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In an ex vivo glioma model using organotypic brain slices, bone marrow-derived macrophages upregulated pro-inflammatory cytokines such as Il1a and Il1b if co-cultured with organotypic tumor slices. In contrast, the microglia, isolated from postnatal pups, cultured with tumor slices showed no increase of these genes [ ] implicating diverse cytokine expression following stimulation by tumor conditions.
In vivo it was observed, if total body irradiated chimeras with either labeled microglia or bone marrow-derived macrophages were analyzed, different morphologies of microglia and macrophages were found by intravital 2-photon microscopy. Bone marrow-derived macrophages showed small cell bodies with few branches and had a high migratory activity in glioma tissue while microglia were bigger, highly branched and rather stationary but sensing their microenvironment through the continuous extension and retraction of ramified processes [ 99 ].
These observations could evidence different migratory behavior of the myeloid cell populations. In this experimental setup, we could show a decrease in vessel density and slowdown in glioma growth indicating microglia as a crucial cell population in the regulation of tumor angiogenesis [ 26 ].
Sole macrophages were not depleted in this context to verify if the observed angiogenic function is really restricted to the microglia population [ 26 ]. Additionally, Arg1 expression, a gene defining an anti-inflammatory phenotype, was analyzed in myeloid cells by separating them via analyzing CD45 expression level one week after tumor cell inoculation [ ].
As already observed for other molecules in vitro, both cell populations expressed this gene but microglia CD45 low to a lower extent as the macrophages CD45 high. In contrast, CCL2 was expressed by microglia and macrophages at comparable levels [ ]. Interestingly, a study using immune checkpoint inhibitors in human glioblastoma and a glioma mouse model postulated that especially macrophages expressing high level of CD73 in the tumor are resistant to therapy and responsible for ongoing immunosuppression during therapeutic treatment [ ].
Using gene signatures, attempts to differentiate microglia from infiltrating macrophages were made. Here, a predominance of blood-derived macrophages in upregulation of immunosuppressive cytokines and phagocytosis-related genes was described [ ] based on the gene signature determined by Bowman et al. A study by Chen et al. A common finding of several studies is a different localization pattern of the myeloid cell populations.
Microglia were detected in the peripheral tumor area, while blood-derived macrophages were associated to blood vessels and necrotic areas especially in the tumor core. Here, defining microglia and macrophages by gene signature [ 59 ], determined that accordingly to location of the myeloid cells, their expression profile changed between periphery and tumor core [ ].
In summary, in vitro stimulated microglia and bone marrow-derived macrophages showed overexpression of immunosuppressive relevant proteins, but microglia expressed molecules less strong than the BMDMs. The ex vivo culture model implicates differences in activation of both cell populations. In vivo the function of microglia and macrophages remain questionable due to only few reports and the difficulty to compare the various methods of distinction.
Thus, present data do not allow assigning a specific function to the microglia or macrophage population. If the functions of microglia and macrophages differ, the question is whether microglia or macrophages predominate the glioma tissue. This would be an important aspect for development of future therapeutic strategies. Interestingly, reports about the composition of the myeloid cell population in gliomas are limited.
However, based on the applied model, in literature different ratios of microglia and macrophages that infiltrate glioma tissues can be found Table 1. Badie and Schartner were the first to use the discrimination of microglia and macrophages by their CD45 expression level in various models of rat glioma, where allogeneic and syngeneic tumor cell grafts, such as C6, 9L and RG-2, were used [ 64 ]. They calculated the infiltration of the myeloid cell populations in relation to all living cells.
Thus, the infiltration rates of both microglia and macrophages were relatively low. The RG-2 model showed the lowest frequencies of myeloid cells but in each tumor the microglia population prevailed [ 64 ]. This was confirmed by a recent study, where C6 glioma cells were implanted into rat brains. Here, it was found that the CD45 high population increased with tumor progression implicating a stronger influx of macrophages at a later time point of growth [ 66 ].
In a glioma mouse model GL , the same kinetic could be detected. Consequently, when discrimination is based on CD45 expression level of myeloid cells, more microglia occurred in glioma-bearing brains during early tumor progression but at later times macrophages gained a bigger share.
If chimeras were used to investigate the proportions of microglia and macrophages in glioma tissues, the observations varied. Thus, in these chimeras, macrophages are the main population of myeloid cells in the brain tumor hemisphere. Nevertheless, using the head protected irradiation, our group demonstrated only a moderate influx of macrophages into glioma tissues not before day In contrast to TBI where macrophages were detected additionally in the peritumoral area, the HPI method led to restriction of macrophages to the glioma mass [ 79 ].
