title: Recruitment and retention of human autologous CD34+ CD117+ CD133+ bone marrow stem cells to infarcted myocardium followed by directed vasculogenesis: Novel strategy for cardiac regeneration.
abstract: BACKGROUND
  Ongoing clinical trials, in regenerative therapy of patients suffering from myocardial infarctions, rely primarily upon administration of bone marrow stem cells to the infarcted zones. Unfortunately, low retention of these cells, to the therapeutic delivery sites, reduces effectiveness of this strategy; thus it has been identified as the most critical problem for advancement of cardiac regenerative medicine.
  
  
  OBJECTIVE
  The specific aim of this work was three-fold: (1) to isolate highly viable populations of human, autologous CD34+, CD117+, and CD133+ bone marrow stem cells; (2) to bioengineer heterospecific, tetravalent antibodies and to use them for recruiting of the stem cells to regenerated zones of infarcted myocardium; (3) to direct vasculogenesis of the retained stem cells with the defined factors.
  
  
  METHODS
  Cardiac tissue was biopsied from the hearts of the patients, who were receiving orthotopic heart transplants after multiple cardiac infarctions. This tissue was used to engineer fully humanin vitromodels of infarcted myocardium. Bone marrow was acquired from these patients. The marrow cells were sorted into populations of cells displaying CD34, CD117, and CD133. Heterospecific, tetravalent antibodies were bioengineered to bridge CD34, CD117, CD133 displayed on the stem cells with cardiac myosin of the infarcted myocardium. The sorted stem cells were administered to the infarcted myocardium in thein vitromodels.
  
  
  RESULTS
  Administration of the bioengineered, heterospecific antibodies preceding administration of the stem cells greatly improved the stem cells' recruitment and retention to the infarcted myocardium. Treatment of the retained stem cells with vascular endothelial growth factor and angiopoietin efficiently directed their differentiation into endothelial cells, which expressed vascular endothelial cadherin, platelet / endothelial cell adhesion molecule, claudin, and occludin, while forming tight and adherens junctions.
  
  
  CONCLUSIONS
  This novel strategy improved retention of the patients' autologous bone marrow stem cells to the infarcted myocardium followed by directed vasculogenesis. Therefore, it is worth pursuing it in support of the ongoing clinical trials of cardiac regenerative therapy.
authors.affiliation: Phoenix Biomolecular Engineering Foundation, San Francisco, CA, USA ; National Magnetic Resonance Facility, National Institutes of Health ; University of Wisconsin, Madison, WI, USA.
authors.forename: Marek
authors.initials: M
authors.lastname: Malecki
authors.affiliation: University of Wisconsin, Madison, WI, USA ; University of Sheffield, Sheffield, EU, UK.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Sabo
authors.affiliation: University of Wisconsin, Madison, WI, USA ; American Youth Center, Washington, DC, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Putzer
authors.affiliation: University of Minnesota, Minneapolis, MN, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Stampe
authors.affiliation: Phoenix Biomolecular Engineering Foundation, San Francisco, CA, USA ; Western University, Lebanon, OR, USA.
authors.forename: Afsoon
authors.initials: A
authors.lastname: Foorohar
authors.affiliation: Phoenix Biomolecular Engineering Foundation, San Francisco, CA, USA ; Western University, Pomona, CA, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Quach
authors.affiliation: AXS Bruker, Madison, WI, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Beauchaine
authors.affiliation: BioSpin Bruker, The Woodlands, TX, USA.
authors.forename: Xenia
authors.initials: X
authors.lastname: Tombokan
authors.affiliation: National Magnetic Resonance Facility, National Institutes of Health ; University of Wisconsin, Madison, WI, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Anderson
keywords: Bone marrow stem cells; Heterospecific tetravalent antibodies; Myocardial infarction; Regenerative medicine; Stem cell therapy; Vasculogenesis