Apelin directs endothelial cell differentiation and vascular repair following immune-mediated injury

Masoud, Andrew G.; Lin, Jiaxin; Azad, Abul Kalam; Farhan, Maikel; Fischer, Conrad; Zhu, Lin; Zhang, Hao; Sis, B.; Kassiri, Zamaneh; Moore, Ronald B.; Kim, Daniel; Anderson, Colin C.; Vederas, John C.; Adam, Benjamin; Oudit, Gavin Y.; Murray, Allan G.

doi:10.1172/jci128469

Cited by 49 publications

(38 citation statements)

References 60 publications

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“…In contrast, shear stress downregulated the vascular tone regulator EDN1 44 in all flow clusters ( Figure 7C). Flow promoted quiescence in endothelial cells and this was consistent with the finding of several angiogenesis genes such as APLN 45 , ANGPT2, CITED2 46 , DDAH1 47 , and THBS1 48 being downregulated by flow ( Figure 7C). The arterial-type FlowEC 4 cluster seemed to have attenuated response to flow, based on the lower expression of flow-induced genes compared to the other three flow clusters, however they still clearly differed from the static cells.…”

Section: The Data Supplement)supporting

confidence: 88%

Modeling cellular crosstalk and organotypic vasculature development with human iPSC-derived endothelial cells and cardiomyocytes

Helle

Ampuja

Dainis

et al. 2020

Preprint

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RationaleCell-cell interactions are crucial for the development and function of the organs. Endothelial cells act as essential regulators of tissue growth and regeneration. In the heart, endothelial cells engage in delicate bidirectional communication with cardiomyocytes. The mechanisms and mediators of this crosstalk are still poorly known. Furthermore, endothelial cells in vivo are exposed to blood flow and their phenotype is greatly affected by shear stress. ObjectiveWe aimed to elucidate how cardiomyocytes regulate the development of organotypic phenotype in endothelial cells. In addition, the effects of flow-induced shear stress on endothelial cell phenotype were studied. Methods and resultsHuman induced pluripotent stem cell (hiPSC) -derived cardiomyocytes and endothelial cells were grown either as a monoculture or as a coculture. hiPS-endothelial cells were exposed to flow using the Ibidi-pump system. Single-cell RNA sequencing was performed to define cell populations and to uncover the effects on their transcriptomic phenotypes. The hiPS-cardiomyocyte differentiation resulted in two distinct populations; atrial and ventricular. Coculture had a more pronounced effect on hiPS-endothelial cells compared to hiPS-cardiomyocytes. Coculture increased hiPS-endothelial cell expression of transcripts related to vascular development and maturation, cardiac development, and the expression of cardiac endothelial cell -specific genes. Exposure to flow significantly reprogrammed the hiPS-endothelial cell transcriptome, and surprisingly, promoted the appearance of both venous and arterial clusters. ConclusionsSingle-cell RNA sequencing revealed distinct atrial and ventricular cell populations in hiPScardiomyocytes, and arterial and venous-like cell populations in flow exposed hiPS-endothelial cells. hiPS-endothelial cells acquired cardiac endothelial cell identity in coculture. Our study demonstrated that hiPS-cardiomoycytes and hiPS-endothelial cells readily adapt to coculture and flow in a consistent and relevant manner, indicating that the methods used represent improved physiological cell culturing conditions that potentially are more relevant in disease modelling. In addition, novel cardiomyocyte-endothelial cell crosstalk mediators were revealed.

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Section: The Data Supplement)supporting

confidence: 88%

Modeling cellular crosstalk and organotypic vasculature development with human iPSC-derived endothelial cells and cardiomyocytes

Helle

Ampuja

Dainis

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Flow promoted quiescence in hiPS-ECs, demonstrated by downregulation of several angiogenesis and EC activation marker genes (APLN, ANGPT2, CITED2, DDAH1 and THBS1) (Freedman et al, 2003;Smadja et al, 2011;Trittmann et al, 2019;Masoud et al, 2020) (Figure 5B and Supplementary Tables S1A-C) and by the upregulation of TEK (TIE2), that contributes to the maintenance of vascular quiescence (Augustin et al, 2009) (Supplementary Tables S1A-C). Vascular endothelial protein tyrosine phosphatase (VE-PTP, also known as PTPRB), that regulates blood vessel remodeling and angiogenesis (Küppers et al, 2014), was also markedly induced by flow together with other PTPs PTPRG and PTPRE (Supplementary Tables S1A-C and Figure 6A).…”

Section: Flow-exposed Hips-ecs Represent a More Stable And Homeostatimentioning

confidence: 99%

Flow-Induced Transcriptomic Remodeling of Endothelial Cells Derived From Human Induced Pluripotent Stem Cells

et al. 2020

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The vascular system is essential for the development and function of all organs and tissues in our body. The molecular signature and phenotype of endothelial cells (EC) are greatly affected by blood flow-induced shear stress, which is a vital component of vascular development and homeostasis. Recent advances in differentiation of ECs from human induced pluripotent stem cells (hiPSC) have enabled development of in vitro experimental models of the vasculature containing cells from healthy individuals or from patients harboring genetic variants or diseases of interest. Here we have used hiPSCderived ECs and bulk-and single-cell RNA sequencing to study the effect of flow on the transcriptomic landscape of hiPSC-ECs and their heterogeneity. We demonstrate that hiPS-ECs are plastic and they adapt to flow by expressing known flow-induced genes. Single-cell RNA sequencing showed that flow induced a more homogenous and homeostatically more stable EC population compared to static cultures, as genes related to cell polarization, barrier formation and glucose and fatty acid transport were induced. The hiPS-ECs increased both arterial and venous markers when exposed to flow. Interestingly, while in general there was a greater increase in the venous markers, one cluster with more arterial-like hiPS-ECs was detected. Single-cell RNA sequencing revealed that not all hiPS-ECs are similar even after sorting, but exposing them to flow increases their homogeneity. Since hiPS-ECs resemble immature ECs and demonstrate high plasticity in response to flow, they provide an excellent model to study vascular development.

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“…Apelin upregulates ACE2 gene transcription in murine heart [ 49 , 50 ], cardiomyocytes and adipose tissue of diabetic rats [ 51 ]. It also promotes vascular repair following immune-mediated injury [ 52 ]. Accordingly, genetic deletion of apelin causes downregulation of cardiac ACE2 transcription and ACE2 protein levels, which can be reversed by infusion of apelin, indicating an important regulatory role of apelin in ACE2 gene expression [ 50 , 53 ].…”

Section: Enzymatic Functions Of Ace2 In Plasmamentioning

confidence: 99%

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury

Öz¹,

Lorke²

2021

Biomedicine & Pharmacotherapy

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Apelin directs endothelial cell differentiation and vascular repair following immune-mediated injury

Cited by 49 publications

References 60 publications

Modeling cellular crosstalk and organotypic vasculature development with human iPSC-derived endothelial cells and cardiomyocytes

Modeling cellular crosstalk and organotypic vasculature development with human iPSC-derived endothelial cells and cardiomyocytes

Flow-Induced Transcriptomic Remodeling of Endothelial Cells Derived From Human Induced Pluripotent Stem Cells

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury

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