Lowering the increased intracellular pH of human‐induced pluripotent stem cell‐derived endothelial cells induces formation of mature Weibel‐Palade bodies
Differentiation of human‐induced pluripotent stem cells (hiPSCs) into vascular endothelium is of great importance to tissue engineering, disease modeling, and use in regenerative medicine. Although differentiation of hiPSCs into endothelial‐like cells (hiPSC‐derived endothelial cells [hiPSC‐ECs]) ha...
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Published in | Stem cells translational medicine Vol. 9; no. 7; pp. 758 - 772 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken, USA
John Wiley & Sons, Inc
01.07.2020
Oxford University Press |
Subjects | |
Online Access | Get full text |
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Summary: | Differentiation of human‐induced pluripotent stem cells (hiPSCs) into vascular endothelium is of great importance to tissue engineering, disease modeling, and use in regenerative medicine. Although differentiation of hiPSCs into endothelial‐like cells (hiPSC‐derived endothelial cells [hiPSC‐ECs]) has been demonstrated before, controversy exists as to what extent these cells faithfully reflect mature endothelium. To address this issue, we investigate hiPSC‐ECs maturation by their ability to express von Willebrand factor (VWF) and formation of Weibel‐Palade bodies (WPBs). Using multiple hiPSCs lines, hiPSC‐ECs failed to form proper VWF and WPBs, essential for angiogenesis, primary and secondary homeostasis. Lowering the increased intracellular pH (pHi) of hiPSC‐ECs with acetic acid did result in the formation of elongated WPBs. Nuclear magnetic resonance data showed that the higher pHi in hiPSC‐ECs occurred in association with decreased intracellular lactate concentrations. This was explained by decreased glycolytic flux toward pyruvate and lactate in hiPSC‐ECs. In addition, decreased expression of monocarboxylate transporter member 1, a member of the solute carrier family (SLC16A1), which regulates lactate and H+ uptake, contributed to the high pHi of hiPSC‐EC. Mechanistically, pro‐VWF dimers require the lower pH environment of the trans‐Golgi network for maturation and tubulation. These data show that while hiPSC‐ECs may share many features with mature EC, they are characterized by metabolic immaturity hampering proper EC function.
Formation of mature Weibel‐Palade bodies in human‐induced pluripotent stem cell‐derived endothelial cells is limited by the increased intracellular pH (pHi) around the Golgi apparatus and trans‐Golgi network. This increase in pHi is caused by reduced intracellular lactate accompanied by reduced H+, caused by reduced glycolysis, and reduced the uptake of lactate and H+ via monocarboxylate transporter member 1. |
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Bibliography: | Funding information Bontius Stichting; LUMC MD/PhD track; Health~Holland, Top Sector Life Sciences & Health ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Funding information Bontius Stichting; LUMC MD/PhD track; Health~Holland, Top Sector Life Sciences & Health Data Availability Statement:The RNA‐sequencing data that support the findings of this study are openly available at ArrayExpress (https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8392/) under accession number E‐MTAB‐8392. |
ISSN: | 2157-6564 2157-6580 2157-6580 |
DOI: | 10.1002/sctm.19-0392 |