Functional Effect of Pim1 Depends upon Intracellular Localization in Human Cardiac Progenitor Cells

• Published in: The Journal of biological chemistry Vol. 290; no. 22; pp. 13935 - 13947
• Main Authors: Samse, Kaitlen, Emathinger, Jacqueline, Hariharan, Nirmala, Quijada, Pearl, Ilves, Kelli, Völkers, Mirko, Ormachea, Lucia, De La Torre, Andrea, Orogo, Amabel M., Alvarez, Roberto, Din, Shabana, Mohsin, Sadia, Monsanto, Megan, Fischer, Kimberlee M., Dembitsky, Walter P., Gustafsson, Åsa B., Sussman, Mark A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.05.2015; American Society for Biochemistry and Molecular Biology
• Subjects: aging; Apoptosis; beta-Galactosidase - metabolism; Cell Biology; Cell Cycle; Cell Nucleus - metabolism; Cell Proliferation; Cell Survival; Cellular Senescence; Gene Expression Regulation; Green Fluorescent Proteins - metabolism; Heart - physiology; Heart Failure; Heart Ventricles - metabolism; human cardiac progenitor cell; Humans; Lentivirus - metabolism; Mitochondria - metabolism; Myocardium - cytology; Myocardium - metabolism; Phenotype; Pim1; proliferation; Proto-Oncogene Proteins c-pim-1 - metabolism; Regeneration; senescence; Stem Cells - cytology; Stem Cells - metabolism; Subcellular Fractions - metabolism; senescence; heart failure; proliferation; human cardiac progenitor cell; Pim1; apoptosis; aging
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.617431

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. Background: Age and disease affect cardiac expression and localization of Pim1. Results: Survival and proliferation are enhanced and senescence is antagonized by intracellular targeting of Pim1. Conclusion: Cardioprotective properties are emphasized by targeting Pim1 expression in human cardiac progenitor cells. Significance: Compartmentalizing Pim1 to enhance stem cell characteristics can be used for targeted molecular intervention to improve cell-based regenerative therapy.