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2.
Elife ; 122024 May 22.
Article in English | MEDLINE | ID: mdl-38775664

ABSTRACT

Cardiac macrophages are heterogenous in phenotype and functions, which has been associated with differences in their ontogeny. Despite extensive research, our understanding of the precise role of different subsets of macrophages in ischemia/reperfusion (I/R) injury remains incomplete. We here investigated macrophage lineages and ablated tissue macrophages in homeostasis and after I/R injury in a CSF1R-dependent manner. Genomic deletion of a fms-intronic regulatory element (FIRE) in the Csf1r locus resulted in specific absence of resident homeostatic and antigen-presenting macrophages, without affecting the recruitment of monocyte-derived macrophages to the infarcted heart. Specific absence of homeostatic, monocyte-independent macrophages altered the immune cell crosstalk in response to injury and induced proinflammatory neutrophil polarization, resulting in impaired cardiac remodeling without influencing infarct size. In contrast, continuous CSF1R inhibition led to depletion of both resident and recruited macrophage populations. This augmented adverse remodeling after I/R and led to an increased infarct size and deterioration of cardiac function. In summary, resident macrophages orchestrate inflammatory responses improving cardiac remodeling, while recruited macrophages determine infarct size after I/R injury. These findings attribute distinct beneficial effects to different macrophage populations in the context of myocardial infarction.


Subject(s)
Macrophages , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor , Animals , Macrophages/immunology , Mice , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Myocardial Ischemia/immunology , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Infarction/immunology , Male , Myocardial Reperfusion Injury/immunology , Myocardial Reperfusion Injury/pathology , Mice, Inbred C57BL , Myocardium/pathology , Myocardium/immunology , Disease Models, Animal
3.
Stem Cells Transl Med ; 8(9): 898-910, 2019 09.
Article in English | MEDLINE | ID: mdl-31054183

ABSTRACT

Recent advances in the understanding of lipid metabolism suggest a critical role of endoplasmic reticulum (ER) stress in obesity-induced kidney injury. Hepatocyte growth factor (HGF) is a pleiotropic cytokine frequently featured in stem cell therapy with distinct renotropic benefits. This study aims to define the potential link between human induced pluripotent stem cell-derived mesenchymal stem cells (iPS-MSCs)/bone marrow-derived MSCs (BM-MSCs) and ER stress in lipotoxic kidney injury induced by palmitic acid (PA) in renal tubular cells and by high-fat diet (HFD) in mice. iPS-MSCs or BM-MSCs alleviated ER stress (by preventing induction of Bip, chop, and unfolded protein response), inflammation (Il6, Cxcl1, and Cxcl2), and apoptosis (Bax/Bcl2 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells) in renal cortex of animals exposed to HFD thus mitigating histologic damage and albuminuria, via activating HGF/c-Met paracrine signaling that resulted in enhanced HGF secretion in the glomerular compartment and c-Met expression in the tubules. Coculture experiments identified glomerular endothelial cells (GECs) to be the exclusive source of glomerular HGF when incubated with either iPS-MSCs or BM-MSCs in the presence of PA. Furthermore, both GEC-derived HGF and exogenous recombinant HGF attenuated PA-induced ER stress in cultured tubular cells, and this effect was abrogated by a neutralizing anti-HGF antibody. Taken together, this study is the first to demonstrate that MSCs ameliorate lipotoxic kidney injury via a novel microenvironment-dependent paracrine HGF/c-Met signaling mechanism to suppress ER stress and its downstream pro-inflammatory and pro-apoptotic consequences. Stem Cells Translational Medicine 2019;8:898&910.


Subject(s)
Endoplasmic Reticulum Stress , Hepatocyte Growth Factor/metabolism , Obesity/pathology , Proto-Oncogene Proteins c-met/metabolism , Animals , Apoptosis/drug effects , Coculture Techniques , Culture Media, Conditioned/chemistry , Culture Media, Conditioned/pharmacology , Diet, High-Fat , Endoplasmic Reticulum Stress/drug effects , Endothelial Cells/cytology , Endothelial Cells/metabolism , Hepatocyte Growth Factor/genetics , Kidney/metabolism , Kidney/pathology , Kidney Tubules/cytology , Male , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Mice , Mice, Inbred C57BL , Obesity/metabolism , Palmitic Acid/toxicity , Paracrine Communication/drug effects , Recombinant Proteins/biosynthesis , Recombinant Proteins/isolation & purification , Recombinant Proteins/pharmacology , Signal Transduction/drug effects
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