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Exosomes from SIRT1-Overexpressing ADSCs Restore Cardiac Function by Improving Angiogenic Function of EPCs.

ABSTRACT: Acute myocardial infarction (AMI) is one of the leading causes of mortality in cardiovascular diseases. The aim of this study was to investigate whether exosomes from Sirtuin 1 (SIRT1)-overexpressing adipose-derived stem cells (ADSCs) had a protective effect on AMI. The expression of C-X-C chemokine receptor type 7 (CXCR7) was significantly downregulated in peripheral blood endothelial progenitor cells (EPCs) from AMI patients (AMI-EPCs) compared with that in healthy donors, which coincided with impaired tube formation. The exosomes from SIRT1 overexpression in ADSCs (ADSCs-SIRT1-Exos) increased the expression of C-X-C motif chemokine 12 (CXCL12) and nuclear factor E2 related factor 2 (Nrf2) in AMI-EPCs, which promoted migration and tube formation of AMI-EPCs, and overexpression of CXCR7 helped AMI-EPCs to restore the function of cell migration and tube formation. Moreover, CXCR7 was downregulated in the myocardium of AMI mice, and knockout of CXCR7 exacerbated AMI-induced impairment of cardiovascular function. Injection of ADSCs-SIRT1-Exos increased the survival and promoted the recovery of myocardial function with reduced infarct size and post-AMI left ventricular remodeling, induced vasculogenesis, and decreased AMI-induced myocardial inflammation. These findings showed that ADSCs-SIRT1-Exos may recruit EPCs to the repair area and that this recruitment may be mediated by Nrf2/CXCL12/CXCR7 signaling.

SUBMITTER: Huang H

PROVIDER: S-EPMC7412761 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Exosomes from SIRT1-Overexpressing ADSCs Restore Cardiac Function by Improving Angiogenic Function of EPCs.

Huang Hui H Xu Zhenxing Z Qi Yuan Y Zhang Wei W Zhang Chenjun C Jiang Mei M Deng Shengqiong S Wang Hairong H

Molecular therapy. Nucleic acids 20200710

Acute myocardial infarction (AMI) is one of the leading causes of mortality in cardiovascular diseases. The aim of this study was to investigate whether exosomes from Sirtuin 1 (SIRT1)-overexpressing adipose-derived stem cells (ADSCs) had a protective effect on AMI. The expression of C-X-C chemokine receptor type 7 (CXCR7) was significantly downregulated in peripheral blood endothelial progenitor cells (EPCs) from AMI patients (AMI-EPCs) compared with that in healthy donors, which coincided with ...[more]

PMID: 32771925

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Project description:Endothelial progenitor cells (EPCs) are reduced in number and impaired in function in diabetic patients. Whether and how Nrf2 regulates the function of diabetic EPCs remains unclear. In this study, we found that the expression of Nrf2 and its downstream genes were decreased in EPCs from both diabetic patients and db/db mice. Survival ability and angiogenic function of EPCs from diabetic patients and db/db mice also were impaired. Gain- and loss-of-function studies, respectively, showed that knockdown of Nrf2 increased apoptosis and impaired tube formation in EPCs from healthy donors and wild-type mice, while Nrf2 overexpression decreased apoptosis and rescued tube formation in EPCs from diabetic patients and db/db mice. Additionally, proangiogenic function of Nrf2-manipulated mouse EPCs was validated in db/db mice with hind limb ischemia. Mechanistic studies demonstrated that diabetes induced mitochondrial fragmentation and dysfunction of EPCs by dysregulating the abundance of proteins controlling mitochondrial dynamics; upregulating Nrf2 expression attenuated diabetes-induced mitochondrial fragmentation and dysfunction and rectified the abundance of proteins controlling mitochondrial dynamics. Further RNA-sequencing analysis demonstrated that Nrf2 specifically upregulated the transcription of isocitrate dehydrogenase 2 (IDH2), a key enzyme regulating tricarboxylic acid cycle and mitochondrial function. Overexpression of IDH2 rectified Nrf2 knockdown- or diabetes-induced mitochondrial fragmentation and EPC dysfunction. In a therapeutic approach, supplementation of an Nrf2 activator sulforaphane enhanced angiogenesis and blood perfusion recovery in db/db mice with hind limb ischemia. Collectively, these findings indicate that Nrf2 is a potential therapeutic target for improving diabetic EPC function. Thus, elevating Nrf2 expression enhances EPC resistance to diabetes-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia likely via transcriptional upregulating IDH2 expression and improving mitochondrial function of diabetic EPCs.

