Dual chemotactic factors-secreting human amniotic mesenchymal stem cells via TALEN-mediated gene editing enhanced angiogenesis

• Published in: International journal of cardiology Vol. 260; pp. 156 - 162
• Main Authors: Jeong, In Sil, Park, Youngjin, Ryu, Hyun Aae, An, Hyun Sook, Han, Ju Hye, Kim, Sung-Whan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2018
• Subjects: Amnion - cytology; Amnion - physiology; Angiogenesis; Animals; Chemotaxis - physiology; Endothelial cells; Gene editing; Gene Editing - methods; Human Umbilical Vein Endothelial Cells - physiology; Humans; Ischemia - pathology; Ischemia - therapy; Ischemic vascular disease; Male; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - physiology; Mice; Mice, Nude; Neovascularization, Physiologic - physiology; Stem cells; Transcription Activator-Like Effector Nucleases - physiology; Angiogenesis; Gene editing; Endothelial cells; Ischemic vascular disease; Stem cells
• ISSN: 0167-5273; 1874-1754
• DOI: 10.1016/j.ijcard.2018.02.043

Even though mesenchymal stem cells (MSCs) have angiogenic property, their cytokine secretory capacity is limited to treat ischemic vascular disorders. In present study, we produced genome-edited MSCs that secreted dual chemokine granulocyte chemotactic protein-2 (GCP-2) and stromal-derived factor-1α (SDF-1α) and determined their therapeutic potential in the context of experimental ischemia. GCP-2 and SDF-1α genes were integrated into safe harbor site at the safe harbor genomic locus of amniotic mesenchymal stem cells (AMM) via transcription activator-like effector nucleases (TALEN). GCP-2 and SDF-1α gene-edited AMM (AMM/GS) were used for quantitative (q)-PCR, Matrigel tube formation, cell migration, Matrigel plug assays and in vivo therapeutic assays using hindlimb ischemia mouse model. AMM/GS-derived culture media (CM) induced significantly higher tube lengths and branching points as compared to AMM/S CM and AMM CM. Interestingly, Matrigel plug assays revealed that significantly higher levels of red blood cells were found in AMM/GS than AMM/S and AMM Matigel plugs and exhibited micro-vascular like formation. Cells was transplanted into ischemic mouse hindlimbs and compared with control groups. AMM/GS injection prevented limb loss and augmented blood perfusion, suggesting that enhances neovascularization in hindlimb ischemia. In addition, transplanted AMM/GS revealed high vasculogenic potential in vivo compared with transplanted AMM/S. Taken together, genome-edited MSCs that express dual chemokine GCP-2 and SDF-1α might be alternative therapeutic options for the treatment of ischemic vascular disease. •Dual chemokine gene-edited MSCs (AMM/GS) were successfully generated.•Transplantation of AMM/GS into ischemic hindlimbs resulted in enhanced recovery of ischemic tissues.•Transplanted AMM/GS provided a favorable environment for neovascularization.