Specification of fetal liver endothelial progenitors to functional zonated adult sinusoids requires c-Maf induction

Gómez-Salinero, Jesús M.; Izzo, Franco; Yang, Lin; Houghton, Sean; Itkin, Tomer; Geng, Fuqiang; Bram, Yaron; Adelson, Robert P.; Lu, Tyler M.; Inghirami, Giorgio; Xiang, Jenny; Lis, Raphaël; Redmond, David; Schreiner, Ryan; Rabbany, Sina Y.; Landau, Dan A.; Schwartz, Robert E.; Rafii, Shahin

doi:10.1016/j.stem.2022.03.002

Cited by 45 publications

(71 citation statements)

References 58 publications

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“…On the other hand, the present and previous studies demonstrate that local microenvironmental cues might play a bigger role in not only the acquisition but also the maintenance of the organ-specific characteristics. This is also in line with recent study on sinusoidal ECs of the liver (Gómez-Salinero et al, 2022). Earlier studies have demonstrated the importance of the Gata4 transcription factor in the differentiation of liver ECs and the acquisition of sinusoidal-like identity (Géraud et al, 2017; Zhang et al, 2016b).…”

Section: Discussionsupporting

confidence: 93%

“…Earlier studies have demonstrated the importance of the Gata4 transcription factor in the differentiation of liver ECs and the acquisition of sinusoidal-like identity (Géraud et al, 2017; Zhang et al, 2016b). However, scRNA-seq analysis of liver ECs showed that Gata4 is not restricted to sinusoidal ECs but it is expressed by all ECs in the liver (Gómez-Salinero et al, 2022). Instead, the c-Maf transcription factor was restricted to sinusoidal liver ECs and was regulated by BMP9 that is highly expressed by hepatic stellate cells (HSC) (Breitkopf-Heinlein et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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Tissue microenvironment dictates the state of human induced pluripotent stem cell-derived endothelial cells of distinct developmental origin in 3D cardiac microtissues

Cao

Mircea

Hil

et al. 2022

Preprint

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Each tissue and organ in the body has its own type of vasculature. Here we demonstrate that organotypic vasculature for the heart can be recreated in a three-dimensional cardiac microtissue (MT) model composed of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), cardiac fibroblasts (CFs) and endothelial cells (ECs). ECs in cardiac MTs upregulated expression of markers enriched in human intramyocardial ECs (iECs), such as CD36, CLDN5, APLNR, NOTCH4, IGFBP3, ARHGAP18, which were previously identified in the single-cell RNA-seq dataset from the human fetal heart (6.5-7 weeks post coitum). We further show that the local microenvironment largely dictates the organ-specific identity of hiPSC-derived ECs: we compared ECs of different developmental origins derived from two distinct mesoderm subtypes (cardiac and paraxial mesoderm) and found that independent of whether the ECs were cardiac or paraxial mesoderm derived, they acquired similar identities upon integration into cardiac microtissues. This was confirmed by single-cell RNA-seq. Overall, the results indicated that whilst the initial gene profile of ECs was dictated by developmental origin, this could be modified by the local tissue environment such that the original identity was lost and the organotypic identity acquired through local environmental signals. This developmental "plasticity" in ECs has implications for multiple pathological and disease states.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Tissue microenvironment dictates the state of human induced pluripotent stem cell-derived endothelial cells of distinct developmental origin in 3D cardiac microtissues

Cao

Mircea

Hil

et al. 2022

Preprint

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“…In addition, there were no significant differences in serum AST and ALT levels, which are criteria for liver function (Supplemental Figure 1H, I). In fact, time-specific c-Maf loss did not alter the fractal dimension patterning and did not induce liver damage, such as fibrosis, under basal conditions (23).…”

Section: C-maf δTam Mice Develop Severe Renal Glycosuria Basic Aminoa...mentioning

