Dataset Information

Inhibition of p16INK4A to Rejuvenate Aging Human Cardiac Progenitor Cells via the Upregulation of Anti-oxidant and NF?B Signal Pathways.

ABSTRACT: Autologous human cardiac stem/progenitor cell (hCPC) therapy is a promising treatment that has come into use in recent years for patients with cardiomyopathy. Though innovative in theory, a major hindrance to the practical application of this treatment is that the hCPCs of elderly patients, who are most susceptible to myocardial disease, are senescent and prone to cell death. Rejuvenating hCPCs from elderly patients may help overcome this obstacle, and can be accomplished by reversing entry into the cellular stage of senescence. p16INK4A, a cyclin dependent kinase inhibitor, is an important player in the regulation of cell senescence. In this study, we investigated whether knockdown of p16INK4A will rejuvenate aging hCPCs to a youthful phenotype. Our data indicated that upregulation of p16INK4A is associated with hCPC senescence. Both cell proliferation and survival capacity were significantly increased in hCPCs infected with lentivirus expressing p16INK4A shRNA when compared to control hCPCs. The knockdown of p16INK4A also induced antioxidant properties as indicated by a 50% decrease in ROS generation at basal cell metabolism, and a 25% decrease in ROS generation after exposure to oxidative stress. Genes associated with cell senescence (p21CIP1), anti-apoptosis (BCL2 and MCL1), anti-oxidant (CYGB, PRDX1 and SRXN1), and NF?B signal pathway (p65, IKBKB, HMOX1, etc.), were significantly upregulated after the p16INK4A knockdown. Knocking down the NF?B-p65 expression also significantly diminished the cytoprotective effect caused by the p16INK4A knockdown. Our results suggest that genetic knockdown of p16INK4A may play a significant role in inducing antioxidant effects and extending lifespan of aging hCPCs. This genetic modification may enhance the effectiveness of autologous hCPC therapy for repair of infarcted myocardium.

SUBMITTER: Khatiwala RV

PROVIDER: S-EPMC6014915 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Inhibition of p16<sup>INK4A</sup> to Rejuvenate Aging Human Cardiac Progenitor Cells via the Upregulation of Anti-oxidant and NFκB Signal Pathways.

Khatiwala Roshni V RV Zhang Shuning S Li Xiuchun X Devejian Neil N Bennett Edward E Cai Chuanxi C

Stem cell reviews and reports 20180801 4

Autologous human cardiac stem/progenitor cell (hCPC) therapy is a promising treatment that has come into use in recent years for patients with cardiomyopathy. Though innovative in theory, a major hindrance to the practical application of this treatment is that the hCPCs of elderly patients, who are most susceptible to myocardial disease, are senescent and prone to cell death. Rejuvenating hCPCs from elderly patients may help overcome this obstacle, and can be accomplished by reversing entry into ...[more]

PMID: 29675777

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Project description:BackgroundFunctional decline in stem cell-mediated regeneration contributes to aging associated with cellular senescence in c-kit+ cardiac progenitor cells (CPCs). Clinical implementation of CPC-based therapy in elderly patients would benefit tremendously from understanding molecular characteristics of senescence to antagonize aging. Nucleostemin (NS) is a nucleolar protein regulating stem cell proliferation and pluripotency.ObjectivesThis study sought to demonstrate that NS preserves characteristics associated with "stemness" in CPCs and antagonizes myocardial senescence and aging.MethodsCPCs isolated from human fetal (fetal human cardiac progenitor cell [FhCPC]) and adult failing (adult human cardiac progenitor cell [AhCPC]) hearts, as well as young (young cardiac progenitor cell [YCPC]) and old mice (old cardiac progenitor cell [OCPC]), were studied for senescence characteristics and NS expression. Heterozygous knockout mice with 1 functional allele of NS (NS+/-) were used to demonstrate that NS preserves myocardial structure and function and slows characteristics of aging.ResultsNS expression is decreased in AhCPCs relative to FhCPCs, correlating with lowered proliferation potential and shortened telomere length. AhCPC characteristics resemble those of OCPCs, which have a phenotype induced by NS silencing, resulting in cell flattening, senescence, multinucleated cells, decreased S-phase progression, diminished expression of stemness markers, and up-regulation of p53 and p16. CPC senescence resulting from NS loss is partially p53 dependent and is rescued by concurrent silencing of p53. Mechanistically, NS induction correlates with Pim-1 kinase-mediated stabilization of c-Myc. Engineering OCPCs and AhCPCs to overexpress NS decreases senescent and multinucleated cells, restores morphology, and antagonizes senescence, thereby preserving phenotypic properties of "stemness." Early cardiac aging with a decline in cardiac function, an increase in senescence markers p53 and p16, telomere attrition, and accompanied CPC exhaustion is evident in NS+/- mice.ConclusionsYouthful properties and antagonism of senescence in CPCs and the myocardium are consistent with a role for NS downstream from Pim-1 signaling that enhances cardiac regeneration.

Project description:True cardiac regeneration of the injured heart has been broadly described in lower vertebrates by active replacement of lost cardiomyocytes to functionally and structurally restore the myocardial tissue. On the contrary, following severe injury (i.e., myocardial infarction) the adult mammalian heart is endowed with an impaired reparative response by means of meager wound healing program and detrimental remodeling, which can lead over time to cardiomyopathy and heart failure. Lately, a growing body of basic, translational and clinical studies have supported the therapeutic use of stem cells to provide myocardial regeneration, with the working hypothesis that stem cells delivered to the cardiac tissue could result into new cardiovascular cells to replenish the lost ones. Nevertheless, multiple independent evidences have demonstrated that injected stem cells are more likely to modulate the cardiac tissue via beneficial paracrine effects, which can enhance cardiac repair and reinstate the embryonic program and cell cycle activity of endogenous cardiac stromal cells and resident cardiomyocytes. Therefore, increasing interest has been addressed to the therapeutic profiling of the stem cell-derived secretome (namely the total of cell-secreted soluble factors), with specific attention to cell-released extracellular vesicles, including exosomes, carrying cardioprotective and regenerative RNA molecules. In addition, the use of cardiac decellularized extracellular matrix has been recently suggested as promising biomaterial to develop novel therapeutic strategies for myocardial repair, as either source of molecular cues for regeneration, biological scaffold for cardiac tissue engineering or biomaterial platform for the functional release of factors. In this review, we will specifically address the translational relevance of these two approaches with ad hoc interest in their feasibility to rejuvenate endogenous mechanisms of cardiac repair up to functional regeneration.

Dataset Information

Inhibition of p16INK4A to Rejuvenate Aging Human Cardiac Progenitor Cells via the Upregulation of Anti-oxidant and NF?B Signal Pathways.

Publications

Inhibition of p16<sup>INK4A</sup> to Rejuvenate Aging Human Cardiac Progenitor Cells via the Upregulation of Anti-oxidant and NFκB Signal Pathways.

Similar Datasets

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