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Liver sinusoidal endothelial cells constitute a major route for hemoglobin clearance

ABSTRACT: Hemolysis of senescent erythrocytes occurs in the spleen, resulting in hemoglobin (Hb) release. Several diseases are associated with an increased risk of erythrocyte rupture. Iron recycling from Hb and Hb detoxification have been attributed to the sequestration of Hb-haptoglobin complexes by macrophages, however, other routes of Hb clearance might exist. We identified liver sinusoidal endothelial cells (LSECs) as the major cell type that sequesters Hb. Hb uptake involves macropinocytosis and is independent of haptoglobin and the Hb-haptoglobin receptor CD163. LSECs expressed heme oxygenase 1 and hepcidin-controlled ferroportin and were the most efficient cellular scavengers of Hb at doses below the haptoglobin binding capacity. Erythrocyte transfusion assays demonstrated that while splenic red pulp macrophages are efficient in erytrophagocytosis, liver Kupffer cells and LSECs are primarily involved in the clearance of erythrocyte ghosts and Hb, respectively. Using time-course injections of high doses of Hb in mice, we detected transient hepatic iron retention, early induction of Hmox1 specifically in LSECs, and elevation of ferroportin levels. This was associated with transcriptional activation of LSEC Bmp6, followed by hepcidin-mediated transient hypoferremia. Injection of Hb and iron-citrate elicited distinct transcriptional signatures in LSECs and the early Bmp6 induction was phenocopied by erythrocyte lysis upon phenylhydrazine. Collectively, we propose that LSECs provide a key mechanism for Hb clearance, a function that establishes the spleen-liver axis for physiological iron recycling from Hb and contributes to heme detoxification during hemolysis, coupled with the induction of the BMP6-hepcidin axis that restores homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE240270 | GEO | 2025/08/01

REPOSITORIES: GEO

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Project description:Hepcidin, a peptide hormone that decreases intestinal iron absorption and macrophage iron release, is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. Endogenous stimulants of Hepcidin transcription include bone morphogenic protein 6 (BMP) and interleukin-6 (IL-6) via effects on Smad4 or Stat3, respectively. We conducted a small-scale chemical screen in zebrafish embryos to identify small molecules that modulate hepcidin expression. We found that treatment with the isoflavone genistein from 28−52 hours post-fertilization in zebrafish embryos enhanced Hepcidin transcript levels as assessed by whole mount in situ hybridization and quantitative realtime RT-PCR. Genistein’s stimulatory effect was conserved in human hepatocytes: genistein treatment of HepG2 cells increased both Hepcidin transcript levels and Hepcidin promoter activity. We found that genistein’s effect on Hepcidin expression did not depend on estrogen receptor signaling or increased cellular iron uptake, but was impaired by mutation of either the BMP response elements or the Stat3 binding site in the Hepcidin promoter. RNA-sequencing of transcripts from genistein-treated hepatocytes indicated that genistein upregulated 68% of the transcripts that were upregulated by BMP6, however genistein raised the levels of several transcripts involved in Stat3 signaling that were not upregulated by BMP6. Chromatin-immunoprecipitation and ELISA experiments revealed that genistein enhanced Stat3 binding to the Hepcidin promoter and increased phosphorylation of Stat3 in HepG2 cells. CONCLUSION: Genistein is the first small molecule experimental drug that stimulates Hepcidin expression in vivo and in vitro. These experiments demonstrate the feasibility of identifying and characterizing small molecules that increase Hepcidin expression. Genistein and other candidate molecules may subsequently be developed into new therapies for iron overload syndromes. RNA-seq of HepG2 cells treated with DMSO 1%, BMP6 50 ng/ml, or genistein 10 micromolar. The numbers of biological replicates were 3, 2, and 3.

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Liver sinusoidal endothelial cells constitute a major route for hemoglobin clearance

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