Author response: Apelin signaling drives vascular endothelial cells toward a pro-angiogenic state

Helker, Christian S. M.; Eberlein, Jean; Wilhelm, Kerstin; Sugino, Toshiya; Malchow, Julian; Schuermann, Annika; Baumeister, Stefan; Kwon, Hyouk-Bum; Maischein, Hans-Martin; Potente, Michael; Herzog, Wiebke; Stainier, Didier Y. R.

doi:10.7554/elife.55589.sa2

Cited by 3 publications

(3 citation statements)

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“…Moreover, OPC-Wnt signaling was required specifically to maintain expression of Apelin in angiogenic tip cells in contrast to other pro-angiogenic cues in Wntless mutants. A recent study has shown Apelin signaling promotes a pro-angiogenic state in zebrafish endothelial cells (Helker et al, 2020), and interestingly, loss of Apelin function caused tip cell defects similar to those we observed in OPC-Wntless mutants. While autocrine Wnt signaling inhibits OPC differentiation (Fancy et al, 2009(Fancy et al, , 2011(Fancy et al, , 2014Hammond et al, 2015), we found that expression of the Wnt downstream target Axin2 was unaltered within the OPCs themselves in Wnt mutant animals, and we did not observe precocious OPC differentiation; thus, we found no evidence for autocrine effects.…”

Section: Opc-encoded Wnt Signaling Is Essential For Neonatal Wm Angiogenesis and Axonal But Not Bbb Integritysupporting

confidence: 86%

Wnt-Dependent Oligodendroglial-Endothelial Interactions Regulate White Matter Vascularization and Attenuate Injury

Chavali

Ulloa-Navas

Pérez-Borredá

et al. 2020

Neuron

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Section: Opc-encoded Wnt Signaling Is Essential For Neonatal Wm Angiogenesis and Axonal But Not Bbb Integritysupporting

confidence: 86%

Wnt-Dependent Oligodendroglial-Endothelial Interactions Regulate White Matter Vascularization and Attenuate Injury

Chavali

Ulloa-Navas

Pérez-Borredá

et al. 2020

Neuron

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“…Thus, in Ctnnb1 OE−EC mice de novo Apln expression in transdifferentiated LSECs may be involved in dysregulated lipid homeostasis. Yet, one has to consider that aberrant Apln expression is also found in CD34 + capillarized LSECs in liver fibrosis (Winkler et al, 2021) and cirrhosis (Yokomori et al, 2012) and also pro-angiogenic effects were similar to the vascular apelin signaling (Helker et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation

et al. 2021

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Endothelial wingless-related integration site (Wnt)-/β-catenin signaling is a key regulator of the tightly sealed blood–brain barrier. In the hepatic vascular niche angiokine-mediated Wnt signaling was recently identified as an important regulator of hepatocyte function, including the determination of final adult liver size, liver regeneration, and metabolic liver zonation. Within the hepatic vasculature, the liver sinusoidal endothelial cells (LSECs) are morphologically unique and functionally specialized microvascular endothelial cells (ECs). Pathological changes of LSECs are involved in chronic liver diseases, hepatocarcinogenesis, and liver metastasis. To comprehensively analyze the effects of endothelial Wnt-/β-catenin signaling in the liver, we used endothelial subtype-specific Clec4g-iCre mice to generate hepatic ECs with overexpression of Ctnnb1. In the resultant Clec4g-iCretg/wt;Ctnnb1(Ex3)fl/wt (Ctnnb1OE−EC) mice, activation of endothelial Wnt-/β-catenin signaling resulted in sinusoidal transdifferentiation with disturbed endothelial zonation, that is, loss of midzonal LSEC marker lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve1) and enrichment of continuous EC genes, such as cluster of differentiation (CD)34 and Apln. Notably, gene set enrichment analysis revealed overrepresentation of brain endothelial transcripts. Activation of endothelial Wnt-/β-catenin signaling did not induce liver fibrosis or alter metabolic liver zonation, but Ctnnb1OE−EC mice exhibited significantly increased plasma triglyceride concentrations, while liver lipid content was slightly reduced. Ctnnb1 overexpression in arterial ECs of the heart has been reported previously to cause cardiomyopathy. As Clec4g-iCre is active in a subset of cardiac ECs, it was not unexpected that Ctnnb1OE−EC mice showed reduced overall survival and cardiac dysfunction. Altogether, balanced endothelial Wnt-/β-catenin signaling in the liver is required for normal LSEC differentiation and for maintenance of normal plasma triglyceride levels.

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“…S1D). In the network periphery, where active angiogenesis occurs (angiogenic front), endothelial cells marked by the VEGFR co-receptor NRP2 (Alghamdi et al, 2020) and enriched in APLNR (Helker et al, 2020) appeared to lead the vessel formation and exhibited tip cell morphology with extended filopodia (Fig. 1C; Fig.…”

Section: Resultsmentioning

confidence: 99%

Fate and state transitions during human blood vessel organoid development

Nikolova

Wimmer

et al. 2022

Preprint

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Blood vessel organoids (BVOs) derived from human pluripotent stem cells have emerged as a novel system to understand human vascular development, model disorders, and develop regenerative therapies. However, it is unclear which molecular states constitute BVOs and how cells differentiate and self-organize within BVOs in vitro and after transplantation. Here we reconstruct BVO development over a time course using single-cell transcriptomics. We observe progenitor states that bifurcate into endothelial and mural fates, and find that BVOs do not acquire definitive arterio-venous endothelial identities in vitro. Chromatin accessibility profiling identifies gene regulatory network (GRN) features associated with endothelial and mural fate decisions, and transcriptome-coupled lineage recording reveals multipotent progenitor states within BVOs. We perform single-cell genetic perturbations within mosaic BVOs to dissect the impact of transcription factor (TF) and receptor depletion on cell differentiation, and highlight multiple TFs including MECOM and ETV2 as strong-effect regulators of human BVO development. We show that manipulation of VEGF and Notch signaling pathways alters BVO morphogenesis and endothelial GRNs, and induces arteriovenous-like state differentiation. We analyze matured BVOs after transplantation using scRNA-seq, and observe matured endothelium with clear arteriovenous specification. We also observe off-target cell fates with bone and adipocyte features, suggesting multipotent states reside within the BVOs in vitro that expand and diversify in less restrictive conditions. Finally, we map vascular disease associated genes to BVO cell states to highlight the potential of BVOs for disease modeling. Altogether, our data and analyses provide the first comprehensive cell state atlas of BVO development and illuminate both the power and limitation of BVOs for translational research.

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Author response: Apelin signaling drives vascular endothelial cells toward a pro-angiogenic state

Cited by 3 publications

References 0 publications

Wnt-Dependent Oligodendroglial-Endothelial Interactions Regulate White Matter Vascularization and Attenuate Injury

Wnt-Dependent Oligodendroglial-Endothelial Interactions Regulate White Matter Vascularization and Attenuate Injury

Imbalanced Activation of Wnt-/β-Catenin-Signaling in Liver Endothelium Alters Normal Sinusoidal Differentiation

Fate and state transitions during human blood vessel organoid development

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