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Long noncoding RNA LUCAT1 enhances the survival and therapeutic effects of mesenchymal stromal cells post-myocardial infarction.

ABSTRACT: Mesenchymal stromal cell (MSC) transplantation has been a promising therapeutic strategy for repairing heart tissues post-myocardial infarction (MI). Nevertheless, its therapeutic efficacy remains low, which is mainly ascribed to the low viability of transplanted MSCs. Recently, long noncoding RNAs (lncRNAs) have been reported to participate in diverse physiological and pathological processes, but little is known about their role in MSC survival. Using unbiased transcriptome profiling of hypoxia-preconditioned MSCs (HP-MSCs) and normoxic MSCs (N-MSCs), we identified a lncRNA named lung cancer-associated transcript 1 (LUCAT1) under hypoxia. LUCAT1 knockdown reduced the survival of engrafted MSCs and decreased the MSC-based therapeutic potency, as shown by impaired cardiac function, reduced cardiomyocyte survival, and increased fibrosis post-MI. Conversely, LUCAT1 overexpression had the opposite results. Mechanistically, LUCAT1 bound with and recruited jumonji domain-containing 6 (JMJD6) to the promoter of forkhead box Q1 (FOXQ1), which demethylated FOXQ1 at H4R3me^2(s) and H3R2me^2(a), thus downregulating Bax expression and upregulating Bcl-2 expression to attenuate MSC apoptosis. Therefore, our findings revealed the protective effects of LUCAT1 on MSC apoptosis and demonstrated that the LUCAT1-mediated JMJD6-FOXQ1 pathway might represent a novel target to potentiate the therapeutic effect of MSC-based therapy for ischemic cardiovascular diseases.

SUBMITTER: Tao Y

PROVIDER: S-EPMC8733180 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Long noncoding RNA LUCAT1 enhances the survival and therapeutic effects of mesenchymal stromal cells post-myocardial infarction.

Tao Yue Y Liu Qingnian Q Wu Rongrong R Xiao Changchen C Ni Cheng C Wang Kan K Hu Wangxing W Zhong Zhiwei Z Zhao Jing J Li Qingju Q Zhu Dan D Zhong Shuhan S Yu Hong H Zhu Wei W Chen Jinghai J Hu Xinyang X Wang Jian'an J

Molecular therapy. Nucleic acids 20211211

Mesenchymal stromal cell (MSC) transplantation has been a promising therapeutic strategy for repairing heart tissues post-myocardial infarction (MI). Nevertheless, its therapeutic efficacy remains low, which is mainly ascribed to the low viability of transplanted MSCs. Recently, long noncoding RNAs (lncRNAs) have been reported to participate in diverse physiological and pathological processes, but little is known about their role in MSC survival. Using unbiased transcriptome profiling of hypoxia ...[more]

PMID: 35036054

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Project description:BackgroundThe LIM-homeobox transcription factor islet-1 (ISL1) has been proposed as a marker for cardiovascular progenitor cells. This study investigated whether forced expression of ISL1 in human mesenchymal stem cells (hMSCs) improves myocardial infarction (MI) treatment outcomes.MethodsThe lentiviral vector containing the human elongation factor 1α promoter, which drives the expression of ISL1 (EF1α-ISL1), was constructed using the Multisite Gateway System and used to transduce hMSCs. Flow cytometry, immunofluorescence, Western blotting, TUNEL assay, and RNA sequencing were performed to evaluate the function of ISL1-overexpressing hMSCs (ISL1-hMSCs).ResultsThe in vivo results showed that transplantation of ISL1-hMSCs improved cardiac function in a rat model of MI. Left ventricle ejection fraction and fractional shortening were greater in post-MI hearts after 4 weeks of treatment with ISL1-hMSCs compared with control hMSCs or phosphate-buffered saline. We also found that ISL1 overexpression increased angiogenesis and decreased apoptosis and inflammation. The greater potential of ISL1-hMSCs may be attributable to an increased number of surviving cells after transplantation. Conditioned medium from ISL1-hMSCs decreased the apoptotic effect of H2O2 on the cardiomyocyte cell line H9c2. To clarify the molecular basis of this finding, we employed RNA sequencing to compare the apoptotic-related gene expression profiles of control hMSCs and ISL1-hMSCs. The results showed that insulin-like growth factor binding protein 3 (IGFBP3) was the only gene in ISL1-hMSCs with a RPKM value higher than 100 and that the difference fold-change between ISL1-hMSCs and control hMSCs was greater than 3, suggesting that IGFBP3 might play an important role in the anti-apoptosis effect of ISL1-hMSCs through paracrine effects. Furthermore, the expression of IGFBP3 in the conditioned medium from ISL1-hMSCs was almost fourfold greater than that in conditioned medium from control hMSCs. Moreover, the IGFBP3 neutralization antibody reversed the apoptotic effect of ISL1-hMSCs-CM.ConclusionsThese results suggest that overexpression of ISL1 in hMSCs promotes cell survival in a model of MI and enhances their paracrine function to protect cardiomyocytes, which may be mediated through IGFBP3. ISL1 overexpression in hMSCs may represent a novel strategy for enhancing the effectiveness of stem cell therapy after MI.

