Expression data from macrophages sorted from the heart tissue of WT mice post-IR
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE246339 | GEO | 2023/10/31
REPOSITORIES: GEO
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Project description:Cardiac resident MerTK+ macrophages exert multiple protective roles post-ischemic injury, however, the mechanisms regulating their fate are not fully understood. Here we show that GAS6-inducible transcription factor ATF3 prevents apoptosis of MerTK+ macrophages after ischemia-reperfusion (IR) injury, by repressing the transcription of multiple genes involved in type I interferon expression (Ifih1 and Infb1) and apoptosis (Apaf1). Mice lacking ATF3 in cardiac macrophages or myeloid cells showed excessive loss of MerTK+ cardiac macrophages, poor angiogenesis, and worse heart dysfunction post-IR, which were rescued by the transfer of MerTK+ cardiac macrophages. GAS6 administration improved cardiac repair in an ATF3-dependent manner. Finally, we showed a negative association of GAS6 and ATF3 expression with the risk of major adverse cardiac events in patients with ischemic heart disease. These results indicate that the GAS6-ATF3 axis has a protective role against IR injury by regulating MerTK+ cardiac macrophage survival/proliferation.
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Project description:Tissue-resident macrophages represent a group of highly responsive innate immune cells that acquire diverse functions by polarizing towards distinct subgroups. The subgroups of macrophages that reside in skeletal muscle (SKM) and their changes during aging are not fully understood. By single-cell transcriptomic analysis, we found that mouse SKM macrophages comprise two large populations, Lyve1+ and Lyve1-. Lyve1+ macrophages expressed high levels of mRNAs encoding angiogenesis and tissue repair proteins, while Lyve1- macrophages expressed high levels of mRNAs encoding proteins with functions in translation, antigen presentation, and the proinflammatory response. SKM macrophages were further classified into four functional subgroups based on the expression levels of another cell surface marker MHCII: Lyve1+/MHCII-lo (similar to alternatively activated M2), Lyve1-/MHCII-hi (similar to classically activated M1), and two new subgroups, Lyve1+/MHCII-hi and Lyve1-/MHCII-lo, all displayed strong phagocytic capacities. Flow cytometric analysis validated the presence of the four macrophage subgroups in SKM. The new subgroup Lyve1+/MHCII-hi had traits of both M2 and M1 macrophages, while the other subgroup, Lyve1-/MHCII-lo, expressed high levels of mRNAs encoding cytotoxicity proteins. In old SKM, Lyve1+/MHCII-hi macrophages were less abundant and Lyve1-/MHCII-hi macrophages were more abundant. Furthermore, complementary unsupervised classification revealed the emergence of small clusters expressing proinflammatory markers including S100a8 and S100a9 mRNAs in aged SKM. In sum, our study has identified dynamically polarized mouse SKM macrophages and a shift toward a proinflammatory status during aging.
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Project description:To determine the mechanism by which ATF3 regulated the survival/proliferation of MerTK+ cardiac macrophages, microarray was performed to identify gene expression differences in MerTK+ macrophages from WT and ATF3-CKO mice under the HR state.
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Project description:Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, microvascular dysfunction and myocardial fibrosis with recent evidence implicating the immune system in orchestrating cardiac remodeling. Here, we show the mouse model of deoxycorticosterone acetate (DOCA)-salt hypertension induces key elements of HFpEF, including diastolic dysfunction, exercise intolerance, and pulmonary congestion in the setting of preserved ejection fraction. CITE-Seq analysis of cardiac immune cells reveals an altered abundance and/or transcriptional signature in multiple cell types, most notably cardiac macrophages. The DOCA-salt model results in differential expression of several known and novel genes in cardiac macrophages, including upregulation of Trem2, which was also recently implicated in obesity and atherosclerosis. The role of macrophage Trem2 in cardiac remodeling, however, is unknown. We found that mice with genetic deletion of Trem2 exhibit increased cardiac hypertrophy and decreased cardiac capillary density after DOCA-salt treatment compared to wild-type controls, and Trem2-deficient macrophages have impaired expression of pro-angiogenic gene programs. Furthermore, we found that plasma levels of soluble TREM2 are elevated in human heart failure. Together, our data suggest a novel cardioprotective role for macrophage Trem2 in cardiac remodeling and heart failure and provide an atlas for the identification of additional targets that can lead to improved diagnostic and therapeutic strategies for HFpEF.
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Project description:Recent reports have suggested a protective role for vascular endothelial growth factor C (VEGFC) during acute cardiac lymphangiogenesis post MI. Glinton et al. report that defective efferocytosis by macrophages after experimental MI leads to a reduction in cardiac lymphangiogenesis and Vegfc expression.
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Project description:The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during the stressful events surrounding early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.
2024-04-03 | PXD050996 | Pride
Project description:The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during the stressful events surrounding early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.
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