The journey from stem cell to macrophage

Abstract

Essential protectors against infection and injury, macrophages can also contribute to many common and fatal diseases. Here, we discuss the mechanisms that control different types of macrophage activities in mice. We follow the cells' maturational pathways over time and space and elaborate on events that influence the type of macrophage eventually settling a particular destination. The nature of the precursor cells, developmental niches, tissues, environmental cues, and other connecting processes appear to contribute to the identity of macrophage type. Together, the spatial and developmental relationships of macrophages compose a topo-ontogenic map that can guide our understanding of their biology.

Keywords: hematopoesis; macrophage; monocyte.

Fig. 1

Topo-ontogenic map of macrophages and their progenitors in steady state. HSCs in bone marrow produce discrete intermediate progenitor populations, which increasingly lose self-renewing capacity as they commit to a given lineage. HSC-derived monocytes are found in circulation and in a splenic reservoir and can renew macrophages upon tissue extravasation. Some tissue macrophages develop in the embryo (yolk sac) before the appearance of HSCs and are maintained independently from the bone marrow.

Fig. 2

Monocyte production in bone marrow. Working model describing how long-term HSCs may produce monocytes in vivo. Several exogenous cells and soluble factors promote the retention and self-renewal/survival of HSCs (presumably in a quiescent niche) but also instruct commitment toward the myeloid lineage (presumably in an instructive/proliferative niche). The cartoon describes how monocyte production is controlled in steady state (white inserts) and in response to inflammatory cues (orange insert), which can induce HSCs to proliferate and skew them to the myeloid lineage.

Fig. 3

Monocyte production in extramedullary tissue. (A) A small fraction of HSPCs constitutively exit the bone marrow. Under inflammatory conditions, extramedullary HSPCs can be retained and amplified in the spleen, where they produce and replenish reservoir monocytes. Bottom left inserts provide additional information on how bone marrow and splenic activities differ in steady-state and inflammation. (B) Intravital micrographs depict the formation of splenic proliferative niches upon adoptive transfer of green GMPs. Cell clusters are highlighted in circles, venous sinuses in red. Bottom right: co-transfer of green and red GMPs identifies the formation of distinct green and red colonies. Images reproduced from refs^, .

Fig. 4

Distinct mechanisms of monocyte mobilization from medullary and extramedullary tissue. The mobilization of monocytes from the bone marrow or spleen is a controlled process and is reviewed in detail elsewhere. In order to leave the bone marrow, Ly-6C^hi monocytes require the chemokine receptor CCR2, which recognizes MCP-1 and MCP-3, two chemokines produced by medullary MSCs and CAR cells and secreted close to (and perhaps into) the lumen, and increase monocyte movement and intravasation. This process can be activated through sensing of bacterial products by TLRs expressed on MSCs and CAR cells. Panel A shows bone marrow sections illustrating emigration of monocytes in response to LPS, a process that depends on CCR2 signaling. Mobilization of monocytes from extramedullary sites such as the spleen, however, is independent of CCR2 and instead can be triggered by the peptide hormone angiotensin II (panel B). Whether accessory cells are involved in this process remains unknown. Increased concentrations of angiotensin II induce AGTR1A receptor dimerization on splenic monocytes, an event that increases monocyte motility and promotes intravasation (tracking of a departing monocyte shows time in min:sec). Images are reproduced from Refs and .

Fig. 5

Expanding macrophage diversity in tissue. The cartoon illustrates three different origins of tissue macrophages (A) Selective accumulation of monocyte subsets committed with separate functions contributes different types of macrophages. For instance, CCR2-dependent recruitment of Ly-6C^hi monocytes mediates tissue inflammation and proteolysis. This response is triggered upon intracellular pathogen infection or tissue damage. Ly-6C^hi monocytes made both in medullary and extramedullary sites express CCR2 and response to MCP-1 for recruitment to tissues; however these cells might be equipped with divergent effector functions. Also, CX3CR1-dependent recruitment of Ly-6C^lo monocytes may be associated with resolution of inflammation and mediation of tissue remodeling and healing. The recruited cells are also educated and polarized by their environment through cell-cell communication, sensing of soluble factors and interactions with extracellular matrix. (B) Local proliferation of tissue-resident macrophages. Some macrophages may proliferate at very low levels in steady-state conditions to maintain cell repertoires locally. Abnormal conditions, such as helminth infection and cardiovascular disease can induce potent macrophage proliferation in pleural cavity and atherosclerotic lesions, respectively. Such amplification can an occur in presence or absence of Ly-6C^hi monocytes, and be promoted by locally produced factors including IL-4. (C) Maintenance of primitive macrophages. A lineage independent of HSCs is seeded during embryonic life and generates a repertoire of macrophages in various tissues, that is maintained after birth. These cells are often associated with epithelial structures, are thought to be unable to exit their tissue of residence, and may be poor antigen-presenting cells. These cells might serve in part as structural components that protect the tissue by sequestering foreign material and/or be involved in specific (non-immune) tissue functions.

Fig. 6

New targets in macrophage pathways? Drugs can attack cells at different developmental stages, from HSC to macrophage. The cartoon illustrates drugs that can interfere with macrophage differentiation survival and proliferation, monocyte recruitment to tissue, monocyte release from bone marrow or spleen, and production, amplification and release of bone marrow HSPCs.