Induced Pluripotent Stem Cell-Derived Endothelial Cells Overexpressing Interleukin-8 Receptors A/B and/or C-C Chemokine Receptors 2/5 Inhibit Vascular Injury Response

Giordano, Samantha; Zhao, Xiangmin; Chen, Yiu‐Fai; Litovsky, Silvio; Hage, Fadi G.; Townes, Tim M.; Sun, Chengzhen; Wu, Li‐Chen; Oparil, Suzanne; Xing, Dong

doi:10.1002/sctm.16-0316

Cited by 7 publications

(12 citation statements)

References 67 publications

(136 reference statements)

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“…In addition, adult stem cells such as bone marrow‐derived mesenchymal stromal cells , muscle‐derived progenitor cells , and adipose‐derived stem cells , are candidate alternative cell sources for endothelial lineage differentiation. Furthermore, ESCs and induced pluripotent stem cells (iPSCs) have successfully been differentiated into ECs. Nonetheless, the limited quantity and donor site morbidity of somatic ECs, risk of oncogenesis from iPSCs, and ethical issues surrounding use of ESCs have hindered their extension to clinical application.…”

Section: Introductionmentioning

confidence: 99%

Human Urine-Derived Stem Cell Differentiation to Endothelial Cells with Barrier Function and Nitric Oxide Production

Liu

Yang

et al. 2018

Stem Cells Translational Medicine

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Endothelial cells (ECs) play a key role in revascularization within regenerating tissue. Stem cells are often used as an alternative cell source when ECs are not available. Several cell types have been used to give rise to ECs, such as umbilical cord vessels, or differentiated from somatic stem cells, embryonic, or induced pluripotent stem cells. However, the latter carry the potential risk of chronic immune rejection and oncogenesis. Autologous endothelial precursors are an ideal resource, but currently require an invasive procedure to obtain them from the patient's own blood vessels or bone marrow. Thus, the goal of this study was to determine whether urine‐derived stem cells (USCs) could differentiate into functional ECs in vitro. Urine‐derived cells were then differentiated into cells of the endothelial lineage using endothelial differentiation medium for 14 days. Changes in morphology and ultrastructure, and functional endothelial marker expression were assessed in the induced USCs in vitro. Grafts of the differentiated USCs were then subcutaneously injected into nude mice. Induced USCs expressed significantly higher levels of specific markers of ECs (CD31, vWF, eNOS) in vitro and in vivo, compared to nondifferentiated USCs. In addition, the differentiated USC formed intricate tubular networks and presented similar tight junctions, and migration and invasion ability, as well as ability to produce nitric oxide (NO) compared to controls. Using USCs as autologous EC sources for vessel, tissue engineering strategies can yield a sufficient number of cells via a noninvasive, simple, and low‐cost method suitable for rapid clinical translation. stem cells translational medicine 2018 Stem Cells Translational Medicine 2018;7:686–698

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Section: Introductionmentioning

confidence: 99%

Human Urine-Derived Stem Cell Differentiation to Endothelial Cells with Barrier Function and Nitric Oxide Production

Liu

Yang

et al. 2018

Stem Cells Translational Medicine

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“…Induced pluripotent stem (iPS) cell‐derived endothelial cells (iPS‐ECs) have shown notable therapeutic potential in preclinical studies, which includes the ability to incorporate into and re‐endothelialize damaged vasculature as well as to inhibit neointimal and inflammatory responses to vascular injury . In addition, they have shown great functional promise in providing opportunities for disease modeling .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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

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“…CCR5 is a receptor that binds multiple ligands, including macrophage inﬂammatory protein‐1b, RANTES, etc. CCR5 functions to modulate the survival and retention of macrophages in the tissue . In this study, we detected that the expression of CCR2 protein in VEGF‐RAW264.7 cells was still as high as that in ZsGreen1‐RAW264.7 and untransfected RAW264.7 cells.…”

Section: Discussionmentioning

confidence: 92%

“…The first phase of acute endoluminal vascular injury is characterized by increased inﬂammatory cytokine production and leukocyte (neutrophil, monocyte/macrophage, and T‐cell) inﬁltration into the injured vasculature within 48 hours postinjury . Recruitment of monocytes/macrophages to the site of vascular injury is mediated by binding of CCR2 and CCR5 expressed on monocyte/macrophage membranes .…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor‐modified macrophages accelerate reendothelialization and attenuate neointima formation after arterial injury in atherosclerosis‐prone mice

Yan

Zhang

Lü

et al. 2019

J of Cellular Biochemistry

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Vascular endothelial growth factor (VEGF) is a promising molecule for cardiovascular diseases therapy. But lack of a targeted delivery system limits its translation into clinical application. This study aimed to develop stably overexpressing VEGF macrophages for targeted VEGF delivery to injured arteries and determine their potential for repairing of the damaged endothelium. Wire-induced carotid artery injury model was established in atherosclerosis-prone mice. It was observed that the VEGF-modified macrophages were recruited to the site of vascular injury and incorporated into new endothelium formation. VEGF-modified macrophages therapy accelerated reendothelialization and attenuated neointima formation. The VEGF protein level in tissues of injured arteries treated with VEGF-modified macrophages was increased. The upregulated C-C chemokine receptor type 5 (CCR5) and unaltered CCR2 protein levels were verified in VEGF-modified macrophages in vitro. Moreover, enhanced nitric oxide (NO) production in the culture medium of VEGF-modified macrophages was demonstrated. Our results indicated that VEGF-modified macrophages acted as vectors of VEGF targeting injured arteries, promoting the repairing directly by incorporating into new endothelium formation and indirectly by secreting sustainable VEGF and producing NO locally. This study represents a novel therapeutic application of targeted cell therapy with VEGF-modified macrophages for cardiovascular diseases.

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Induced Pluripotent Stem Cell-Derived Endothelial Cells Overexpressing Interleukin-8 Receptors A/B and/or C-C Chemokine Receptors 2/5 Inhibit Vascular Injury Response

Cited by 7 publications

References 67 publications

Human Urine-Derived Stem Cell Differentiation to Endothelial Cells with Barrier Function and Nitric Oxide Production

Human Urine-Derived Stem Cell Differentiation to Endothelial Cells with Barrier Function and Nitric Oxide Production

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

Vascular endothelial growth factor‐modified macrophages accelerate reendothelialization and attenuate neointima formation after arterial injury in atherosclerosis‐prone mice

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