title: Human Stem Cells Overexpressing miR-21 Promote Angiogenesis in Critical Limb Ischemia by Targeting CHIP to Enhance HIF-1α Activity.
abstract: Critical limb ischemia (CLI) is a severe blockage in the arteries of the lower extremities. However, the effective and optimal treatment for CLI remains to be elucidated. Previous therapeutic research is mainly focused on proangiogenic growth factors administrations. Recently, miR-21 has been revealed to play a crucial role in angiogenesis. Thus, we hypothesize that miR-21 over-expression in human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) can effectively treat CLI. Herein, UCBMSCs were transduced with lentivirus-miR-21-Luciferase (Lenti-miR-21) or lentivirus- LacZ-Luciferase (Lenti-LacZ). The results indicated that miR-21 induced UCBMSCs proliferation, migration, and angiogenesis in vitro. Subsequently, general observation and laser Doppler perfusion imaging were introduced to detect perfusion in muscles of CLI-nude mice on 1, 4, 7, 14, and 28 day postoperation. There was a significant improvement in blood vessels of the ischemic limb in Lenti-miR-21 group at 7 day compared with the saline or Lenti-LacZ groups. At 28 day, histological analysis confirmed that UCBMSCs over-expressing miR-21 increased neovascularization in CLI. Furthermore, carboxyl terminus of Hsc70-interacting protein (CHIP) was found to be the target gene for miR-21-mediated activation of hypoxia-inducible factor 1α (HIF-1α) in UCBMSCs. In summary, our study demonstrated that over-expressing miR-21 in UCBMSCs could improve neovascularization in CLI through enhancing HIF-1α activity by targeting CHIP, which may hold great therapeutic promise in treating CLI.
authors: Department of Dental Implant Center, Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, PR, China.
authors: Yong
authors: Y
authors: Zhou
authors: Department of Dental Implant Center, Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, PR, China.
authors: Youming
authors: Y
authors: Zhu
authors: Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, PR, China.
authors: Li
authors: L
authors: Zhang
authors: Department of Dental Implant Center, Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, PR, China.
authors: Tao
authors: T
authors: Wu
authors: Department of Dental Implant Center, Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, PR, China.
authors: Tingting
authors: T
authors: Wu
authors: Department of Oral and Maxillofacial Surgery, Oral Implant, and Prosthodontics, School of Medicine, Ninth People's Hospital Affiliated with Shanghai Jiao Tong University, Shanghai, PR, China.
authors: Wenjie
authors: W
authors: Zhang
authors: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry 1210 Eisenhower Place, Ann Arbor, Michigan, USA.
authors: Ann Marie
authors: AM
authors: Decker
authors: Department of Dental Implant Center, Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, PR, China.
authors: Jiacai
authors: J
authors: He
authors: Translational Center for Stem Cell Research, Tongji Hospital, Stem Cell Research Center, Tongji University School of Medicine, Shanghai, PR, China.
authors: Jie
authors: J
authors: Liu
authors: Department of Oral and Maxillofacial Surgery, Oral Implant, and Prosthodontics, School of Medicine, Ninth People's Hospital Affiliated with Shanghai Jiao Tong University, Shanghai, PR, China.
authors: Yiqun
authors: Y
authors: Wu
authors: Department of Oral and Maxillofacial Surgery, Oral Implant, and Prosthodontics, School of Medicine, Ninth People's Hospital Affiliated with Shanghai Jiao Tong University, Shanghai, PR, China.
authors: Xinqun
authors: X
authors: Jiang
authors: Department of Oral and Maxillofacial Surgery, Oral Implant, and Prosthodontics, School of Medicine, Ninth People's Hospital Affiliated with Shanghai Jiao Tong University, Shanghai, PR, China.
authors: Zhiyuan
authors: Z
authors: Zhang
authors: Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, PR, China.
authors: Chaozhao
authors: C
authors: Liang
authors: Department of Dental Implant Center, Stomatologic Hospital & College, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei, PR, China.
authors: Duohong
authors: D
authors: Zou
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005121:Extremities / Q000473:pathology; D005312:Fetal Blood / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007511:Ischemia / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016086:Lentivirus / Q000235:genetics; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Angiogenesis; Carboxyl terminus of Hsc70-interacting protein; Gene therapy; Human stem cells; Hypoxia-inducible factor 1a; miR-21