title: Negative Regulation of miR-375 by Interleukin-10 Enhances Bone Marrow-Derived Progenitor Cell-Mediated Myocardial Repair and Function After Myocardial Infarction.
abstract: Poor survival and function of transplanted cells in ischemic and inflamed myocardium likely compromises the functional benefit of stem cell-based therapies. We have earlier reported that co-administration of interleukin (IL)-10 and BMPAC enhances cell survival and improves left ventricular (LV) functions after acute myocardial infarction (MI) in mice. We hypothesized that IL-10 regulates microRNA-375 (miR-375) signaling in BMPACs to enhance their survival and function in ischemic myocardium after MI and attenuates left ventricular dysfunction after MI. miR-375 expression is significantly upregulated in BMPACs upon exposure to inflammatory/hypoxic stimulus and also after MI. IL-10 knockout mice display significantly elevated miR-375 levels. We report that ex vivo miR-375 knockdown in BMPAC before transplantation in the ischemic myocardium after MI significantly improve the survival and retention of transplanted BMPACs and also BMPAC-mediated post-infarct repair, neovascularization, and LV functions. Our in vitro studies revealed that knockdown of miR-375-enhanced BMPAC proliferation and tube formation and inhibited apoptosis; over expression of miR-375 in BMPAC had opposite effects. Mechanistically, miR-375 negatively regulated 3-phosphoinositide-dependent protein kinase-1 (PDK-1) expression and PDK-1-mediated activation of PI3kinase/AKT signaling. Interestingly, BMPAC isolated from IL-10-deficient mice showed elevated basal levels of miR-375 and exhibited functional deficiencies, which were partly rescued by miR-375 knockdown, enhancing BMPAC function in vitro and in vivo. Taken together, our studies suggest that miR-375 is negatively associated with BMPAC function and survival and IL-10-mediated repression of miR-375 enhances BMPAC survival and function.
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Venkata Naga Srikanth
authors.initials: VN
authors.lastname: Garikipati
authors.affiliation: Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, Texas, USA.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Krishnamurthy
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Suresh Kumar
authors.initials: SK
authors.lastname: Verma
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, Illinois, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Abramova
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, Illinois, USA.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Mackie
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, Illinois, USA.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Benedict
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Nickoloff
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Ehre
authors.initials: E
authors.lastname: Gao
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, Illinois, USA.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.|Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.|Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.|Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, Illinois, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: C556062:IL10 protein, mouse; D035683:MicroRNAs; C540349:Mirn375 microRNA, mouse; D016753:Interleukin-10
keywords: Angiogenesis; Bone marrow progenitor angiogenic cells; Inflammation; Left ventricular remodeling; miRNA