Wyss Institute, Harvard University, Cambridge, MA 02138, USA.
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3287-92. doi: 10.1073/pnas.0903875106. Epub 2009 Dec 4.
Regenerative efforts typically focus on the delivery of single factors, but it is likely that multiple factors regulating distinct aspects of the regenerative process (e.g., vascularization and stem cell activation) can be used in parallel to affect regeneration of functional tissues. This possibility was addressed in the context of ischemic muscle injury, which typically leads to necrosis and loss of tissue and function. The role of sustained delivery, via injectable gel, of a combination of VEGF to promote angiogenesis and insulin-like growth factor-1 (IGF1) to directly promote muscle regeneration and the return of muscle function in ischemic rodent hindlimbs was investigated. Sustained VEGF delivery alone led to neoangiogenesis in ischemic limbs, with complete return of tissue perfusion to normal levels by 3 weeks, as well as protection from hypoxia and tissue necrosis, leading to an improvement in muscle contractility. Sustained IGF1 delivery alone was found to enhance muscle fiber regeneration and protected cells from apoptosis. However, the combined delivery of VEGF and IGF1 led to parallel angiogenesis, reinnervation, and myogenesis; as satellite cell activation and proliferation was stimulated, cells were protected from apoptosis, the inflammatory response was muted, and highly functional muscle tissue was formed. In contrast, bolus delivery of factors did not have any benefit in terms of neoangiogenesis and perfusion and had minimal effect on muscle regeneration. These results support the utility of simultaneously targeting distinct aspects of the regenerative process.
再生努力通常集中在单一因素的传递上，但很可能可以同时使用多种调节再生过程不同方面的因素（例如血管生成和干细胞激活）来影响功能性组织的再生。在涉及缺血性肌肉损伤的情况下，这种可能性得到了探讨，这种损伤通常会导致组织坏死和功能丧失。通过可注射凝胶持续递送电结合物 VEGF 以促进血管生成和胰岛素样生长因子-1（IGF1）直接促进肌肉再生和恢复缺血性啮齿动物后肢的肌肉功能的作用进行了研究。单独持续 VEGF 传递导致缺血肢体中的新血管生成，到第 3 周时组织灌注完全恢复到正常水平，同时防止缺氧和组织坏死，从而改善肌肉收缩力。单独持续 IGF1 传递被发现可增强肌肉纤维再生并保护细胞免受细胞凋亡。然而，VEGF 和 IGF1 的联合传递导致血管生成、再神经支配和肌生成的并行发生；由于刺激了卫星细胞的激活和增殖，细胞免受细胞凋亡的影响，炎症反应减弱，形成了具有高度功能性的肌肉组织。相比之下，因子的推注传递在新血管生成和灌注方面没有任何益处，对肌肉再生的影响也很小。这些结果支持同时针对再生过程不同方面的效用。
