Functional significance of mononuclear phagocyte populations generated through adult hematopoiesis

Abstract

Tissue homeostasis requires a complete repertoire of functional macrophages in peripheral tissues. Recent evidence indicates that many resident tissue macrophages are seeded during embryonic development and persist through adulthood as a consequence of localized proliferation. Mononuclear phagocytes are also produced during adult hematopoiesis; these cells are then recruited to sites throughout the body, where they function in tissue repair and remodeling, resolution of inflammation, maintenance of homeostasis, and disease progression. The focus of this review is on mononuclear phagocytes that comprise the nonresident monocyte/macrophage populations in the body. Key features of monocyte differentiation are presented, focusing primarily on the developmental hierarchy that is established through this process, the markers used to identify discrete cell populations, and novel, functional attributes of these cells. These features are then explored in the context of the tumor microenvironment, where mononuclear phagocytes exhibit extensive plasticity in phenotype and function.

Keywords: MDSC; monocyte differentiation; tumor microenvironment.

© 2014 Society for Leukocyte Biology.

Figures

Figure 1.. The development of mononuclear phagocytes.

Lineage-committed mononuclear phagocytes are generated primarily in the BM through the tightly regulated differentiation of HSCs to progressively more committed cell populations. Key steps in this pathway include the formation of the CMP, GMP, MDP, and cMoP populations. The recently identified cMoP represents the least differentiated, committed monocyte population. CSF-1 has been shown to be a critical regulatory factor in the generation of monocyte populations, both in instructing myeloid cell fate through activation of the transcription factor PU.1 and in promoting the differentiation of GMP to mononuclear phagocytes. The transcription factor MafB functions to repress the activity of CSF-1 in the HSC. Sca-1, stem cell antigen-1.

Figure 2.. Monocyte differentiation and trafficking.

Ly6Chigh monocytes retain proliferative potential in the BM and can differentiate or transmigrate to the blood. Two populations of blood monocytes persist in steady state and are distinguished by the relative expression of several functionally important molecules. The patrolling nature of Ly6Clow monocytes on the vascular endothelium is an additional characteristic of this subset. Ly6Chigh and Ly6Clow populations can infiltrate peripheral tissues under the appropriate stimuli. Macrophages derived through the differentiation of recruited monocytes and those generated through the local proliferation of resident macrophages established during embryonic development comprise the tissue macrophage populations.

Figure 3.. The regulation of mononuclear phagocyte accumulation and activity in the tumor microenvironment.

The expression of soluble chemotactic factors by tumor-associated cells recruits circulating monocytes and M-MDSCs, which have the potential to differentiate to TAMs in response to tumor-derived factors. CSF-1 can regulate TAM function in the tumor microenvironment in several ways. First, a CSF-1/EGF paracrine loop is established [110, 111]. Second, CSF-1 has been shown to increase angiogenesis by inducing TAM to express VEGF [112]. Finally, CSF-1 can stimulate TAMs to secrete MMPs, which in turn, can cause the release of sequestered growth factors from the ECM [112, 113]. TAMs are also critical for the establishment of TMEM, which promotes intravasation of the tumor cells [114].