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Pluripotent Stem Cell Derived Cardiac Cells for Myocardial Repair
Published on: February 3, 2017
The stem cell adjuvant with Exendin-4 repairs the heart after myocardial infarction via STAT3 activation
Jianfeng Liu1, Haibin Wang, Yan Wang
1Department of Cardiology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China; Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences, Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, China.
Insights
Exendin-4 improves the survival of transplanted adipose-derived stem cells (ADSCs) in myocardial infarction models. This enhances cardiac function and regeneration by reducing cell death and promoting differentiation.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Cell Biology
Background:
- Stem cell therapy for myocardial infarction faces challenges due to poor cell survival in the ischemic environment.
- Exendin-4 exhibits cardioprotective properties, suggesting potential benefits in conjunction with stem cells.
Purpose of the Study:
- To investigate the combined effects of Exendin-4 and adipose-derived stem cells (ADSCs) on stem cell survival and myocardial repair after infarction.
- To elucidate the underlying mechanisms of Exendin-4's protective effects on ADSCs.
Main Methods:
- Myocardial infarction was induced in rats, followed by injection of ADSCs with or without Exendin-4 treatment.
- In vivo bioluminescence imaging tracked ADSC survival; assessments included oxidative stress, apoptosis, fibrosis, cardiac function, and cell differentiation.
- In vitro experiments exposed ADSCs to an ischemic environment (H2O2/SD) to evaluate Exendin-4's effects on apoptosis, paracrine signaling, and key protein expressions (STAT3, Akt, ERK1/2, Bcl-2, Bax).
Main Results:
- Exendin-4 significantly enhanced the survival of transplanted ADSCs in vivo.
- Combined treatment reduced oxidative stress, apoptosis, and fibrosis, while improving myocardial viability, cardiac function, and ADSC differentiation into cardiomyocytes and vascular smooth muscle cells.
- In vitro, Exendin-4 decreased ADSC apoptosis, boosted their paracrine effect, activated STAT3 signaling via Akt and ERK1/2 phosphorylation, and modulated Bcl-2/Bax expression.
Conclusions:
- Exendin-4 improves transplanted ADSC survival and therapeutic efficacy in myocardial infarction models.
- The mechanism involves STAT3 activation through Akt and ERK1/2 phosphorylation, leading to reduced apoptosis and enhanced paracrine function.
- Exendin-4 shows promise for enhancing stem cell-based heart regeneration strategies.
Abstract:
The poor survival of cells in ischaemic myocardium is a major obstacle for stem cell therapy. Exendin-4 holds the potential of cardioprotective effect based on its pleiotropic activity. This study investigated whether Exendin-4 in conjunction with adipose-derived stem cells (ADSCs) could improve the stem cell survival and contribute to myocardial repairs after infarction. Myocardial infarction (MI) was induced by the left anterior descending artery ligation in adult male Sprague-Dawley rats. ADSCs carrying double-fusion reporter gene [firefly luciferase and monomeric red fluorescent protein (fluc-mRFP)] were quickly injected into border zone of MI in rats treated with or without Exendin-4. Exendin-4 enhanced the survival of transplanted ADSCs, as demonstrated by the longitudinal in vivo bioluminescence imaging. Moreover, ADSCs adjuvant with Exendin-4 decreased oxidative stress, apoptosis and fibrosis. They also improved myocardial viability and cardiac function and increased the differentiation rates of ADSCs into cardiomyocytes and vascular smooth muscle cells in vivo. Then, ADSCs were exposed to hydrogen peroxide/serum deprivation (H(2)O(2)/SD) to mimic the ischaemic environment in vitro. Results showed that Exendin-4 decreased the apoptosis and enhanced the paracrine effect of ADSCs. In addition, Exendin-4 activated signal transducers and activators of transcription 3 (STAT3) through the phosphorylation of Akt and ERK1/2. Furthermore, Exendin-4 increased the anti-apoptotic protein Bcl-2, but decreased the pro-apoptotic protein Bax of ADSCs. In conclusion, Exendin-4 could improve the survival and therapeutic efficacy of transplanted ADSCs through STAT3 activation via the phosphorylation of Akt and ERK1/2. This study suggests the potential application of Exendin-4 for stem cell-based heart regeneration.
