title: Functional Effect of Pim1 Depends upon Intracellular Localization in Human Cardiac Progenitor Cells.
abstract: Human cardiac progenitor cells (hCPC) improve heart function after autologous transfer in heart failure patients. Regenerative potential of hCPCs is severely limited with age, requiring genetic modification to enhance therapeutic potential. A legacy of work from our laboratory with Pim1 kinase reveals effects on proliferation, survival, metabolism, and rejuvenation of hCPCs in vitro and in vivo. We demonstrate that subcellular targeting of Pim1 bolsters the distinct cardioprotective effects of this kinase in hCPCs to increase proliferation and survival, and antagonize cellular senescence. Adult hCPCs isolated from patients undergoing left ventricular assist device implantation were engineered to overexpress Pim1 throughout the cell (PimWT) or targeted to either mitochondrial (Mito-Pim1) or nuclear (Nuc-Pim1) compartments. Nuc-Pim1 enhances stem cell youthfulness associated with decreased senescence-associated β-galactosidase activity, preserved telomere length, reduced expression of p16 and p53, and up-regulation of nucleostemin relative to PimWT hCPCs. Alternately, Mito-Pim1 enhances survival by increasing expression of Bcl-2 and Bcl-XL and decreasing cell death after H2O2 treatment, thereby preserving mitochondrial integrity superior to PimWT. Mito-Pim1 increases the proliferation rate by up-regulation of cell cycle modulators Cyclin D, CDK4, and phospho-Rb. Optimal stem cell traits such as proliferation, survival, and increased youthful properties of aged hCPCs are enhanced after targeted Pim1 localization to mitochondrial or nuclear compartments. Targeted Pim1 overexpression in hCPCs allows for selection of the desired phenotypic properties to overcome patient variability and improve specific stem cell characteristics.
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Kaitlen
authors.initials: K
authors.lastname: Samse
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Emathinger
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Hariharan
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Pearl
authors.initials: P
authors.lastname: Quijada
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Kelli
authors.initials: K
authors.lastname: Ilves
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ormachea
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Andrea
authors.initials: A
authors.lastname: De La Torre
authors.affiliation: the Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, and.
authors.forename: Amabel M
authors.initials: AM
authors.lastname: Orogo
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Roberto
authors.initials: R
authors.lastname: Alvarez
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Shabana
authors.initials: S
authors.lastname: Din
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Sadia
authors.initials: S
authors.lastname: Mohsin
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Megan
authors.initials: M
authors.lastname: Monsanto
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182.
authors.forename: Kimberlee M
authors.initials: KM
authors.lastname: Fischer
authors.affiliation: the Sharp Memorial Hospital, San Diego, California 92123.
authors.forename: Walter P
authors.initials: WP
authors.lastname: Dembitsky
authors.affiliation: the Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, and.
authors.forename: Åsa B
authors.initials: ÅB
authors.lastname: Gustafsson
authors.affiliation: From the San Diego Heart Research Institute, San Diego State University, San Diego, California 92182, heartman4ever@icloud.com.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D016922:Cellular Senescence; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006333:Heart Failure; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D012038:Regeneration; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D049452:Green Fluorescent Proteins; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1; D001616:beta-Galactosidase
keywords: Pim1; aging; apoptosis; heart failure; human cardiac progenitor cell; proliferation; senescence