Dataset Information

PKC-epsilon deficiency alters progenitor cell populations in favor of megakaryopoiesis.

ABSTRACT:

Background

It has long been postulated that Protein Kinase C (PKC) is an important regulator of megakaryopoiesis. Recent contributions to the literature have outlined the functions of several individual PKC isoforms with regard to megakaryocyte differentiation and platelet production. However, the exact role of PKC? remains elusive.

Objective

To delineate the role of PKC? in megakaryopoiesis.

Approach and results

We used a PKC? knockout mouse model to examine the effect of PKC? deficiency on platelet mass, megakaryocyte mass, and bone marrow progenitor cell distribution. We also investigated platelet recovery in PKC? null mice and TPO-mediated signaling in PKC? null megakaryocytes. PKC? null mice have higher platelet counts due to increased platelet production compared to WT littermate controls (p<0.05, n = 8). Furthermore, PKC? null mice have more bone marrow megakaryocyte progenitor cells than WT littermate control mice. Additionally, thrombopoietin-mediated signaling is perturbed in PKC? null mice as Akt and ERK1/2 phosphorylation are enhanced in PKC? null megakaryocytes stimulated with thrombopoietin. Finally, in response to immune-induced thrombocytopenia, PKC? null mice recovered faster and had higher rebound thrombocytosis than WT littermate control mice.

Conclusions

Enhanced platelet recovery could be due to an increase in megakaryocyte progenitor cells found in PKC? null mice as well as enhanced thrombopoietin-mediated signaling observed in PKC? deficient megakaryocytes. These data suggest that PKC? is a negative regulator of megakaryopoiesis.

SUBMITTER: Kostyak JC

PROVIDER: S-EPMC5544228 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

PKC-epsilon deficiency alters progenitor cell populations in favor of megakaryopoiesis.

Kostyak John C JC Liverani Elisabetta E Kunapuli Satya P SP

PloS one 20170804 8

<h4>Background</h4>It has long been postulated that Protein Kinase C (PKC) is an important regulator of megakaryopoiesis. Recent contributions to the literature have outlined the functions of several individual PKC isoforms with regard to megakaryocyte differentiation and platelet production. However, the exact role of PKCε remains elusive.<h4>Objective</h4>To delineate the role of PKCε in megakaryopoiesis.<h4>Approach and results</h4>We used a PKCε knockout mouse model to examine the effect of ...[more]

PMID: 28783756

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Project description:Rationale: Systemic inflammation compromises the reparative properties of endothelial progenitor cell (EPC) and their exosomes on myocardial repair, although the underlying mechanism of loss of function of exosomes from inflamed EPCs is still obscure. Objective: To determine the mechanisms of IL-10 (interleukin-10) deficient-EPC-derived exosome dysfunction in myocardial repair and to investigate if modification of specific exosome cargo can rescue reparative activity. Methods and Results: Using IL-10 knockout mice mimicking systemic inflammation condition, we compared therapeutic effect and protein cargo of exosomes isolated from wild-type EPC and IL-10 knockout EPC. In a mouse model of myocardial infarction (MI), wild-type EPC-derived exosome treatment significantly improved left ventricle cardiac function, inhibited cell apoptosis, reduced MI scar size, and promoted post-MI neovascularization, whereas IL-10 knockout EPC-derived exosome treatment showed diminished and opposite effects. Mass spectrometry analysis revealed wild-type EPC-derived exosome and IL-10 knockout EPC-derived exosome contain different protein expression pattern. Among differentially expressed proteins, ILK (integrin-linked kinase) was highly enriched in both IL-10 knockout EPC-derived exosome as well as TNFα (tumor necrosis factor-α)-treated mouse cardiac endothelial cell-derived exosomes (TNFα inflamed mouse cardiac endothelial cell-derived exosome). ILK-enriched exosomes activated NF-κB (nuclear factor κB) pathway and NF-κB-dependent gene transcription in recipient endothelial cells and this effect was partly attenuated through ILK knockdown in exosomes. Intriguingly, ILK knockdown in IL-10 knockout EPC-derived exosome significantly rescued their reparative dysfunction in myocardial repair, improved left ventricle cardiac function, reduced MI scar size, and enhanced post-MI neovascularization in MI mouse model. Conclusions: IL-10 deficiency/inflammation alters EPC-derived exosome function, content and therapeutic effect on myocardial repair by upregulating ILK enrichment in exosomes, and ILK-mediated activation of NF-κB pathway in recipient cells, whereas ILK knockdown in exosomes attenuates NF-κB activation and reduces inflammatory response. Our study provides new understanding of how inflammation may alter stem cell-exosome-mediated cardiac repair and identifies ILK as a target kinase for improving progenitor cell exosome-based cardiac therapies.

Dataset Information

PKC-epsilon deficiency alters progenitor cell populations in favor of megakaryopoiesis.

Background

Objective

Approach and results

Conclusions

Publications

PKC-epsilon deficiency alters progenitor cell populations in favor of megakaryopoiesis.

Similar Datasets

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