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Intra-myocardial injection of both growth factors and heart derived Sca-1+/CD31- cells attenuates post-MI LV remodeling more than does cell transplantation alone: neither intervention enhances functionally significant cardiomyocyte regeneration.

ABSTRACT: Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are two potent cell survival and regenerative factors in response to myocardial injury (MI). We hypothesized that simultaneous delivery of IGF+HGF combined with Sca-1+/CD31- cells would improve the outcome of transplantation therapy in response to the altered hostile microenvironment post MI. One million adenovirus nuclear LacZ-labeled Sca-1+/CD31- cells were injected into the peri-infarction area after left anterior descending coronary artery (LAD) ligation in mice. Recombinant mouse IGF-1+HGF was added to the cell suspension prior to the injection. The left ventricular (LV) function was assessed by echocardiography 4 weeks after the transplantation. The cell engraftment, differentiation and cardiomyocyte regeneration were evaluated by histological analysis. Sca-1+/CD31- cells formed viable grafts and improved LV ejection fraction (EF) (Control, 54.5+/-2.4; MI, 17.6+/-3.1; Cell, 28.2+/-4.2, n = 9, P<0.01). IGF+HGF significantly enhanced the benefits of cell transplantation as evidenced by increased EF (38.8+/-2.2; n = 9, P<0.01) and attenuated adverse structural remodeling. Furthermore, IGF+HGF supplementation increased the cell engraftment rate, promoted the transplanted cell survival, enhanced angiogenesis, and minimally stimulated endogenous cardiomyocyte regeneration in vivo. The in vitro experiments showed that IGF+HGF treatment stimulated Sca-1+/CD31- cell proliferation and inhibited serum free medium induced apoptosis. Supperarray profiling of Sca-1+/CD31- cells revealed that Sca-1+/CD31- cells highly expressed various trophic factor mRNAs and IGF+HGF treatment altered the mRNAs expression patterns of these cells. These data indicate that IGF-1+HGF could serve as an adjuvant to cell transplantation for myocardial repair by stimulating donor cell and endogenous cardiac stem cell survival, regeneration and promoting angiogenesis.

SUBMITTER: Wang X

PROVIDER: S-EPMC4053321 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Intra-myocardial injection of both growth factors and heart derived Sca-1+/CD31- cells attenuates post-MI LV remodeling more than does cell transplantation alone: neither intervention enhances functionally significant cardiomyocyte regeneration.

Wang Xiaohong X Li Qinglu Q Hu Qingsong Q Suntharalingam Piradeep P From Arthur H L AH Zhang Jianyi J

PloS one 20140611 2

Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are two potent cell survival and regenerative factors in response to myocardial injury (MI). We hypothesized that simultaneous delivery of IGF+HGF combined with Sca-1+/CD31- cells would improve the outcome of transplantation therapy in response to the altered hostile microenvironment post MI. One million adenovirus nuclear LacZ-labeled Sca-1+/CD31- cells were injected into the peri-infarction area after left anterior descend ...[more]

PMID: 24919180

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Project description:Objective Myocardial ischemia and reperfusion (I/R) injury is associated with oxidative stress and inflammation, leading to scar development and malfunction. The marine omega-3 fatty acids (?-3 FA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are mediating cardioprotection and improving clinical outcomes in patients with heart disease. Therefore, we tested the hypothesis that docosahexaenoic acid (DHA) supplementation prior to LAD occlusion-induced myocardial injury (MI) confers cardioprotection in mice. Methods C57BL/6N mice were placed on DHA or control diets (CD) beginning 7?d prior to 60?min LAD occlusion-induced MI or sham surgery. The expression of inflammatory mediators was measured via RT-qPCR. Besides FACS analysis for macrophage quantification and subtype evaluation, macrophage accumulation as well as collagen deposition was quantified in histological sections. Cardiac function was assessed using a pressure-volume catheter for up to 14?d. Results DHA supplementation significantly attenuated the induction of peroxisome proliferator-activated receptor-? (PPAR-?) (2.3 ± 0.4 CD vs. 1.4 ± 0.3 DHA) after LAD occlusion. Furthermore, TNF-? (4.0 ± 0.6 CD vs. 1.5 ± 0.2 DHA), IL-1? (60.7 ± 7.0 CD vs. 11.6 ± 1.9 DHA), and IL-10 (223.8 ± 62.1 CD vs. 135.5 ± 38.5 DHA) mRNA expression increase was diminished in DHA-supplemented mice after 72?h reperfusion. These changes were accompanied by a less prominent switch in ?/? myosin heavy chain isoforms. Chemokine mRNA expression was stronger initiated (CCL2 6?h: 32.8 ± 11.5 CD vs. 78.8 ± 13.6 DHA) but terminated earlier (CCL2 72?h: 39.5 ± 7.8 CD vs. 8.2 ± 1.9 DHA; CCL3 72?h: 794.3 ± 270.9 CD vs. 258.2 ± 57.8 DHA) in DHA supplementation compared to CD mice after LAD occlusion. Correspondingly, DHA supplementation was associated with a stronger increase of predominantly alternatively activated Ly6C-positive macrophage phenotype, being associated with less collagen deposition and better LV function (EF 14?d: 17.6 ± 2.6 CD vs. 31.4 ± 1.5 DHA). Conclusion Our data indicate that DHA supplementation mediates cardioprotection from MI via modulation of the inflammatory response with timely and attenuated remodeling. DHA seems to attenuate MI-induced cardiomyocyte injury partly by transient PPAR-? downregulation, diminishing the need for antioxidant mechanisms including mitochondrial function, or ?- to ?-MHC isoform switch.

