title: Nitric oxide releasing hydrogel enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction.
abstract: Stem cell therapy has been proved to be an effective approach to ameliorate the heart remodeling post myocardial infarction (MI). However, poor cell engraftment and survival in ischemic myocardium limits the successful use of cellular therapy for treating MI. Here, we sought to transplant adipose derived-mesenchymal stem cells (AD-MSCs) with a hydrogel (NapFF-NO), naphthalene covalently conjugated a short peptide, FFGGG, and β-galactose caged nitric oxide (NO) donor, which can release NO molecule in response to β-galactosidase. AD-MSCs, either from transgenic mice that constitutively express GFP and firefly luciferase (Fluc), or express Fluc under the control of VEGFR2 promoter, were co-transplanted with NapFF-NO hydrogel into murine MI models. Improved cell survival and enhanced cardiac function were confirmed by bioluminescence imaging (BLI) and echocardiogram respectively. Moreover, increasing VEGFR2-luc expression was also tracked in real-time in vivo, indicating NapFF-NO hydrogel stimulated VEGF secretion of AD-MSCs. To investigate the therapeutic mechanism of NapFF-NO hydrogel, cell migration assay, paracrine action of AD-MSCs, and histology analysis were carried out. Our results revealed that condition medium from AD-MSCs cultured with NapFF-NO hydrogel could promote endothelial cell migration. Additionally, AD-MSCs showed significant improvement secretion of angiogenic factors VEGF and SDF-1α in the presence of NapFF-NO hydrogel. Finally, postmortem analysis confirmed that transplanted AD-MSCs with NapFF-NO hydrogel could ameliorate heart function by promoting angiogenesis and attenuating ventricular remodeling. In conclusion, NapFF-NO hydrogel can obviously improve therapeutic efficacy of AD-MSCs for MI by increasing cell engraftment and angiogenic paracrine action.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Xinpeng
authors.initials: X
authors.lastname: Yao
authors.affiliation: Department of Biology, School of Basic Medicine, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.affiliation: School of Medicine, Nankai University, Tianjin 300071, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Duo
authors.initials: D
authors.lastname: Mao
authors.affiliation: Department for Health Sciences and Biomedicine, Danube University Krems, 3500 Krems, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Stefanitsch
authors.affiliation: School of Medicine, Nankai University, Tianjin 300071, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Lailiang
authors.initials: L
authors.lastname: Ou
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Deling
authors.initials: D
authors.lastname: Kong
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: qiangzhao@nankai.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: School of Medicine, Nankai University, Tianjin 300071, China. Electronic address: zongjinli@nankai.edu.cn.
authors.forename: Zongjin
authors.initials: Z
authors.lastname: Li
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D002478:Cells, Cultured; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000378:metabolism*; D005690:Galactose / Q000737:chemistry / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D041681:NIH 3T3 Cells; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism; D018919:Neovascularization, Physiologic; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000627:therapeutic use; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D061848:Optical Imaging; D020257:Ventricular Remodeling; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D003692:Delayed-Action Preparations; D009281:Naphthalenes; D020030:Nitric Oxide Donors; D009842:Oligopeptides; C031721:naphthalene; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D001616:beta-Galactosidase; D005690:Galactose
keywords: Adipose-derived mesenchymal stem cells (AD-MSCs); Angiogenesis; Hydrogel; Molecular imaging; Myocardial infarction; Nitric oxide