Functional effect of Pim1 depends upon intracellular localization in human cardiac progenitor cells

Kaitlen Samse, Jacqueline Emathinger, Nirmala Hariharan, Pearl Quijada, Kelli Ilves, Mirko Völkers, Lucia Ormachea, Andrea De La Torre, Amabel M. Orogo, Roberto Alvarez, Shabana Din, Sadia Mohsin, Megan Monsanto, Kimberlee M. Fischer, Walter P. Dembitsky, Åsa B. Gustafsson, Mark A. Sussman

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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-XLand 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.

Original languageEnglish (US)
Pages (from-to)13935-13947
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number22
DOIs
StatePublished - May 29 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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