Inhibition of microRNA‐495 Enhances Therapeutic Angiogenesis of Human Induced Pluripotent Stem Cells

Therapeutic angiogenesis has emerged as a promising strategy to regenerate the damaged blood vessels resulting from ischemic diseases such as myocardial infarction (MI). However, the functional integration of implanted endothelial cells (ECs) in infarcted heart remains challenging. We herein develop...

Full description

Saved in:
Bibliographic Details
Published in:Stem cells (Dayton, Ohio) Ohio), 2017-02, Vol.35 (2), p.337-350
Main Authors: Liang, Jialiang, Huang, Wei, Cai, Wenfeng, Wang, Lei, Guo, Linlin, Paul, Christian, Yu, Xi‐Yong, Wang, Yigang
Format: Article
Language:English
Subjects:
Angiogenesis
Animals
Antisense therapy
Base Sequence
Blood vessels
Cardiotonic Agents - metabolism
Cell adhesion & migration
Cell Differentiation - genetics
Cell migration
Computer applications
Coronary Vessels - pathology
Damage
Differentiation
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Endothelial cells
Endothelial Cells - cytology
Endothelial Cells - metabolism
Endothelial differentiation
Engraftment
Functional integration
Gene expression
Genes
Genetic modification
Heart
Humans
Immunodeficiency
Induced pluripotent stem cells
Induced Pluripotent Stem Cells - metabolism
Inhibition
Ischemia
Mice
MicroRNAs
MicroRNAs - antagonists & inhibitors
MicroRNAs - genetics
MicroRNAs - metabolism
miRNA
Multigene Family
Myocardial infarction
Myocardial Infarction - genetics
Myocardial Infarction - pathology
Myocardial Infarction - therapy
Neovascularization
Neovascularization, Physiologic
Pluripotency
Preadipocyte factor 1
Ribonucleic acid
RNA
Rodents
Stem Cell Transplantation
Stem cells
Transcription Factors - genetics
Transcription Factors - metabolism
Transplantation
Vascularization
Zinc
Zinc finger proteins
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Therapeutic angiogenesis has emerged as a promising strategy to regenerate the damaged blood vessels resulting from ischemic diseases such as myocardial infarction (MI). However, the functional integration of implanted endothelial cells (ECs) in infarcted heart remains challenging. We herein develop an EC generation approach by inhibiting microRNA‐495 (miR‐495) in human induced pluripotent stem cells (hiPSCs) and assess the angiogenic potential for MI treatment. The anti‐angiogenic miR‐495 belonging to Dlk1‐Dio3 miR cluster was identified through expression profiling and computational analysis. Loss‐of‐function experiments for miR‐495 were performed using a lentiviral transfer of antisense sequence in hiPSCs. The pluripotency of hiPSCs was not impacted by the genetic modification. Induced with differentiation medium, miR‐495 inhibition enhanced the expression of EC genes of hiPSCs, as well as the yield of ECs. Newly derived ECs displayed prominent angiogenic characteristics including tube formation, cell migration, and proliferation. Mechanistically, miR‐495 mediated the expression of endothelial or angiogenic genes by directly targeting vascular endothelial zinc finger 1. After transplantation in immunodeficient MI mice, the derived ECs significantly increased neovascularization in the infarcted heart, prevented functional worsening, and attenuated expansion of infarct size. The functional integration of the implanted ECs into coronary networks was also enhanced by inhibiting miR‐495. miR‐495 represents a new target not only for promoting EC generation from hiPSCs but also for enhancing angiogenesis and engraftment of hiPSC‐derived ECs in ischemic heart. Stem Cells 2017;35:337–350 The inhibition of miR‐495 in hiPSCs reversed the expression of its target genes such as VEZF1 and then increased the EC differentiation efficiency as well as the yield of ECs. The in vitro angiogenic functions including vessel sprouting, migration, proliferation, and growth factor expression in hiPSC‐derived ECs were enhanced by miR‐495 inhibition. The in vivo transplantation of the derived ECs significantly enhanced angiogenesis in infarcted heart and prevented the functional worsening.
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.2477