Enhanced Function of Induced Pluripotent Stem Cell-Derived Endothelial Cells Through ESM1 Signaling

Abstract

The mortality rate for (cardio)‐vascular disease is one of the highest in the world, so a healthy functional endothelium is of outmost importance against vascular disease. In this study, human induced pluripotent stem (iPS) cells were reprogrammed from 1 ml blood of healthy donors and subsequently differentiated into endothelial cells (iPS‐ECs) with typical EC characteristics. This research combined iPS cell technologies and next‐generation sequencing to acquire an insight into the transcriptional regulation of iPS‐ECs. We identified endothelial cell‐specific molecule 1 (ESM1) as one of the highest expressed genes during EC differentiation, playing a key role in EC enrichment and function by regulating connexin 40 (CX40) and eNOS. Importantly, ESM1 enhanced the iPS‐ECs potential to improve angiogenesis and neovascularisation in in vivo models of angiogenesis and hind limb ischemia. These findings demonstrated for the first time that enriched functional ECs are derived through cell reprogramming and ESM1 signaling, opening the horizon for drug screening and cell‐based therapies for vascular diseases. Therefore, this study showcases a new approach for enriching and enhancing the function of induced pluripotent stem (iPS) cell‐derived ECs from a very small amount of blood through ESM1 signaling, which greatly enhances their functionality and increases their therapeutic potential. S tem C ells 2019;37:226–239

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

“…A small number of cells expressed the smooth muscle cell marker ACTA2, and these cells clustered far from other hiPS-ECs. Monoculture hiPS-ECs under static conditions expressed more arterial than venous markers, which is consistent with previous reports 54,55 . However, the cells did not cluster according to arterial or venous phenotype in static monoculture.…”

LncRNA MALAT1 Regulates iPSC-derived Β-cell Differentiation by Targeting the miR-15b-5p/Ihh Axis

“…Additionally, iPSCs can be reprogrammed from somatic cells with speci c TFs such as Pituitary-Octamer-Unc-86 (POU) class 5 homeobox 4 (OCT4), Nanog, sex-determining region Y-related high-mobility group (HMG) box 12 (SOX12) and Krüppel-like factor 4 (KLF4) without the limitations of embryonic damage and use of immunosuppressants [33]. As reported, differentiation of iPSCs into all kinds of somatic cells is in uenced by numerous factors, such as extracellular matrix (ECM), TFs, cell signaling transduction, ncRNAs and other complex biological process [34][35][36][37]. LncRNAs, a hot area of research in epigenetic regulation, participate in numerous biological and cellular processes, including chromatin remodeling, transcription, metabolism, development, differentiation and tumorigenesis [38][39][40][41].…”

New artery of knowledge: 3D models of angiogenesis

“…After purification, cells express CD31, VE-Cadherin, von Willebrand Factor, Neuropilin-1, CD34, VEGFR and laminin alpha 4, as demonstrated by FACS or immunofluorescence analysis (35,36,40). Moreover, hPSC-EC showed a similar transcriptional signature and metabolomic profile to primary endothelial cultures (HUVEC, HAEC, and human saphenous vein EC), when gene expression profiles and metabolites were compared by RNA-sequencing and liquid chromatography mass spectrometry respectively (35,41). However, variations in the expression profiles are expected, depending on the protocol used for the differentiation and time point of the analysis.…”