Increased mitotic rate coincident with transient telomere lengthening resulting from pim-1 overexpression in cardiac progenitor cells.
Cardiac regeneration following myocardial infarction rests with the potential of c-kit+ cardiac progenitor cells (CPCs) to repopulate damaged myocardium. The ability of CPCs to reconstitute the heart is restricted by patient age and disease progression. Increasing CPC proliferation, telomere length, and survival will improve the ability of autologous CPCs to be successful in myocardial regeneration. Prior studies have demonstrated enhancement of myocardial regeneration by engineering CPCs to express Pim-1 kinase, but cellular and molecular mechanisms for Pim-1-mediated effects on CPCs remain obscure. We find CPCs rapidly expand following overexpression of cardioprotective kinase Pim-1 (CPCeP), however, increases in mitotic rate are short-lived as late passage CPCePs proliferate similar to control CPCs. Telomere elongation consistent with a young phenotype is observed following Pim-1 modification of CPCeP; in addition, telomere elongation coincides with increased telomerase expression and activity. Interestingly, telomere length and telomerase activity normalize after several rounds of passaging, consistent with the ability of Pim-1 to transiently increase mitosis without resultant oncogenic transformation. Accelerating mitosis in CPCeP without immortalization represents a novel strategy to expand the CPC population in order to improve their therapeutic efficacy.
San Diego State Heart Institute, San Diego State University, San Diego, California, USA.
Christopher T
CT
Cottage
Lauren
L
Neidig
Balaji
B
Sundararaman
Shabana
S
Din
Anya Y
AY
Joyo
Brandi
B
Bailey
Natalie
N
Gude
Nirmala
N
Hariharan
Mark A
MA
Sussman
D000818:Animals; D054715:Cardiotoxins / Q000494:pharmacology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D015870:Gene Expression; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008938:Mitosis; D009206:Myocardium / Q000166:cytology*; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism*; D044968:Regenerative Medicine; D013234:Stem Cells / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D019098:Telomerase / Q000378:metabolism; D059505:Telomere Homeostasis / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology
C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; D054715:Cardiotoxins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D013844:Thiazoles; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D004317:Doxorubicin; C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1; D019098:Telomerase