Preconditioned adipose-derived stem cells ameliorate cardiac fibrosis by regulating macrophage polarization in infarcted rat hearts through the PI3K/STAT3 pathway
| Autor: | Shinn Zong Lin, Po Cheng Lin, Ming Hsi Chuang, Tzyy-Wen Chiou, Chi Hsuan Chuang, Chun-Hung Chen, Horng-Jyh Harn, Tsung Ming Lee |
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| Rok vydání: | 2019 |
| Předmět: |
Male
STAT3 Transcription Factor 0301 basic medicine Cardiotonic Agents Cardiac fibrosis Morpholines Myocardial Infarction Macrophage polarization Adipose tissue Lithium Pharmacology Pathology and Forensic Medicine Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Adipocytes medicine Animals Humans Rats Wistar Molecular Biology Protein kinase B Cells Cultured PI3K/AKT/mTOR pathway Cardioprotection Chemistry Myocardium Stem Cells Cell Biology Macrophage Activation M2 Macrophage medicine.disease Fibrosis 030104 developmental biology Chromones Phthalic Anhydrides 030220 oncology & carcinogenesis Stem cell Signal Transduction |
| Zdroj: | Laboratory Investigation. 99:634-647 |
| ISSN: | 0023-6837 |
| DOI: | 10.1038/s41374-018-0181-x |
| Popis: | Stem cells can modify macrophage phenotypes; however, the mechanisms remain unclear. We investigated whether n-butylidenephthalide (BP) primed adipose-derived stem cells (ADSCs) attenuated cardiac fibrosis via regulating macrophage phenotype by a PI3K/STAT3-dependent pathway in postinfarcted rats. Male Wistar rats after coronary ligation were allocated to receive either intramyocardial injection of vehicle, ADSCs (1 × 106 cells), BP-preconditioned ADSCs, (BP + lithium)-preconditioned ADSCs, (BP + LY294002)-preconditioned ADSCs, and (BP + S3I-201)-preconditioned ADSCs. ADSCs were primed for 16 h before implantation. BP-pretreated ADSCs increased the cell viability compared with naive ADSCs in the in vitro experiments. Infarct sizes were similar among the infarcted groups at the acute and chronic stages of infarction. At day 3 after infarction, post-infarction was associated with increased M1 macrophage infiltration, which was inhibited by administering naive ADSCs. Compared with naive ADSCs, BP-preconditioned ADSCs provided a significant increase of Akt and STAT3 phosphorylation, STAT3 activity, STAT3 nuclear translocation, myocardial IL-10 levels, and the percentage of M2 macrophage infiltration. The effects of BP on M2 polarization were reversed by LY294002 or S3I-201. Furthermore, the phosphorylation of both Akt and STAT3 was abolished by LY294002, whereas Akt phosphorylation was not affected following the inhibition of STAT3. The addition of lithium did not have additional effects compared with BP alone. After 4 weeks of implantation, ADSCs remained in the myocardium, and reduced fibrosis and improved cardiac function. BP-preconditioned ADSCs provided superior cardioprotection, greater ADSC engraftment, and antifibrotic effects compared with naive ADSCs. These results suggest that BP-pretreated ADSCs polarize macrophages into M2 cells more efficiently than naive ADSCs via the PI3K/STAT3 pathway. |
| Databáze: | OpenAIRE |
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