Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction
Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction
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DOI：
10.1161/circulationaha.107.718718
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发表时间：
2007-10-09
期刊：
影响因子：
37.8
通讯作者：
Lee, Richard T.
中科院分区：
文献类型：
--
作者：
Segers, Vincent F. M.;Tokunou, Tomotake;Lee, Richard T.
背景-局部传递趋化因子是组织再生的一种新方法。然而，成功的趋化因子蛋白递送受到障碍的挑战，包括趋化因子的快速扩散和在受伤组织中被激活的蛋白酶对趋化因子的裂解。基质细胞衍生因子- 1 （SDF- 1）是一种具有良好特征的趋化因子，可吸引干细胞，因此是促进再生的有力候选因子。然而，SDF- 1被外肽酶和基质金属蛋白酶- 2切割，产生一种与某些形式的痴呆有关的神经毒素。方法和结果-我们设计了一种新的趋化因子S- SDF-1 (S4V)，它可以抵抗基质金属蛋白酶- 2和外肽酶的切割，但保留趋化生物活性，降低天然SDF-1的神经毒性潜力。为了传递S- SDF- 1(S4V)，我们表达并纯化了融合蛋白，将趋化因子连接到自组装肽上，形成纳米纤维并允许局部传递。心肌梗死后心肌内输送S- SDF- 1（S4V）可招募CXCR4(+)/c-Kit（+）干细胞（每切片46+/-7至119+/-18个细胞），并增加毛细血管密度（从每1mm 169+/-42至283 +/- 27个(2)）。此外，在一项对176只心肌梗死大鼠的随机盲法研究中，纳米纤维递送蛋白酶抗性S- SDF- 1（S4V）改善了心功能（射血分数从34.0 +/- 2.5%增加到50.7 +/- 3.1%），而天然SDF- 1没有任何有益作用。结论：一种新的蛋白酶抗性SDF- 1和纳米纤维介导的递送促进了心肌梗死后干细胞的募集和心脏功能的改善。这些数据表明，通过局部趋化因子的传递来驱动干细胞的趋化性是一种很有前途的组织再生新策略。
Background - Local delivery of chemotactic factors represents a novel approach to tissue regeneration. However, successful chemokine protein delivery is challenged by barriers including the rapid diffusion of chemokines and cleavage of chemokines by proteases that are activated in injured tissues. Stromal cell - derived factor- 1 ( SDF- 1) is a well- characterized chemokine for attracting stem cells and thus a strong candidate for promoting regeneration. However, SDF- 1 is cleaved by exopeptidases and matrix metalloproteinase- 2, generating a neurotoxin implicated in some forms of dementia.Methods and Results - We designed a new chemokine called S- SDF- 1( S4V) that is resistant to matrix metalloproteinase- 2 and exopeptidase cleavage but retains chemotactic bioactivity, reducing the neurotoxic potential of native SDF-1. To deliver S- SDF- 1( S4V), we expressed and purified fusion proteins to tether the chemokine to self- assembling peptides, which form nanofibers and allow local delivery. Intramyocardial delivery of S- SDF- 1( S4V) after myocardial infarction recruited CXCR4(+)/c-Kit(+) stem cells (46+/-7 to 119+/-18 cells per section) and increased capillary density ( from 169+/-42 to 283 +/- 27 per 1 mm(2)). Furthermore, in a randomized, blinded study of 176 rats with myocardial infarction, nanofiber delivery of the protease- resistant S- SDF- 1( S4V) improved cardiac function ( ejection fraction increased from 34.0 +/- 2.5% to 50.7 +/- 3.1%), whereas native SDF- 1 had no beneficial effects.Conclusions - The combined advances of a new, protease- resistant SDF- 1 and nanofiber- mediated delivery promoted recruitment of stem cells and improved cardiac function after myocardial infarction. These data demonstrate that driving chemotaxis of stem cells by local chemokine delivery is a promising new strategy for tissue regeneration.