The serine-threonine kinases Pim-1 and Akt regulate cellular proliferation and survival. Although Akt is known to be a crucial signaling protein in the myocardium, the role of Pim-1 has been overlooked. Pim-1 expression in the myocardium of mice decreased during postnatal development, re-emerged after acute pathological injury in mice and was increased in failing hearts of both mice and humans. Cardioprotective stimuli associated with Akt activation induced Pim-1 expression, but compensatory increases in Akt abundance and phosphorylation after pathological injury by infarction or pressure overload did not protect the myocardium in Pim-1-deficient mice. Transgenic expression of Pim-1 in the myocardium protected mice from infarction injury, and Pim-1 expression inhibited cardiomyocyte apoptosis with concomitant increases in Bcl-2 and Bcl-X(L) protein levels, as well as in Bad phosphorylation levels. Relative to nontransgenic controls, calcium dynamics were significantly enhanced in Pim-1-overexpressing transgenic hearts, associated with increased expression of SERCA2a, and were depressed in Pim-1-deficient hearts. Collectively, these data suggest that Pim-1 is a crucial facet of cardioprotection downstream of Akt.
Background Despite numerous studies demonstrating efficacy of cellular adoptive transfer for therapeutic myocardial regeneration, problems remain for donated cells with regard to survival, persistence, engraftment, and long-term benefits. This study redresses these concerns by enhancing the regenerative potential of adoptively transferred cardiac progenitor cells (CPCs) via genetic engineering to overexpress Pim-1, a cardioprotective kinase that enhances cell survival and proliferation. Methods and Results Intramyocardial injections of CPCs overexpressing Pim-1 were given to infarcted female mice. Animals were monitored over 4, 12, and 32-weeks to assess cardiac function and engraftment of Pim-1 CPCs using echocardiography, in vivo hemodynamics, and confocal imagery. CPCs overexpressing Pim-1 show increased proliferation and expression of markers consistent with cardiogenic lineage commitment following dexamethasone exposure in vitro. Animals that received CPCs overexpressing Pim-1 also produce greater levels of cellular engraftment, persistence, and functional improvement relative to control CPCs up to 32-weeks post-delivery. Salutary effects include reduction of infarct size, greater number of c-kit+ cells, and increased vasculature in the damaged region. Conclusions Myocardial repair is significantly enhanced by genetic engineering of CPCs using Pim-1 kinase. Ex vivo gene delivery to enhance cellular survival, proliferation, and regeneration may overcome current limitations of stem cell-based therapeutic approaches.
STEM CELLS 2008;26:1315-1324 Disclosure of potential conflicts of interest is found at the end of this article.
to total body metabolic rate during the breath-hold. Extreme hypoxemic tolerance in these seals was demonstrated by arterial P O 2 values during late apnea that were less than human thresholds for shallow-water blackout. Despite such low P O 2s, there was no evidence of significant anaerobic metabolism, as changes in blood pH were minimal and attributable to increased P CO 2. These findings and the previously reported lack of lactate accumulation during these breath-holds are consistent with the maintenance of aerobic metabolism even at low oxygen tensions during rest-associated apneas. Such hypoxemic tolerance is necessary in order to allow dissociation of O 2 from hemoglobin and provide effective utilization of the blood O 2 store.
Abstract-Stem cell-specific proteins and regulatory pathways that determine self-renewal and differentiation have become of fundamental importance in understanding regenerative and reparative processes in the myocardium. One such regulatory protein, named nucleostemin, has been studied in the context of stem cells and several cancer cell lines, where expression is associated with proliferation and maintenance of a primitive cellular phenotype. We find nucleostemin is present in young myocardium and is also induced following cardiomyopathic injury. Nucleostemin expression in cardiomyocytes is induced by fibroblast growth factor-2 and accumulates in response to Pim-1 kinase activity. Cardiac stem cells also express nucleostemin that is diminished in response to commitment to a differentiated phenotype. Overexpression of nucleostemin in cultured cardiac stem cells increases proliferation while preserving telomere length, providing a mechanistic basis for potential actions of nucleostemin in promotion of cell survival and proliferation as seen in other cell types. (Circ Res. 2008;103:89-97.)Key Words: nucleostemin Ⅲ cardioprotection Ⅲ cardiomyocytes Ⅲ stem cells Ⅲ Pim-1 Ⅲ telomerase C ellular-based myocardial regeneration depends on tightly regulated signaling cascades that control survival and proliferation. In the case of stem cell populations, these signaling pathways have been predominantly defined by decades of study in hematopoietic 1-4 and developmental contexts. [5][6][7] The relatively recent advent of myocardial adult stem cells and their distinctive characteristics has prompted reexamination of the operational definition of "stem cells" and "stemness." 8,9 The traditional view of stem cell behavior as derived from classic lineage studies may not appropriately reflect the biology of stem cells in tissues characterized by slow cellular turnover such as the myocardium. For example, activation of signaling typically associated with regulation of proliferation and survival in stem cells is also observed in combination with partial or fully committed cellular phenotypes following tissue injury. 10 -12 These revelations have prompted dissolution of long-standing assertions related to "stem cell-associated" signaling, now viewed as regulation of tissue repair and regeneration or, in some, cases oncogenic transformation. [13][14][15][16] Nucleostemin is found at high levels in various stem cells and human cancers, 17 where it has been associated with maintenance of proliferation. [17][18][19][20] Expression of nucleostemin drops precipitously during differentiation 21,22 and genetic deletion of nucleostemin results in embryonic lethality at approximately day 4 postcoitum with blastocysts comprised of cells that fail to enter S phase. 23 Similar arrest in G 0 /G 1 phase of cell cycle was observed in HeLa cells if nucleostemin was eliminated by RNA interference. 20 Nucleostemin has been purported to mediate cellular dedifferentiation and regenerative processes in newts. 24 Although the molecular basis of nucleostem...
Rationale Cardiac progenitor cells are important for maintenance of myocardial structure and function, but molecular mechanisms governing these progenitor cells remain obscure and require elucidation to enhance regenerative therapeutic approaches. Objective To understand consequences of stem cell antigen-1 (Sca-1) deletion upon functional properties of c-kit+ cardiac progenitor cells and myocardial performance using a Sca-1 knockout/Green Fluorescent Protein knock-in reporter mouse (ScaKI). Methods and Results Genetic deletion of Sca-1 results in early-onset cardiac contractile deficiency as determined by echocardiography and hemodynamics as well as age-associated hypertrophy. Resident cardiac progenitor cells in ScaKI mice do not respond to pathological damage in vivo, consistent with observations of impaired growth and survival of ScaKI cardiac progenitor cells in vitro. The molecular basis of the defect in ScaKI cardiac progenitor cells is associated with increased canonical Wnt signaling pathway activation consistent with molecular characteristics of lineage commitment. Conclusions Genetic deletion of Sca-1 causes primary cardiac defects in myocardial contractility and repair consistent with impairment of resident cardiac progenitor cell proliferative capacity associated with altered canonical Wnt signaling.
In the version of this article initially published, the meanings of the error bars in the figures and supplementary figures and the error values given in Supplementary Table 2 were not stated. They represent the standard error of the mean in all cases except Supplementary Figure 5, where they represent the standard deviation. The error has been corrected in the supplementary information file and in the PDF version of the article.
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