title: Relative roles of CD90 and c-kit to the regenerative efficacy of cardiosphere-derived cells in humans and in a mouse model of myocardial infarction.
abstract: BACKGROUND
  The regenerative potential of cardiosphere-derived cells (CDCs) for ischemic heart disease has been demonstrated in mice, rats, pigs, and a recently completed clinical trial (CADUCEUS). CDCs are CD105(+) stromal cells of intrinsic cardiac origin, but the antigenic characteristics of the active fraction remain to be defined. CDCs contain a small minority of c-kit(+) cells, which have been argued to be cardiac progenitors, and a variable fraction of CD90(+) cells whose bioactivity is unclear.
  
  
  METHODS
  We performed a retrospective analysis of data from the CADUCEUS trial and a prospective mouse study to elucidate the roles of c-kit(+) and CD90(+) cells in human CDCs. Here, we show, surprisingly, that c-kit expression has no relationship to CDCs' therapeutic efficacy in humans, and depletion of c-kit(+) cells does not undermine the structural and functional benefits of CDCs in a mouse model of myocardial infarction (MI). In contrast, CD90 expression negatively correlates with the therapeutic benefit of CDCs in humans (ie, higher CD90 expression associated with lower efficacy). Depletion of CD90(+) cells augments the functional potency of CDCs in murine MI. CD90(-) CDCs secrete lower levels of inflammatory cytokines and can differentiate into cardiomyocytes in vitro and in vivo.
  
  
  CONCLUSIONS
  The majority population of CDCs (CD105(+)/CD90(-)/c-kit(-)) constitutes the active fraction, both in terms of therapeutic efficacy and in the ability to undergo cardiomyogenic differentiation. The c-kit(+) fraction is neither necessary for, nor contributory to, the regenerative efficacy of CDCs.
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA (K.C., A.I., B.S., R.M., W.L., R.R.S., E.M.) Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, NC (K.C., T.H.) Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University Raleigh, NC (K.C.).
authors.forename: Ke
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA (K.C., A.I., B.S., R.M., W.L., R.R.S., E.M.).
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ibrahim
authors.affiliation: Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, NC (K.C., T.H.).
authors.forename: M Taylor
authors.initials: MT
authors.lastname: Hensley
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (D.S.).
authors.forename: Deliang
authors.initials: D
authors.lastname: Shen
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA (K.C., A.I., B.S., R.M., W.L., R.R.S., E.M.).
authors.forename: Baiming
authors.initials: B
authors.lastname: Sun
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA (K.C., A.I., B.S., R.M., W.L., R.R.S., E.M.).
authors.forename: Ryan
authors.initials: R
authors.lastname: Middleton
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA (K.C., A.I., B.S., R.M., W.L., R.R.S., E.M.).
authors.forename: Weixin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA (K.C., A.I., B.S., R.M., W.L., R.R.S., E.M.) Capricor Therapeutics Inc, Beverly Hills, CA (R.R.S.).
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Smith
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, CA (K.C., A.I., B.S., R.M., W.L., R.R.S., E.M.).
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation / Q000502:physiology; D017690:Cell Transplantation / Q000379:methods; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006334:Heart Function Tests; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000637:transplantation*; D011446:Prospective Studies; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D012380:Role; D012680:Sensitivity and Specificity; D018800:Thy-1 Antigens / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D018800:Thy-1 Antigens; D019009:Proto-Oncogene Proteins c-kit
keywords: CD90; cardiosphere‐derived cells; ckit; myocardial infarction