Project description:RationaleEndothelial progenitor cells (EPCs) respond to stromal cell-derived factor 1 (SDF-1) through chemokine receptors CXCR7 and CXCR4. Whether SDF-1 receptors involves in diabetes mellitus-induced EPCs dysfunction remains unknown.ObjectiveTo determine the role of SDF-1 receptors in diabetic EPCs dysfunction.Methods and resultsCXCR7 expression, but not CXCR4 was reduced in EPCs from db/db mice, which coincided with impaired tube formation. Knockdown of CXCR7 impaired tube formation of EPCs from normal mice, whereas upregulation of CXCR7 rescued angiogenic function of EPCs from db/db mice. In normal EPCs treated with oxidized low-density lipoprotein or high glucose also reduced CXCR7 expression, impaired tube formation, and increased oxidative stress and apoptosis. The damaging effects of oxidized low-density lipoprotein or high glucose were markedly reduced by SDF-1 pretreatment in EPCs transduced with CXCR7 lentivirus but not in EPCs transduced with control lentivirus. Most importantly, EPCs transduced with CXCR7 lentivirus were superior to EPCs transduced with control lentivirus for therapy of ischemic limbs in db/db mice. Mechanistic studies demonstrated that oxidized low-density lipoprotein or high glucose inhibited protein kinase B and glycogen synthase kinase-3β phosphorylation, nuclear export of Fyn and nuclear localization of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), blunting Nrf2 downstream target genes heme oxygenase-1, NAD(P)H dehydrogenase (quinone 1) and catalase, and inducing an increase in EPC oxidative stress. This destructive cascade was blocked by SDF-1 treatment in EPCs transduced with CXCR7 lentivirus. Furthermore, inhibition of phosphatidylinositol 3-kinase/protein kinase B prevented SDF-1/CXCR7-mediated Nrf2 activation and blocked angiogenic repair. Moreover, Nrf2 knockdown almost completely abolished the protective effects of SDF-1/CXCR7 on EPC function in vitro and in vivo.ConclusionsElevated expression of CXCR7 enhances EPC resistance to diabetes mellitus-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia. The benefits of CXCR7 are mediated predominantly by a protein kinase B/glycogen synthase kinase-3β/Fyn pathway via increased activity of Nrf2.

Project description:BackgroundHuman amniotic epithelial cells (hAECs) exhibit a strong capability to restore ovarian function in chemotherapy-induced premature ovarian failure (POF). However, the therapeutic efficacy of hAECs is usually affected by the limited number and proliferative ability of grafted hAECs in target organs. The transplantation of stem cells encapsulated in sodium alginate-bioglass (SA-BG) composite hydrogel has recently been shown to be an effective strategy for tissue regeneration. The current study aims to investigate the therapeutic potential of hAECs or hAEC-derived conditioned medium (CM) encapsulated in SA-BG in mice with chemotherapy-induced POF.MethodsC57BL/6 mice were intraperitoneally injected with chemotherapy drugs to induce POF. hAECs or CM were harvested and encapsulated in SA-BG composite hydrogel, which were transplanted onto the injured ovaries of mice with POF. Follicle development, granulosa cell function, and ovarian angiogenesis were evaluated by morphological methods. To further elucidate the effect of SA-BG-encapsulated hAECs/CM on vascularization, the tube formation of human umbilical vein epithelial cells (hUVECs) was conducted in vitro. Cytokine array and ELISA were used to analyze and quantify the effects of bioactive components released by SA-BG on the secretion of angiogenic factors by hAECs.ResultsThe transplantation of SA-BG-encapsulated hAECs/CM restored follicle development, repaired granulosa cell function, and enhanced ovarian angiogenesis in POF mice. The further study showed that SA-BG significantly promoted the tube formation of hUVECs in vitro. Moreover, encapsulating hAECs could facilitate the effect of SA-BG on inducing the formation of the capillary tube in a paracrine manner. In addition, we found that SA-BG extracts significantly enhanced the viability of hAECs and stimulated the secretion of pro-angiogenic factors of hAECs. Notably, compared with SA-BG/CM, SA-BG/hAECs achieve better therapeutic effects, possibly because stimulation of BG enhanced the viability and paracrine capacity of hAECs.ConclusionsThe present study initially demonstrates that SA-BG-encapsulated hAECs or CM can exert a therapeutic effect on chemotherapy-induced POF mainly by protecting granulosa cell function and enhancing ovarian vascularization, which might provide a novel strategy for the delivery of hAECs for treating POF.

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Exosomes from SIRT1-Overexpressing ADSCs Restore Cardiac Function by Improving Angiogenic Function of EPCs.

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Exosomes from SIRT1-Overexpressing ADSCs Restore Cardiac Function by Improving Angiogenic Function of EPCs.

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