Mregs. In addition, donor-derived TRMs also persist within the graft. The figure illustrates the dynamic cellular composition and highlights the contribution of both donor- and recipient-derived macrophages within the graft environment. Potential interactions and phenotypic conversions among macrophage subtypes are detailed in Figure 1.