Negative Regulation of miR-375 by Interleukin-10 Enhances Bone Marrow-Derived Progenitor Cell-Mediated Myocardial Repair and Function After Myocardial Infarction

Garikipati, Venkata Naga Srikanth; Krishnamurthy, Prasanna; Verma, Suresh; Khan, Mohsin; Abramova, Tatiana; Mackie, Alexander R; Qin, Gangjian; Benedict, Cynthia; Nickoloff, Emily; Johnson, Jennifer A.; Gao, Ehre; Losordo, Douglas W.; Houser, Steven R.; Koch, Walter J.; Kishore, Raj

doi:10.1002/stem.2121

Cited by 63 publications

(50 citation statements)

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“…We and others reported that transplantation of BMCs improved angiogenesis/neovascularization and blood flow in ischemic heart and limbs. 3, 4 Moreover, the beneficial effects of BMC-based therapy for CLI in diabetic patients have been investigated. 5 However, its functional benefits in diabetic patients are modest due to diabetes-induced cell dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…DATS was administrated orally by gavage one day after the surgery (2 mg/mouse/day, for 3 weeks after surgery). BMCs were isolated from bone marrow of 12- to 14-week-old db/+ or db/db mice by density-gradient centrifugation as previously described 3, 24 and labeled with GFP by transfection with GFP lentivirus (BMCs) or overexpressed CSE by transfection of RFP-tagged CSE lentivirus (CSE-BMCs). Induction of left hind limb ischemia was performed in db/+ and db/db mice as described previously.…”

Section: Methodsmentioning

confidence: 99%

“…3 Cell migration was determined by either transwells or scratch wound assay or scratch wound healing. 3, 27 …”

Section: Methodsmentioning

confidence: 99%

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Restoration of Hydrogen Sulfide Production in Diabetic Mice Improves Reparative Function of Bone Marrow Cells

et al. 2016

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Background Bone marrow cell-based treatment for critical limb ischemia (CLI) in diabetic patients yielded a modest therapeutic effect due to cell dysfunction. Therefore, approaches that improve diabetic stem/progenitor cell functions may provide therapeutic benefits. Here, we tested the hypotheses that restoration of hydrogen sulfide (H2S) production in diabetic bone marrow cells (BMCs) improves their reparative capacities. Methods Mouse BMCs were isolated by density-gradient centrifugation. Unilateral hind limb ischemia (HLI) was conducted in 12- to 14-week old db/+ and db/db mice by ligation of left femoral artery. H2S level was measured by either gas chromatography or staining with florescent dye sulfidefluor 7AM. Results Both H2S production and cystathionine γ-lyase (CSE), an H2S enzyme, levels were significantly decreased in BMCs from diabetic db/db mice. Administration of H2S donor diallyl trisulfide (DATS) or overexpression of CSE restored H2S production and enhanced cell survival and migratory capacity in high glucose (HG)-treated BMCs. Immediately after HLI surgery, the db/+ and db/db mice were administrated with DATS orally and/or local intramuscular injection of GFP-labeled BMCs or RFP-CSE-overexpressing BMCs (CSE-BMCs). Mice with HLI were divided into six groups: 1) db/+; 2) db/db; 3) db/db+BMCs; 4) db/db+DATS; 5) db/db+DATS+BMCs; 6) db/db+CSE-BMCs. DATS and CSE overexpression greatly enhanced diabetic BMCs retention in ischemic hind limbs (IHL) followed by improved blood perfusion, capillary/arteriole density, skeletal muscle architecture and cell survival, and decreased perivascular CD68+ cell infiltration in IHL of diabetic mice. Interestingly, DATS or CSE overexpression rescued HG-impaired migration, tube formation and survival of BMCs or mature human cardiac microvascular endothelial cells (HCMVECs). Mechanistically, DATS restored nitric oxide production and decreased eNOS-pT495 levels in HCMVECs, and improved BMC angiogenic activity under HG condition. Finally, silencing CSE by siRNA significantly increased eNOS-pT495 levels in HCMVECs. Conclusions Decreased CSE-mediated H2S bioavailability is an underlying source of BMC dysfunction in diabetes. Our data indicate that H2S and overexpression of CSE in diabetic BMCs may rescue their dysfunction and open novel avenues for cell-based therapeutics of CLI in diabetic patients.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Restoration of Hydrogen Sulfide Production in Diabetic Mice Improves Reparative Function of Bone Marrow Cells

et al. 2016

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“…PCR-based miRNA array was performed to measured the levels of fibrosis-associated miRNA in BM-FPCs as per manufacturer’s instructions (RT2 Profiler; SABiosciences) 35 . Briefly, total RNA was collected with using Trizol RNA isolation kit (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

