Department of Molecular Pathology, Osaka University Graduate School of Medicine, Suita, Japan.
Cardiovasc Res. 2013 Jul 1;99(1):102-10. doi: 10.1093/cvr/cvt088. Epub 2013 Apr 23.
Transplantation of myoblast sheets is a promising therapy for enhancing cardiac function after heart failure. We have previously demonstrated that a 7-amino-acid sequence (Ser-Val-Val-Tyr-Gly-Leu-Arg) derived from osteopontin (SV peptide) induces angiogenesis. In this study, we evaluated the long-term therapeutic effects of myoblast sheets secreting SV in a rat infarction model.
Two weeks after ligation of the left anterior descending coronary artery, the animals were divided into the following three groups: a group transplanted with wild-type rat skeletal myoblast sheets (WT-rSkMs); a group transplanted with SV-secreting myoblast sheets (SV-rSkMs); and a control group (ligation only). We evaluated cardiac function, histological changes, and smooth muscle actin (SMA) expression through transforming growth factor-β (TGF-β) signalling. The ejection fraction and fractional shortening were significantly better, and the enlargement of end-systolic volume was also significantly attenuated in the SV-rSkM group. Left ventricular remodelling, including fibrosis and hypertrophy, was significantly attenuated in the SV-rSkM group, and SV secreted by the myoblast sheets promoted angiogenesis in the infarcted border area. Furthermore, many clusters of SMA-positive cells were observed in the infarcted areas in the SV-rSkM group. In vitro SMA expression was increased when SV was added to the isolated myocardial fibroblasts. Moreover, SV bound to the TGF-β receptor, and SV treatment activated TGF-β receptor-Smad signalling.
The SV-secreting myoblast sheets facilitate a long-term improvement in cardiac function. The SV can induce differentiation of fibroblasts to myofibroblasts via TGF-β-Smad signalling. This peptide could possibly be used as a bridge to heart transplantation or as an ideal peptide drug for cardiac regeneration therapy.
肌母细胞片移植是增强心力衰竭后心脏功能的一种很有前途的治疗方法。我们之前已经证明，来源于骨桥蛋白的 7 个氨基酸序列（丝氨酸-缬氨酸-缬氨酸-酪氨酸-甘氨酸-亮氨酸-精氨酸）（SV 肽）可诱导血管生成。在这项研究中，我们评估了 SV 分泌的肌母细胞片在大鼠梗死模型中的长期治疗效果。
结扎左前降支冠状动脉 2 周后，将动物分为以下三组：一组移植野生型大鼠骨骼肌母细胞片（WT-rSkMs）；一组移植 SV 分泌的肌母细胞片（SV-rSkMs）；一组为对照组（仅结扎）。我们通过转化生长因子-β（TGF-β）信号通路评估心脏功能、组织学变化和平滑肌肌动蛋白（SMA）表达。SV-rSkM 组的射血分数和缩短分数明显改善，收缩末期容积的增大也明显减弱。SV-rSkM 组左心室重构，包括纤维化和肥大，明显减轻，肌母细胞片分泌的 SV 促进梗死边缘区血管生成。此外，SV-rSkM 组梗死区观察到许多 SMA 阳性细胞簇。SV 被添加到分离的心肌成纤维细胞中时，SMA 的体外表达增加。此外，SV 与 TGF-β 受体结合，SV 处理激活 TGF-β 受体-Smad 信号通路。
SV 分泌的肌母细胞片可长期改善心脏功能。SV 可通过 TGF-β-Smad 信号通路诱导成纤维细胞向肌成纤维细胞分化。该肽可能可用作心脏移植的桥梁或作为心脏再生治疗的理想肽类药物。
