人子宫内膜干细胞通过旁分泌作用保护心肌并促进心肌再生改善大鼠心梗后心功能
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摘要
研究背景及目的：心肌梗死导致心肌细胞不可逆的损伤和丢失,是世界范围内引起充血性心力衰竭导致患者死亡的最主要原因。干细胞移植可激活内源性修复促进心肌再生,代偿损失的心肌的收缩力,是极具潜力的心肌再生疗法。大量临床试验已经显示了自体和异体干细胞移植治疗心肌梗死的有效性和安全性。近年来,研究者们提出建立高质量的“现货”异体干细胞产品来克服自体干细胞移植的不足(如分离培养周期长错过最佳治疗时间窗,干细胞生物学特性有个体差异且受患者伴随疾病影响),提高临床上干细胞移植的疗效。子宫内膜干细胞具有间充质干细胞特性,具有极低的免疫原性,可通过无创技术从年轻健康女性月经血中分离获取。因此,子宫内膜干细胞是建立“现货”异体干细胞系的理想细胞来源,但是其治疗心肌梗死的疗效以及可能的治疗机制仍不清楚。我们将人子宫内膜干细胞移植到急性心肌梗死的免疫健全大鼠,我们的研究结果表明人子宫内膜干细胞移植安全有效,其治疗机制主要为旁分泌效应。
方法和结果：我们结扎大鼠冠脉前降支造成急性心肌梗死,30分钟内将人子宫内膜干细胞经心肌注射到梗死周边区,对照组注射同等体积PBS。28天后,我们发现移植组较对照组相比心功能明显改善,血管密度更高,梗死区有更多存活心肌,但没有充分证据表明人子宫内膜干细胞分化为心肌细胞,内皮细胞或平滑肌细胞。我们检测了人子宫内膜干细胞的条件培养基,发现其中含有较高浓度的多种细胞因子。在体外,同人子宫内膜干细胞共培养可促进心肌细胞存活、进入细胞周期,促进内皮细胞形成管腔。子宫内膜干细胞移植后48小时可显著降低凋亡核的数量,激活AKT和STAT3信号通路,抑制p38途径。移植后7天我们还观察到干细胞周围有更多心肌细胞表达增殖抗原Ki67,并且募集更多c.kit日性细胞。这是首次报道人子宫内膜干细胞在异种免疫健全心脏中的治疗作用及潜在机制。
结论：人子宫内膜干细胞通过旁分泌细胞因子激活促存活信号通路保护缺血心肌,诱导心肌细胞进入细胞周期并募集心脏干细胞来促进梗死后的心肌再生。人子宫内膜干细胞的来源广泛,是建立异体“现货”干细胞产品最具潜力的种子细胞之
Background and objective: Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. Stem cell therapy holds great promise for myocardial regeneration. Autologous and allogeneic mesenchymal stem cells (MSCs) have been tested clinically, and most of the trials to date have reported safety and modest efficacy. Investigators proposed that the generation of "off the shelf" allogeneic stem cell products with selected potent may overcome limitations of autologous cells and improve the clinical outcome of stem cell therapy. Endometrial stem cells (EnSCs) with MSC characteristics are isolated from menstrual blood. A unique feature of these cells is that they can be easily obtained by noninvasive procedures from young and healthy women donors. The MSC characteristics also guarantee their immunoprevilege in allogeneic hosts. Therefore, EnSC is an ideal cell type to generate "off the shelf" cell products, but the efficacy and the mechanism of EnSCs transplantation are still unclear. Here, using an immunocompetent rat model of MI, we provide evidence that the functional benefits of EnSC transplantation is principally and possibly exclusively through paracrine effect.
Methods and Results:Human EnSCs were delivered by intramyocardial injection into rats30min after coronary ligation. EnSC therapy significantly preserved viable myocardium in the infarct zone and improved cardiac function at28days. Despite increased viable myocardium and vascular density, there was scant evidence of differentiation of EnSCs into any cardiovascular cell type. Cultured human EnSCs expressed a distinctive profile of cytokines that enhanced cell survival, proliferation and function of endothelial cells in vitro. When injected into the peri-infarct zone, human EnSCs activated AKT and STAT3but inhibited p38signal pathways. EnSC therapy decreased apoptosis and promoted cell proliferation and stem cell recruitment in vivo. This is the first study to describe EnSC therapy in an immunocompetent heart, the first comparative study of cytokine production, and the first demonstration of cardioprotection by cytokine-mediated activation of survival kinases.