Project description:BACKGROUND:Ischemia related inflammation is the most critical factor for the survival of transplanted mesenchymal stem cells (MSCs), and strategies for controlling excessive inflammation after acute myocardial infarction (AMI) are essential and necessary for cell transplantation therapy. Our present study tested the effect of decreased Ly6C(high) monocytes on mouse MSCs transplantation after AMI. METHODS:BALB/c AMI mice were treated systemically with a CCR2 antagonist (RS 504393, 2 mg/kg, subcutaneously) or normal saline (control group). Next, 10(5) EdU-labeled MSCs were administered by intramyocardial injection to the mice in each group. TUNEL kits were used to identify the apoptotic cardiomyocytes in the infarct. The slides of the infarct border zone were stained with wheat germ agglutinin to measure the vessel density, and anti-myosin heavy chain eFluor 660 was used to measure the cardiac myosin-positive area. A transwell chamber was used to examine the interactions between Ly6C(high) monocytes and MSCs. The inflammatory cytokines expressed by Ly6C(high) monocytes and the SDF-1 expressed by MSCs were detected using ELISA kits. MSC viability was further examined by MTT and mitochondrial membrane potential assays by flow cytometry using JC-1 kits. RESULTS:We first observed the increased survival of transplanted MSCs (11.2 ± 3.4/mm(2) vs. 3.5 ± 1.6/mm(2), p < 0.001), and the decreased apoptosis of cardiomyocytes (11.20% ± 3.55% vs. 20.51% ± 8.17%, p < 0.001) in the infarcts at 3 days in the CCR2 antagonist group. An increased number of capillaries and small arterioles (139.6 ± 21.7/mm(2) vs. 95.4 ± 17.6/mm(2), p < 0.001) and an increased cardiac myosin-positive area (17.9% ± 6.6% vs. 11.8% ± 3.5%, p < 0.001) were also observed in the infarct zone at 21 days post MSC infusion in the CCR2 antagonist group. In addition, a significantly increased LvEF% (50.17 ± 10.06 vs. 45.44 ± 9.45, p < 0.001) was detected at the same time compared to the control mice. We further demonstrated that both the mitochondrial membrane potential of the MSCs (0.45 ± 0.11 vs. 3.4 ± 0.3, p < 0.001) and stromal cell-derived factor-1 (SDF-1) secreted by the MSCs significantly decreased (80.77 ± 39.02 pg/ml vs. 435.5 ± 77.41 pg/ml, p < 0.001) when co-cultured with Ly6C(high) monocytes. This is possibly mediated by the over-expressed cytokines secreted by the Ly6C(high) monocytes compared to the Ly6C(low) monocytes, including IL-1 (139.45 ± 30.44 vs. 80.05 ± 19.33, p < 0.001), IL-6 (187.82 ± 40.43 vs. 135.5 ± 22.09, p < 0.001), TNF-α (121.77 ± 31.65 vs. 75.3 ± 22.14, p < 0.001) and IFN-γ (142.46 ± 27.55 vs. 88.25 ± 19.91, p < 0.001).

Dataset Information

Long noncoding RNA LUCAT1 enhances the survival and therapeutic effects of mesenchymal stromal cells post-myocardial infarction.

Publications

Long noncoding RNA LUCAT1 enhances the survival and therapeutic effects of mesenchymal stromal cells post-myocardial infarction.

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