Crosstalk between SDF-1/CXCR4 and SDF-1/CXCR7 in cardiac stem cell migration

Chen, Dong; Xia, Yanli; Zuo, Ke; Wang, Ying; Zhang, Shiying; Kuang, Dong; Duan, Yaqi; Zhao, Xia; Wang, Guoping

doi:10.1038/srep16813

Cited by 60 publications

(52 citation statements)

References 58 publications

(63 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SDF-1/CXCR7 is thought to promote CD34+ hematopoietic stem/progenitor cell cycling and survival via Akt signaling 27 and SDF-1/CXCR7 also regulates cell migration 28 by Akt signaling. Furthermore, the function of Nrf2 can be regulated by the Akt/GSK-3β/Fyn pathway in fibroblasts and PC12 cells by controlling Fyn-mediated export and degradation of nuclear Nrf2 29, 30 .…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Elevating CXCR7 Improves Angiogenic Function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 Activation in Diabetic Limb Ischemia

Dai

Yan

Zeng

et al. 2017

Circulation Research

125

194

View full text Add to dashboard Cite

Rationale Endothelial progenitor cells (EPCs) respond to SDF-1 through receptors CXCR7 and CXCR4. Whether SDF-1 receptors involves in diabetes induced EPCs dysfunction remains unknown. Objective To determine the role of SDF-1 receptors in diabetic EPCs dysfunction. Methods and Results CXCR7 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, while up-regulation of CXCR7 rescued angiogenic function of EPCs from db/db mice. In normal EPCs treated with oxidized low-density lipoprotein (ox-LDL) or high glucose (HG) also reduced CXCR7 expression, impaired tube formation and increased oxidative stress and apoptosis. The damaging effects of ox-LDL or HG were markedly reduced by SDF-1 pretreatment in EPCs transduced with CXCR7 lentivirus (CXCR7-EPCs) but not in EPCs transduced with control lentivirus (Null-EPCs). Most importantly, CXCR7-EPCs were superior to Null-EPCs for therapy of ischemic limbs in db/db mice. Mechanistic studies demonstrated that ox-LDL or HG inhibited Akt and GSK-3β phosphorylation, nuclear export of Fyn and nuclear localization of Nrf2, blunting Nrf2 downstream target genes HO-1, NQO-1 and catalase, and inducing an increase in EPC oxidative stress. This destructive cascade was blocked by SDF-1 treatment in CXCR7-EPCs. Furthermore, inhibition of PI3K/Akt 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. Conclusions Elevated expression of CXCR7 enhances EPC resistance to diabetes-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia. The benefits of CXCR7 are mediated predominantly by an Akt/GSK-3β/Fyn pathway via increased activity of Nrf2.

show abstract

Section: Resultsmentioning

confidence: 99%

“…In PC12 cells, it was found that puerarin triggers Akt activation, which in turn inhibits GSK-3β activation resulting in more Nrf2 nuclear translocation. Moreover, it was demonstrated that CXCR7 activates PI3K/Akt independently of CXCR4 27, 28 . In this study, diabetes, ox-LDL and HG all reduced Akt phosphorylation in EPCs.…”

Section: Discussionmentioning

confidence: 99%

Elevating CXCR7 Improves Angiogenic Function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 Activation in Diabetic Limb Ischemia

Dai

Yan

Zeng

et al. 2017

Circulation Research

125

194

View full text Add to dashboard Cite

show abstract

“…1C; refs. 21, 26). The tumor phenotype of high levels of CXCR4 expression, in the absence of CXCR7, is in stark contrast to the developing cerebellum, where P6 granule precursor cells express high levels of both CXCR4 and CXCR7.…”

Section: Resultsmentioning

confidence: 99%

Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4

et al. 2017

View full text Add to dashboard Cite

The CXCR4 chemokine and Sonic Hedgehog (SHH) morphogen pathways are well-validated therapeutic targets in cancer, including medulloblastoma. However, single-agent treatments with SHH or CXCR4 antagonists have not proven efficacious in clinical trials to date. Here, we discovered that dual inhibition of the SHH and CXCR4 pathways in a murine model of SHH-subtype medulloblastoma exerts potent antitumor effects. This therapeutic synergy resulted in the suppression of tumor-propagating cell function and correlated with increased histone H3 lysine 27 trimethylation within the promoters of stem cell genes, resulting in their decreased expression. These results demonstrate that CXCR4 contributes to the epigenetic regulation of a tumor-propagating cell phenotype. Moreover, they provide a mechanistic rationale to evaluate the combination of SHH and CXCR4 inhibitors in clinical trials for the treatment of medulloblastoma, as well as other cancers driven by SHH that coexpress high levels of CXCR4.

show abstract

“…The complementary proteins in our system TIMP-3, FGF-2, and SDF-1α have all been reported to prevent cardiomyocyte apoptosis [35, 37, 52–57]. FGF-2 and SDF-1α specifically activate these pathways upon binding with their surface receptors FGFR1 and CRCX4/CRCX7, respectively, improving cell survival and proliferation [52, 58, 59]. Moreover, controlled protein release induced higher secretions levels of IGF-I and Shh.…”

Section: Discussionmentioning

confidence: 99%

A single injection of protein-loaded coacervate-gel significantly improves cardiac function post infarction

et al. 2017

View full text Add to dashboard Cite

After myocardial infarction (MI), the heart undergoes fibrotic pathological remodeling instead of repair and regeneration. With multiple pathologies developing after MI, treatment using several proteins is expected to address this range of pathologies more effectively than a single-agent therapy. A factorial design of experiments study guided us to combine three complementary factors in one injection: tissue inhibitor of metalloproteinases-3 (TIMP-3) was embedded in a fibrin gel for signaling in the initial phase of the treatment, while basic fibroblast growth factor (FGF-2) and stromal cell-derived factor 1-alpha (SDF-1α) were embedded in heparin-based coacervates for sustained release and distributed within the same fibrin gel to exert their effects over a longer period. The gel was then tested in a rat model of myocardial infarction. Contractility of rat hearts treated with the protein coacervate-gel composite stabilized and slightly improved after the first week while contractility continued to decrease in rats treated with free proteins or saline over the 8 week study period. Hearts receiving the protein coacervate-gel composite treatment also exhibited reduced ventricular dilation, inflammation, fibrosis, and extracellular matrix (ECM) degradation. Revascularization, cardiomyocyte preservation, stem cell homing, and increased myocardial strain likely all contributed to the repair. This study demonstrates the potential of a multifactorial therapeutic approach in MI, using three complementary proteins delivered sequentially for comprehensive healing. The study also shows the necessity of controlled delivery for growth factors and cytokines to be an effective treatment.

show abstract

Crosstalk between SDF-1/CXCR4 and SDF-1/CXCR7 in cardiac stem cell migration

Cited by 60 publications

References 58 publications

Elevating CXCR7 Improves Angiogenic Function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 Activation in Diabetic Limb Ischemia

Elevating CXCR7 Improves Angiogenic Function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 Activation in Diabetic Limb Ischemia

Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4

A single injection of protein-loaded coacervate-gel significantly improves cardiac function post infarction

Contact Info

Product

Resources

About