title: Paracrine Engineering of Human Cardiac Stem Cells With Insulin-Like Growth Factor 1 Enhances Myocardial Repair.
abstract: BACKGROUND
  Insulin-like growth factor 1 (IGF-1) activates prosurvival pathways and improves postischemic cardiac function, but this key cytokine is not robustly expressed by cultured human cardiac stem cells. We explored the influence of an enhanced IGF-1 paracrine signature on explant-derived cardiac stem cell-mediated cardiac repair.
  
  
  RESULTS
  Receptor profiling demonstrated that IGF-1 receptor expression was increased in the infarct border zones of experimentally infarcted mice by 1 week after myocardial infarction. Human explant-derived cells underwent somatic gene transfer to overexpress human IGF-1 or the green fluorescent protein reporter alone. After culture in hypoxic reduced-serum media, overexpression of IGF-1 enhanced proliferation and expression of prosurvival transcripts and prosurvival proteins and decreased expression of apoptotic markers in both explant-derived cells and cocultured neonatal rat ventricular cardiomyocytes. Transplant of explant-derived cells genetically engineered to overexpress IGF-1 into immunodeficient mice 1 week after infarction boosted IGF-1 content within infarcted tissue and long-term engraftment of transplanted cells while reducing apoptosis and long-term myocardial scarring.
  
  
  CONCLUSIONS
  Paracrine engineering of explant-derived cells to overexpress IGF-1 provided a targeted means of improving cardiac stem cell-mediated repair by enhancing the long-term survival of transplanted cells and surrounding myocardium.
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Robyn
authors.initials: R
authors.lastname: Jackson
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Everad L
authors.initials: EL
authors.lastname: Tilokee
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Nicholas
authors.initials: N
authors.lastname: Latham
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Seth
authors.initials: S
authors.lastname: Mount
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Rafatian
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Jared
authors.initials: J
authors.lastname: Strydhorst
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Munir
authors.initials: M
authors.lastname: Boodhwani
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Chan
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Marc
authors.initials: M
authors.lastname: Ruel
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Terrence D
authors.initials: TD
authors.lastname: Ruddy
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Suuronen
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Canada (D.J.S.).
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.affiliation: University of Ottawa Heart Institute, Ottawa, Canada (R.J., E.L.T., N.L., S.M., G.R., J.S., B.Y., M.B., V.C., M.R., T.D.R., E.J.S., D.R.D.).
authors.forename: Darryl R
authors.initials: DR
authors.lastname: Davis
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: C583557:IGF1 protein, human; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
keywords: cell survival; cell therapy; heart failure; insulin‐like growth factor 1