Department of Physiology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
Department of Orthopaedic Surgery, Pusan National University School of Medicine, Yangsan, Republic of Korea.
Stem Cells Transl Med. 2019 Mar;8(3):236-246. doi: 10.1002/sctm.18-0035. Epub 2018 Nov 26.
Circulating angiogenic cells (CACs) have been implicated in the repair of ischemic tissues, and their mobilization from bone marrow is known to be regulated by the activations of chemokine receptors, including CXCR2 and CXCR4. This study was conducted to investigate the role of N-acetylated proline-glycine-proline (Ac-PGP; a collagen-derived chemotactic tripeptide) on CAC mobilization and its therapeutic potential for the treatment of peripheral artery diseases. Ac-PGP was administered daily to a murine hind limb ischemia model, and the effects of Ac-PGP on blood perfusion and CAC mobilization (Sca1 Flk1 cells) into peripheral blood were assessed. Intramuscular administration of Ac-PGP significantly improved ischemic limb perfusion and increased limb salvage rate by increasing blood vessel formation, whereas Ac-PGP-induced blood perfusion and angiogenesis in ischemic limbs were not observed in CXCR2-knockout mice. In addition, Ac-PGP-induced CAC mobilization was found to occur in wild-type mice but not in CXCR2-knockout mice. Transplantation of bone marrow from green fluorescent protein (GFP) transgenic mice to wild-type mice showed bone marrow-derived cells homed to ischemic limbs after Ac-PGP administration and that GFP-positive cells contributed to the formation of ILB4-positive capillaries and α smooth muscle actin (α-SMA)-positive arteries. These results suggest CXCR2 activation in bone marrow after Ac-PGP administration improves blood perfusion and reduces tissue necrosis by inducing CAC mobilization. These findings suggest a new pharmaceutical basis for the treatment of critical limb ischemia. Stem Cells Translational Medicine 2019;8:236&246.
循环血管生成细胞(CACs)被认为参与了缺血组织的修复,其从骨髓中的动员被认为是由趋化因子受体(包括 CXCR2 和 CXCR4)的激活所调节的。本研究旨在探讨 N-乙酰化脯氨酸-甘氨酸-脯氨酸(Ac-PGP;一种源自胶原蛋白的趋化三肽)对 CAC 动员的作用及其在治疗外周动脉疾病中的治疗潜力。每天给小鼠后肢缺血模型给予 Ac-PGP,并评估 Ac-PGP 对血液灌注和 CAC 动员(Sca1 Flk1 细胞)进入外周血的影响。肌肉内给予 Ac-PGP 可显著改善缺血肢体的灌注,并通过增加血管形成提高肢体挽救率,而在 CXCR2 敲除小鼠中未观察到 Ac-PGP 诱导的缺血肢体的血液灌注和血管生成。此外,发现 Ac-PGP 诱导的 CAC 动员仅发生在野生型小鼠中,而不在 CXCR2 敲除小鼠中发生。将绿色荧光蛋白(GFP)转基因小鼠的骨髓移植到野生型小鼠中,显示在给予 Ac-PGP 后,骨髓源性细胞归巢到缺血肢体,并且 GFP 阳性细胞有助于形成 ILB4 阳性毛细血管和α平滑肌肌动蛋白(α-SMA)阳性动脉。这些结果表明,Ac-PGP 给药后骨髓中 CXCR2 的激活通过诱导 CAC 动员来改善血液灌注和减少组织坏死。这些发现为治疗严重肢体缺血提供了新的药物治疗基础。《干细胞转化医学》2019 年;8:236&246。