title: Sonic hedgehog-modified human CD34+ cells preserve cardiac function after acute myocardial infarction.
abstract: BACKGROUND
  Ischemic cardiovascular disease represents one of the largest epidemics currently facing the aging population. Current literature has illustrated the efficacy of autologous, stem cell therapies as novel strategies for treating these disorders. The CD34+ hematopoetic stem cell has shown significant promise in addressing myocardial ischemia by promoting angiogenesis that helps preserve the functionality of ischemic myocardium. Unfortunately, both viability and angiogenic quality of autologous CD34+ cells decline with advanced age and diminished cardiovascular health.
  
  
  OBJECTIVE
  To offset age- and health-related angiogenic declines in CD34+ cells, we explored whether the therapeutic efficacy of human CD34+ cells could be enhanced by augmenting their secretion of the known angiogenic factor, sonic hedgehog (Shh).
  
  
  RESULTS
  When injected into the border zone of mice after acute myocardial infarction, Shh-modified CD34+ cells (CD34(Shh)) protected against ventricular dilation and cardiac functional declines associated with acute myocardial infarction. Treatment with CD34(Shh) also reduced infarct size and increased border zone capillary density compared with unmodified CD34 cells or cells transfected with the empty vector. CD34(Shh) primarily store and secrete Shh protein in exosomes and this storage process appears to be cell-type specific. In vitro analysis of exosomes derived from CD34(Shh) revealed that (1) exosomes transfer Shh protein to other cell types, and (2) exosomal transfer of functional Shh elicits induction of the canonical Shh signaling pathway in recipient cells.
  
  
  CONCLUSIONS
  Exosome-mediated delivery of Shh to ischemic myocardium represents a major mechanism explaining the observed preservation of cardiac function in mice treated with CD34(Shh) cells.
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Mackie
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Klyachko
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Schultz
authors.forename: Meredith
authors.initials: M
authors.lastname: Millay
authors.forename: Aiko
authors.initials: A
authors.lastname: Ito
authors.forename: Christine E
authors.initials: CE
authors.lastname: Kamide
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: Rajesh
authors.initials: R
authors.lastname: Gupta
authors.forename: Susmita
authors.initials: S
authors.lastname: Sahoo
authors.forename: Sol
authors.initials: S
authors.lastname: Misener
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000008:administration & dosage* / Q000627:therapeutic use; D002478:Cells, Cultured; D053823:Hedgehog Proteins / Q000008:administration & dosage* / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009203:Myocardial Infarction / Q000503:physiopathology / Q000601:surgery*; D041681:NIH 3T3 Cells; D018754:Ventricular Dysfunction / Q000503:physiopathology / Q000601:surgery
chemical_list: D018952:Antigens, CD34; D053823:Hedgehog Proteins; C509239:SHH protein, human