“…Recently we have shown that recombinant mouse lL10 treatment significantly inhibits local cytokine expression and subsequently attenuates pressure overload-induced inflammation and hypertrophic remodeling 32 . In fact, IL10KO mice showed exaggerated fibrosis and IL10 treatment resulting in attenuated left ventricular fibrosis in multiple heart failure models (aortic banding, isoproterenol, Ang II and myocardial infarction) 32, 34, 35 . However, molecular mechanisms for the anti-fibrotic effect of IL10 are not known.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell–Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium

et al. 2017

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Background Activated fibroblasts (myofibroblasts; myoFBs) play critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast progenitor cells (BM-FPC) in pressure overload (PO)-induced cardiac fibrosis. We have earlier shown that interleukin-10 (IL10) suppresses PO-induced cardiac fibrosis; however, the role of IL10 in inhibition of BM-FPC-mediated cardiac fibrosis is not known. We hypothesized that IL10 inhibits PO-induced homing of BM-FPCs to the heart and their trans-differentiation to myoFBs and thus attenuates cardiac fibrosis. Methods Pressure overload was induced in wild-type (WT) and IL10 knockout (IL10KO) mice by transverse aortic constriction (TAC). To determine the bone marrow origin, chimeric mice were created using eGFP WT mice marrow to the IL10KO mice. For mechanistic studies, fibroblast progenitor cells were isolated from mouse bone marrow. Results Pressure overload enhanced bone marrow fibroblast progenitor cell (BM-FPC) mobilization and homing in IL10KO mice compared to WT mice. Furthermore, WT bone marrow (from eGFP mice) transplantation in BM-depleted IL10KO mice (IL10KO chimeric mice) reduced TAC-induced BM-FPC mobilization compared to IL10KO mice. GFP co-staining with αSMA or collagen 1α in left ventricular tissue sections of IL10KO chimeric mice suggest that myofibroblasts were derived from bone marrow post-TAC. Finally, WT-BMT in IL10KO mice inhibited TAC-induced cardiac fibrosis and improved heart function. At the molecular level, IL10 treatment significantly inhibited TGFβ-induced transdifferentiation and fibrotic signaling in WT BM-FPC in vitro. Furthermore, fibrosis-associated miRNAs expression was highly upregulated in IL10KO-FPCs compared to WT-FPCs. PCR-based selective miRNA analysis revealed that TGFβ-induced enhanced expression of fibrosis-associated miRNAs (miRNA-21, -145 and -208) was significantly inhibited by IL10. Restoration of miRNA-21 levels suppressed the IL10 effects on TGFβ-induced fibrotic signaling in BM-FPC. Conclusion Our findings suggest that IL10 inhibits BM-FPC homing and trans-differentiation to myofibroblasts in pressure overloaded myocardium. Mechanistically for the first time we showed that IL10 suppresses Smad-miRNA-21 mediated activation of BM-FPCs and thus modulates cardiac fibrosis.

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Bioinformatic screening for key miRNAs and genes associated with myocardial infarction

Zhao

et al. 2018

FEBS Open Bio

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Despite significant advances in understanding of the causes of and treatment of myocardial infarction (MI) in recent years, morbidity and mortality is still high. The aim of this study was to identify mi RNA and genes potentially associated with MI. mRNA and mi RNA expression datasets were downloaded from the Gene Expression Omnibus database ( http://www.ncbi.nlm.nih.gov/geo/ ). Interactions between mi RNA and the expression and function of target genes were analyzed, and a protein–protein interaction network was constructed. The diagnostic value of identified mi RNA and genes was assessed. Quantitative RT‐PCR was applied to validate the results of the bioinformatics analysis. MiR‐27a, miR‐31*, miR‐1291, miR‐139‐5p, miR‐204, miR‐375, and target genes including CX 3 CR 1 , HSPA 6, and TPM 3 had potential diagnostic value. The genes TFEB , IRS 2 , GRB 2 , FASLG , LIMS 1 , CX 3 CR 1 , HSPA 6 , TPM 3 , LAT 2 , CEBPD , AQP 9, and MAPKAPK 2 were associated with recovery from MI. In conclusion, the identified mi RNA and genes might be associated with the pathology of MI.

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Negative Regulation of miR-375 by Interleukin-10 Enhances Bone Marrow-Derived Progenitor Cell-Mediated Myocardial Repair and Function After Myocardial Infarction

Cited by 63 publications

References 31 publications

Restoration of Hydrogen Sulfide Production in Diabetic Mice Improves Reparative Function of Bone Marrow Cells

Restoration of Hydrogen Sulfide Production in Diabetic Mice Improves Reparative Function of Bone Marrow Cells

Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell–Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium

Bioinformatic screening for key miRNAs and genes associated with myocardial infarction

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