Conclusions:Myocardial protection and enhanced post-infarction regeneration by EnSCs is mediated primarily by paracrine effects conferred by secreted cytokines that activate survival pathways and recruit endogenous progenitor stem cells. Menstrual blood provides a potentially limitless source of biologically competent "off the shelf" EnSCs for allogeneic myocardial regenerative medicine.
方法和结果：我们结扎大鼠冠脉前降支造成急性心肌梗死,30分钟内将人子宫内膜干细胞经心肌注射到梗死周边区,对照组注射同等体积PBS。28天后,我们发现移植组较对照组相比心功能明显改善,血管密度更高,梗死区有更多存活心肌,但没有充分证据表明人子宫内膜干细胞分化为心肌细胞,内皮细胞或平滑肌细胞。我们检测了人子宫内膜干细胞的条件培养基,发现其中含有较高浓度的多种细胞因子。在体外,同人子宫内膜干细胞共培养可促进心肌细胞存活、进入细胞周期,促进内皮细胞形成管腔。子宫内膜干细胞移植后48小时可显著降低凋亡核的数量,激活AKT和STAT3信号通路,抑制p38途径。移植后7天我们还观察到干细胞周围有更多心肌细胞表达增殖抗原Ki67,并且募集更多c.kit日性细胞。这是首次报道人子宫内膜干细胞在异种免疫健全心脏中的治疗作用及潜在机制。
结论：人子宫内膜干细胞通过旁分泌细胞因子激活促存活信号通路保护缺血心肌,诱导心肌细胞进入细胞周期并募集心脏干细胞来促进梗死后的心肌再生。人子宫内膜干细胞的来源广泛,是建立异体“现货”干细胞产品最具潜力的种子细胞之
Background and objective: Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. Stem cell therapy holds great promise for myocardial regeneration. Autologous and allogeneic mesenchymal stem cells (MSCs) have been tested clinically, and most of the trials to date have reported safety and modest efficacy. Investigators proposed that the generation of "off the shelf" allogeneic stem cell products with selected potent may overcome limitations of autologous cells and improve the clinical outcome of stem cell therapy. Endometrial stem cells (EnSCs) with MSC characteristics are isolated from menstrual blood. A unique feature of these cells is that they can be easily obtained by noninvasive procedures from young and healthy women donors. The MSC characteristics also guarantee their immunoprevilege in allogeneic hosts. Therefore, EnSC is an ideal cell type to generate "off the shelf" cell products, but the efficacy and the mechanism of EnSCs transplantation are still unclear. Here, using an immunocompetent rat model of MI, we provide evidence that the functional benefits of EnSC transplantation is principally and possibly exclusively through paracrine effect.
Methods and Results:Human EnSCs were delivered by intramyocardial injection into rats30min after coronary ligation. EnSC therapy significantly preserved viable myocardium in the infarct zone and improved cardiac function at28days. Despite increased viable myocardium and vascular density, there was scant evidence of differentiation of EnSCs into any cardiovascular cell type. Cultured human EnSCs expressed a distinctive profile of cytokines that enhanced cell survival, proliferation and function of endothelial cells in vitro. When injected into the peri-infarct zone, human EnSCs activated AKT and STAT3but inhibited p38signal pathways. EnSC therapy decreased apoptosis and promoted cell proliferation and stem cell recruitment in vivo. This is the first study to describe EnSC therapy in an immunocompetent heart, the first comparative study of cytokine production, and the first demonstration of cardioprotection by cytokine-mediated activation of survival kinases.
Conclusions:Myocardial protection and enhanced post-infarction regeneration by EnSCs is mediated primarily by paracrine effects conferred by secreted cytokines that activate survival pathways and recruit endogenous progenitor stem cells. Menstrual blood provides a potentially limitless source of biologically competent "off the shelf" EnSCs for allogeneic myocardial regenerative medicine.
引文
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