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Mixed cell-type spheroids endorse the generation and maintenance of heme-TAMs in an experimental tumor microenvironment

ABSTRACT: To more accurately mimic the tumor microenvironment, we established a three-dimensional culture of MC38 cancer cells mixed with heme-treated BMDMs in microwell plates. This resulted in tumor spheroids with uniformly interspersed macrophages. We profiled the transcriptome of macrophages within these spheroids using scRNA-seq 24 hours after spheroid formation. To test the robustness of the heme effects in this model, we conducted a multiplexed experiment evaluating heme alone and in combination with the classical M1-polarization stimuli INFγ and LPS.

ORGANISM(S): Mus musculus

PROVIDER: GSE236576 | GEO | 2024/01/03

REPOSITORIES: GEO

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Heme-induced inhibition of Bach1derepresses Spic.

Project description:Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor Spic is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80+VCAM+ bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor Bach1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Further, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insight into iron homeostasis. Bone marrow derived macrophages were generated in vitro by culturing WT and Bach1 knock out bone marrow in the presence of GM-CSF and their global gene expression pattern were compared in the presence or absence of heme at the various indicated time points after treatment.

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