confidence: 86%

“…The degree of mesangial matrix expansion, tubulointerstitial fibrogenesis, and the number of WT1 positive nuclei were assessed by measuring the PAMS-and mesangial Sirius Redpositive areas, and by performing IHC staining for WT1 in the kidneys. PAMS-stained glomeruli (20-25 fields at 40× magnification), Sirius Red-stained interstitial lesions (20)(21)(22)(23)(24)(25)(26)(27) fields at 20× magnification), and the number of WT1-positive nuclei (15-20 fields at 40× After centrifugation at 2,000 rpm for 5 min at 4 °C, the supernatant was discarded and the antibody-protein-DNA complexes were washed twice with a high salt wash buffer (20 mM Tris-HCl [pH 7.9], 500 mM NaCl, 2 mM EDTA, 1% Triton X-100, and 0.1% SDS), once with LiCl wash buffer (10 mM Tris-HCl [pH 7.9], 250 mM LiCl, 1 mM EDTA, 1% NP-40, and 1% sodium deoxycholate), and twice with Tris-EDTA (pH 7.9). The samples were then incubated in an elution buffer (100 mM NaHCO3, 1% SDS, and 10 mM dithiothreitol (DTT) at about 25 °C for 15 min, centrifuged at 2,000 rpm for 1 min at about 25 °C, and the was collected.…”

Section: Measurement Of Periodic Acid-methenamine Silver (Pams)-and S...mentioning

confidence: 99%

Transcription factor c-Maf deletion improves streptozotocin-induced diabetic nephropathy by directly regulating Sglt2 and Glut2

Fujino¹,

Morito²,

Hayashi³

et al. 2023

JCI Insight

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The transcription factor c-Maf has been widely studied and has been reported to play a critical role in embryonic kidney development; however, the postnatal functions of c-Maf in adult kidneys remain unknown as c-Maf null C57BL/6J mice exhibit embryonic lethality. In this study, we investigated the role of c-Maf in adult mouse kidneys by comparing the phenotypes of tamoxifen (TAM)-inducible c-Maf knockout mice (c-Maf flox/flox ; CAG-Cre-ER TM mice named "c-Maf ΔTAM ") with that of c-Maf flox/flox control mice, 10 days after TAM injection (TAM(10d)). In addition, we examined the effects of c-Maf deletion on diabetic conditions by injecting the mice with streptozotocin (STZ), 4 weeks before TAM injection. c-Maf ΔTAM mice displayed primary glycosuria caused by Sglt2 and Glut2 downregulation in the kidneys without diabetes, as well as morphological changes and life-threatening injuries in the kidneys on TAM(10d). Under diabetic conditions, c-Maf deletion promoted recovery from hyperglycemia and suppressed albuminuria and diabetic nephropathy by causing similar effects as did Sglt2 knockout and SGLT2 inhibitors. In addition to demonstrating the unique gene regulation of c-Maf, these findings highlight the renoprotective effects of c-Maf deficiency under diabetic conditions and suggest that c-Maf could be a novel therapeutic target gene for treating diabetic nephropathy.

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“…Endothelial cell zonation was found to drive much of this functional zonation in hepatocytes via a TIE–WNT signalling axis 150 . The initial establishment of zonation in embryonic endothelial cell progenitors depends on MAF, a transcription factor crucial for sinusoid (or liver capillary) identity 97 .…”

Section: Scrna-seq and Multimodal Omicsmentioning

confidence: 99%

Vascular endothelial cell development and diversity

2022

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Vascular endothelial cells form the inner layer of blood vessels where they have a key role in the development and maintenance of the functional circulatory system and provide paracrine support to surrounding non-vascular cells. Technical advances in the past 5 years in single-cell genomics and in in vivo genetic labelling have facilitated greater insights into endothelial cell development, plasticity and heterogeneity. These advances have also contributed to a new understanding of the timing of endothelial cell subtype differentiation and its relationship to the cell cycle. Identification of novel tissue-specific gene expression patterns in endothelial cells has led to the discovery of crucial signalling pathways and new interactions with other cell types that have key roles in both tissue maintenance and disease pathology. In this Review, we describe the latest findings in vascular endothelial cell development and diversity, which are often supported by large-scale, single-cell studies, and discuss the implications of these findings for vascular medicine. In addition, we highlight how techniques such as single-cell multimodal omics, which have become increasingly sophisticated over the past 2 years, are being utilized to study normal vascular physiology as well as functional perturbations in disease.

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Specification of fetal liver endothelial progenitors to functional zonated adult sinusoids requires c-Maf induction

Cited by 45 publications

References 58 publications

Tissue microenvironment dictates the state of human induced pluripotent stem cell-derived endothelial cells of distinct developmental origin in 3D cardiac microtissues

Tissue microenvironment dictates the state of human induced pluripotent stem cell-derived endothelial cells of distinct developmental origin in 3D cardiac microtissues

Transcription factor c-Maf deletion improves streptozotocin-induced diabetic nephropathy by directly regulating Sglt2 and Glut2

Vascular endothelial cell development and diversity

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