All in all, HPI led to reduced influx of macrophages compared to TBI and microglia cells dominated the glioma brain hemisphere. Results of chimeras generated by busulfan administration depended on the dosage of this chemotherapeutic agent.
Frequently, the infiltration rate of macrophages was determined by flow cytometric analyses, whereby the tumor-bearing hemispheres were used, including non-tumor tissue with uninitiated microglia. This could lead to an assumption of false-high distribution of microglia to the tumor microenvironment. In this setup, the tumor-associated myeloid cells could be clearly defined. It was demonstrated that microglia prevailed on days 7 and 17, while comparable numbers of microglia and macrophages were observed on day 14 [ 96 ].
Interestingly, chimeras analyzed by flow cytometry revealed divergent results describing either microglia [ 96 ] or macrophages [ 80 ] dominated tumors. Mice were analyzed at late stages of tumor progression implicating massive glioma growth. Both glioma settings showed similar results.
Additionally, total body irradiated chimeras were generated and again macrophages represented the main myeloid cell population in glioma tissue [ 69 ], as observed previously by using this method [ 79 ]. In general, this discrimination was also based on the CD45 expression level and precluded an upregulation of CCR2 on microglia under tumor conditions. Depending on the method, model and time of glioma progression, microglia or macrophages were postulated to predominate the glioma tissue.
It is well documented that tumor-associated myeloid cells are highly important for glioma progression. However, past work provides inadequate evidence to finally conclude if discrimination between brain-resident microglia and infiltrating macrophages is required or both populations become same properties following infiltration of the tumor tissue.
New reporter mice could help to solve this problem, but many strategies are based on the CD45 expression level. Thus, finding an unequivocal marker, which could be referred to microglia and macrophages, should take priority. Conceptualization, S. All authors have read and agreed to the published version of the manuscript. National Center for Biotechnology Information , U. Int J Mol Sci. Published online Dec Find articles by Susan Brandenburg. Find articles by Anne Blank. Alexander D.
Find articles by Alexander D. Author information Article notes Copyright and License information Disclaimer. Received Nov 27; Accepted Dec This article has been cited by other articles in PMC. Abstract For decades, it has been known that the tumor microenvironment is significant for glioma progression, namely the infiltration of myeloid cells like microglia and macrophages. Keywords: myeloid cells, glioma, tumor microenvironment. Introduction Glioblastomas belong to primary human brain tumors of WHO grade IV [ 1 ] with highest malignancy and aggressiveness.
Origin and General Function of Microglia The ontological origin of microglia was intensively debated [ 27 ], but current publications make clear that the brain-resident microglia derived from progenitors of the yolk sac [ 28 , 29 ]. Distinction of Microglia and Macrophages in Glioma High amounts of myeloid cells infiltrate the tissue of human and murine glioblastomas [ 7 , 8 ], whereby a direct correlation between the grade of malignancy and the number of myeloid cells was demonstrated [ 7 ].
Classical Differentiation by CD45 Expression Level A favored experimental approach to differentiate between microglia and macrophages in glioblastoma is their expression level of CD Open in a separate window.
Figure 1. Bone Marrow Chimeras Generated by Different Irradiation Strategies Another method to distinguish between microglia and macrophages is the generation of bone marrow chimeras [ 82 ]. Chimeric Mice Generated by Busulfan Administration Besides irradiation strategies, myeloablative chemotherapy by application of busulfan followed by transfer of labeled bone marrow cells can be used to generate chimeras [ 93 , 94 , 95 ].
Reporter Mice Based on the Cx3cr1 Gene Recently, reporter mice were used to differentiate between microglia and macrophages in glioma models. Novel Markers of Microglia Recently, analyses were performed to identify specific marker for microglia which would be the basis for an adequate differentiation between microglia and macrophages.
Depletion Strategies to Verify the Function of Microglia and Macrophages Besides reporter mice, other techniques to study the function of microglia and macrophages were developed, using strategies to deplete one or the other myeloid cell population. Function of Microglia and Macrophages in Glioma Microglia and macrophages have different origins, but their functions appear similar at a first sight.
Proportion of Microglia and Macrophages in Glioblastoma If the functions of microglia and macrophages differ, the question is whether microglia or macrophages predominate the glioma tissue. Conclusions It is well documented that tumor-associated myeloid cells are highly important for glioma progression.
Author Contributions Conceptualization, S. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable.
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