Coronary stents with inducible VEGF/HGF-secreting UCB-MSCs reduced restenosis and increased re-endothelialization in a swine model

Chang, Hyun‐Kyung; Kim, Pyung‐Hwan; Kim, Dong Wook; Cho, Hyunmin; Jeong, Mi Jin; Kim, Dea Han; Joung, Yoon Ki; Lim, Kyung Seob; Kim, Han Byul; Lim, Han Cheol; Han, Dong Keun; Hong, Young Joon; Cho, Je‐Yoel

doi:10.1038/s12276-018-0143-9

Cited by 29 publications

(23 citation statements)

References 38 publications

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“…The current research in this field mainly focuses on improving the function of VSMcs (14)(15)(16)(17)21); however, Ecs have not been extensively investigated. The delay in endothelialization severely compromises the therapeutic effect of Ecs (40). Previously published data by the authors of the current study demonstrated that miR-24 was enriched in VSMcs rather than Ecs (41).…”

Section: Discussionmentioning

confidence: 54%

MicroRNA‑24 attenuates diabetic vascular remodeling by�suppressing the NLRP3/caspase‑1/IL‑1β signaling pathway

Fan

Yang

et al. 2020

Int J Mol Med

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Vascular remodeling plays an important role in the pathogenesis of diabetic cardiovascular complications. Previous published research has indicated that microRNA-24 (miR-24) is involved in diabetic vascular remodeling, but the underlying molecular mechanisms have yet to be fully elucidated. The aim of the present study was to investigate whether adenovirus-mediated miR-24 overexpression can suppress the NOd-like receptor family pyrin domain-containing 3 (NLRP3)-related inflammatory signaling pathway and attenuate diabetic vascular remodeling. The carotid arteries of diabetic rats were harvested and prepared for analysis. Reverse transcription-quantitative PcR and western blotting assays were used to detect the expressions of related mRNAs and proteins. Morphological examinations, including hematoxylin and eosin, immunohistochemical and Masson's trichrome staining, were also performed. The results of the present study demonstrated that miR-24 upregulation suppressed neointimal hyperplasia and accelerated reendothelialization in the injured arteries, lowered the expression of NLRP3, apoptosis-associated speck-like protein, caspase-1, proliferating cell nuclear antigen, cd45, interleukin (IL)-1β, IL-18 and tumor necrosis factor-α, and increased the expression of cd31, smooth muscle (SM) α-actin and SM-myosin heavy chain. These data indicated that miR-24 overexpression can attenuate vascular remodeling in a diabetic rat model through suppressing the NLRP3/caspase-1/IL-1β signaling pathway.

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Section: Discussionmentioning

confidence: 54%

MicroRNA‑24 attenuates diabetic vascular remodeling by�suppressing the NLRP3/caspase‑1/IL‑1β signaling pathway

Fan

Yang

et al. 2020

Int J Mol Med

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“…Immunohistochemistry analysis was done as previously reported by our group . Briefly, after paraffin‐embedded sections were cut at 4‐μm sections, the slides were deparaffinized and transferred through progressive ethanol gradients for rehydration.…”

Section: Methodsmentioning

confidence: 99%

CD276 (B7-H3) Maintains Proliferation and Regulates Differentiation in Angiogenic Function in Late Endothelial Progenitor Cells