Project description:IntroductionIntra-articular (IA) injection of hyaluronic acid (HA) and corticosteroid (CS) is a common treatment for osteoarthritis (OA) of the knee. As a drug treatment for patients with depression, duloxetine has been shown in many studies to effectively relieve the pain of OA and improve function of the knee joint. However, evidence regarding the efficacy of IA injection of HA+CS combined with duloxetine for pain management in patients with OA of the knee is lacking. The aim of this study was to test the hypothesis that IA injection of HA+CS combined with duloxetine could achieve pain management superior to that of IA injection of HA+CS alone in patients experiencing knee OA pain.MethodsThis study will adopt a prospective, randomised, open-label blind endpoint study design. In total, 150 patients with OA of the knee will be enrolled in the study. The participants will be randomly allocated to receive either a single IA injection of HA+CS combined with duloxetine or a single IA injection of HA+CS alone, and both groups will complete a 24-week follow-up to assess pain and functional improvements. The primary outcome measure is the change in the weekly mean of the 24 hours average pain scores from baseline to the end of 24 weeks in patients with OA of the knee, and the secondary outcomes include the response to treatment, changes from baseline in the brief pain inventory, improvement in the Western Ontario and McMaster Universities Osteoarthritis index scores, patient global impression of improvement scale, Hospital Anxiety and Depression Scale and adverse events during the 24-week follow-up. The data will be analysed by the intention-to-treat principle.Ethics approval and disseminationThis study was approved by the institutional ethics committee of the Beijing Tiantan Hospital (approval number: KY 2019-086-02). The results of the study will be published in peer-reviewed journals, and the findings will be presented at scientific meetings.Trial registration numberClinicalTrials.gov Identifier: NCT04117893; Pre-results.

Project description:Most forms of arthritis are incurable, difficult to treat, and a major cause of disability in Western countries. Better local treatment of arthritis is impaired by the pharmacokinetics of the joint that make it very difficult to deliver drugs to joints at sustained, therapeutic concentrations. This is especially true of biologic drugs, such as proteins and RNA, many of which show great promise in preclinical studies. Gene transfer provides a strategy for overcoming this limitation. The basic concept is to deliver cDNAs encoding therapeutic products by direct intra-articular injection, leading to sustained, endogenous synthesis of the gene products within the joint. Proof of concept has been achieved for both in vivo and ex vivo gene delivery using a variety of vectors, genes, and cells in several different animal models. There have been a small number of clinical trials for rheumatoid arthritis (RA) and osteoarthritis (OA) using retrovirus vectors for ex vivo gene delivery and adeno-associated virus (AAV) for in vivo delivery. AAV is of particular interest because, unlike other viral vectors, it is able to penetrate deep within articular cartilage and transduce chondrocytes in situ. This property is of particular importance in OA, where changes in chondrocyte metabolism are thought to be fundamental to the pathophysiology of the disease. Authorities in Korea have recently approved the world's first arthritis gene therapy. This targets OA by the injection of allogeneic chondrocytes that have been transduced with a retrovirus carrying transforming growth factor-?1 cDNA. Phase III studies are scheduled to start in the United States soon. Meanwhile, two additional Phase I trials are listed on Clinicaltrials.gov , both using AAV. One targets RA by transferring interferon-?, and the other targets OA by transferring interleukin-1 receptor antagonist. The field is thus gaining momentum and promises to improve the treatment of these common and debilitating diseases.

Dataset Information

Intra-myocardial injection of both growth factors and heart derived Sca-1+/CD31- cells attenuates post-MI LV remodeling more than does cell transplantation alone: neither intervention enhances functionally significant cardiomyocyte regeneration.

Publications

Intra-myocardial injection of both growth factors and heart derived Sca-1+/CD31- cells attenuates post-MI LV remodeling more than does cell transplantation alone: neither intervention enhances functionally significant cardiomyocyte regeneration.

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