title: Rejuvenation of human cardiac progenitor cells with Pim-1 kinase.
abstract: BACKGROUND
  Myocardial function is enhanced by adoptive transfer of human cardiac progenitor cells (hCPCs) into a pathologically challenged heart. However, advanced age, comorbidities, and myocardial injury in patients with heart failure constrain the proliferation, survival, and regenerative capacity of hCPCs. Rejuvenation of senescent hCPCs will improve the outcome of regenerative therapy for a substantial patient population possessing functionally impaired stem cells.
  
  
  OBJECTIVE
  Reverse phenotypic and functional senescence of hCPCs by ex vivo modification with Pim-1.
  
  
  RESULTS
  C-kit-positive hCPCs were isolated from heart biopsy samples of patients undergoing left ventricular assist device implantation. Growth kinetics, telomere lengths, and expression of cell cycle regulators showed significant variation between hCPC isolated from multiple patients. Telomere length was significantly decreased in hCPC with slow-growth kinetics concomitant with decreased proliferation and upregulation of senescent markers compared with hCPC with fast-growth kinetics. Desirable youthful characteristics were conferred on hCPCs by genetic modification using Pim-1 kinase, including increases in proliferation, telomere length, survival, and decreased expression of senescence markers.
  
  
  CONCLUSIONS
  Senescence characteristics of hCPCs are ameliorated by Pim-1 kinase resulting in rejuvenation of phenotypic and functional properties. hCPCs show improved cellular properties resulting from Pim-1 modification, but benefits were more pronounced in hCPC with slow-growth kinetics relative to hCPC with fast-growth kinetics. With the majority of patients with heart failure presenting advanced age, infirmity, and impaired regenerative capacity, the use of Pim-1 modification should be incorporated into cell-based therapeutic approaches to broaden inclusion criteria and address limitations associated with the senescent phenotype of aged hCPC.
authors.affiliation: From the San Diego Heart Research Institute and Biology Department, San Diego State University, CA, and Sharp Memorial Hospital, San Diego, CA.
authors.forename: Sadia
authors.initials: S
authors.lastname: Mohsin
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.forename: Jonathan
authors.initials: J
authors.lastname: Nguyen
authors.forename: Monique
authors.initials: M
authors.lastname: Alkatib
authors.forename: Sailay
authors.initials: S
authors.lastname: Siddiqi
authors.forename: Nirmala
authors.initials: N
authors.lastname: Hariharan
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wallach
authors.forename: Megan
authors.initials: M
authors.lastname: Monsanto
authors.forename: Natalie
authors.initials: N
authors.lastname: Gude
authors.forename: Walter
authors.initials: W
authors.lastname: Dembitsky
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D018797:Cell Cycle Proteins / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D006333:Heart Failure / Q000473:pathology / Q000628:therapy; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology*; D010641:Phenotype; D051573:Proto-Oncogene Proteins c-pim-1 / Q000502:physiology*; D012060:Rejuvenation / Q000502:physiology*; D013234:Stem Cells / Q000473:pathology*; D059505:Telomere Homeostasis / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D051573:Proto-Oncogene Proteins c-pim-1
keywords: aging; cell cycle proteins; heart failure; telomere lengthening
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