2018

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Endothelial progenitor cells (EPCs) provide an important source of recovery from blood vessel dysfunction. Late EPCs (LEPCs) are circulating blood cells that are capable of promoting vascular repair. Using transcriptome analysis, we identified distinctive LEPC profiles and found that CD276 (B7‐H3) mRNA is strongly expressed in LEPCs. CD276 protein is present abundantly on the cell surface of LEPC when analyzed by fluorescence‐activated cell sorter and immunocytochemistry. CD276, a B7 family member, is a type I transmembrane glycoprotein. The role of CD276 in LEPCs remains unknown. CD276 knockdown by lentivirus transduction in LEPCs significantly decreased proliferation and increased apoptosis of LEPCs in vitro. After CD276 silencing, the cell cycle of LEPCs was prone to remain at the G0/G1 phase, and the cell migration rates as well as transwell and wound‐healing migration were decreased. CD276 knockdown in LEPCs increased the G1 phase regulators cyclin D2/D3/E1‐cyclin‐dependent kinases (CDK2/4/6), but decreased the S‐G2‐M phase regulators cyclin A/B‐CDK1. However, LEPCs with CD276 knockdown resulted in increased tube formation in vitro and angiogenesis in a Matrigel plug assay in vivo. FoxC1/C2, an upstream signal of Notch in arterial cell proliferation, and Hey1/2, which is known to promote arterial differentiation in the vasculature, were upregulated in CD276 knockdown LEPCs. In LEPCS, CD276 has a positive effect on proliferation and migration of endothelial cells, but negative effects on angiogenesis, particularly endothelial cell differentiation. Our data indicate, for therapeutic purpose, that CD276 can be used to acquire and maintain cell populations of LEPCs and blocking CD276 will promote angiogenetic differentiation. We found that CD276 (B7‐H3) is enriched on the cell membrane of LEPCs. CD276 knockdown reduced proliferation and migration of LEPCs by increasing cell cycle inhibitors such as p21cip1 and pRb and decreasing pErk1/2 and pAkt but promoted angiogenesis and endothelial cell differentiation by elevating vascular endothelial growth factor‐vascular endothelial growth factor receptor 1 and p‐p38. Stem Cells 2019;37:382–394

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“…Growth factors and cytokines, such as VEGF, insulin-like growth factor (IGF), HGF, interleukin-1b (IL-1b), and IL-6, have been investigated as therapeutic targets in various cell types and diseases. 8,[36][37][38] Recently, these molecules, secreted by MSCs, have been examined in repair and regeneration therapy. 35 We thus investigated the para-crine effect of LEF1/hUCB-MSCs via enhanced secretion of growth factors and cytokines.…”

Section: Lef1 Expression In Hucb-mscs Triggers the Production Of Varimentioning

confidence: 99%

Transplantation of hMSCs Genome Edited with LEF1 Improves Cardio-Protective Effects in Myocardial Infarction

Cho

Lee

Shen

et al. 2020

Molecular Therapy - Nucleic Acids

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Stem cell-based therapy is one of the most attractive approaches to ischemic heart diseases, such as myocardial infarction (MI). We evaluated the cardio-protective effects of the human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) stably expressing lymphoid enhancer-binding factor 1 (LEF1; LEF1/hUCB-MSCs) in a rat model of MI. LEF1 overexpression in hUCB-MSCs promoted cell-proliferation and anti-apoptotic effects in hypoxic conditions. For the application of its therapeutic effects in vivo, the LEF1 gene was introduced into an adenoassociated virus integration site 1 (AAVS1) locus, known as a safe harbor site on chromosome 19 by CRISPR/Cas9-mediated gene integration in hUCB-MSCs. Transplantation of LEF1/hUCB-MSCs onto the infarction region in the rat model significantly improved overall survival. The cardio-protective effect of LEF1/hUCB-MSCs was proven by echocardiogram parameters, including greatly improved left-ventricle ejection fraction (EF) and fractional shortening (FS). Moreover, histology and immunohistochemistry successfully presented reduced MI region and fibrosis by LEF1/hUCB-MSCs. We found that these overall positive effects of LEF1/hUCB-MSCs are attributed by increased proliferation and survival of stem cells in oxidative stress conditions and by the secretion of various growth factors by LEF1. In conclusion, this study suggests that the stem cell-based therapy, conjugated with genome editing of transcription factor LEF1, which promotes cell survival, could be an effective therapeutic strategy for cardiovascular disease.

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Coronary stents with inducible VEGF/HGF-secreting UCB-MSCs reduced restenosis and increased re-endothelialization in a swine model

Cited by 29 publications

References 38 publications

MicroRNA‑24 attenuates diabetic vascular remodeling by�suppressing the NLRP3/caspase‑1/IL‑1β signaling pathway

MicroRNA‑24 attenuates diabetic vascular remodeling by�suppressing the NLRP3/caspase‑1/IL‑1β signaling pathway

CD276 (B7-H3) Maintains Proliferation and Regulates Differentiation in Angiogenic Function in Late Endothelial Progenitor Cells

Transplantation of hMSCs Genome Edited with LEF1 Improves Cardio-Protective Effects in Myocardial Infarction

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