Transplantation of insulin-like growth factor-1 laden scaffolds combined with exercise promotes neuroregeneration and angiogenesis in a preclinical muscle injury model.
Transplantation of insulin-like growth factor-1 laden scaffolds combined with exercise promotes neuroregeneration and angiogenesis in a preclinical muscle injury model.
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DOI：
10.1039/d0bm00990c
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发表时间：
2020-10-07
影响因子：
6.6
通讯作者：
Nakayama KH
中科院分区：
文献类型：
--
作者：
Alcazar CA ;Hu C ;Rando TA ;Huang NF ;Nakayama KH
尽管骨骼肌的再生能力很高，但创伤性损伤会永久性地损害骨骼肌的再生。将现成的工程仿生支架植入肌肉损伤部位以促进肌肉再生是一种有吸引力的治疗方法。各向异性纳米纤维支架提供空间图案线索以产生组织化的肌纤维，并且生长因子如胰岛素样生长因子-1（IGF-1）是肌肉再生以及血管再生的有效诱导剂。本研究的目的是测试各向异性IGF-1释放胶原支架结合自愿运动治疗急性体积性肌肉损失的疗效，重点是组织形态学效应。为了增强受损小鼠骨骼肌的血管生成和再生潜力，使用剪切介导的挤出方法制造具有对齐拓扑结构的IGF-1负载纳米纤维支架，然后进行生长因子吸附。单个支架在体外21天的过程中释放了累积总量为1244 ng ± 153 ng的IGF-1。为了测试IGF-1释放支架的生物活性，对鼠成肌细胞的肌管形成能力进行定量。在用成肌细胞接种的IGF-1释放支架上，与没有IGF-1的支架相比，形成的肌管长度长1.5倍，每个肌管含有2倍的细胞核。当植入消融的小鼠胫骨前肌时，与无IGF-1的支架治疗相比，IGF-1负载的支架与自主轮跑步一起显著增加灌注微血管的密度，增加了3倍以上。与移植到未接受运动的小鼠中的对照支架相比，在用IGF-1负载支架与运动相结合治疗的动物中也观察到增强的肌生成。此外，与不运动的相同治疗相比，当与运动配对时，用IGF-1负载的支架治疗的肌肉中成熟神经肌肉接头的丰度增加约2倍。这些发现表明，自愿运动通过增强神经血管再生来改善生长因子负载支架的再生效果，并且在设计用于治疗创伤性肌肉损伤的现成疗法中具有重要的转化意义。
Skeletal muscle regeneration can be permanently impaired by traumatic injuries, despite the high regenerative capacity of skeletal muscle. Implantation of off-the-shelf engineered biomimetic scaffolds to the site of muscle injury to enhance muscle regeneration is an attractive therapeutic approach. Anisotropic nanofibrillar scaffolds provide spatial patterning cues to create organized myofibers, and growth factors such as insulin-like growth factor-1 (IGF-1) are potent inducers of both muscle regeneration as well as vascular regeneration. The aim of this study was to test the therapeutic efficacy of anisotropic IGF-1-releasing collagen scaffolds combined with voluntary exercise for the treatment of acute volumetric muscle loss, with a focus on histomorphological effects. To enhance the angiogenic and regenerative potential of injured murine skeletal muscle, IGF-1-laden nanofibrillar scaffolds with aligned topography were fabricated using a shear-mediated extrusion approach, followed by growth factor adsorption. Individual scaffolds released a cumulative total of 1244 ng ± 153 ng of IGF-1 over the course of 21 days in vitro. To test the bioactivity of IGF-1-releasing scaffolds, the myotube formation capacity of murine myoblasts was quantified. On IGF-1-releasing scaffolds seeded with myoblasts, the resulting myotubes formed were 1.5-fold longer in length and contained 2-fold greater nuclei per myotube, when compared to scaffolds without IGF-1. When implanted into the ablated murine tibialis anterior muscle, the IGF-1-laden scaffolds, in conjunction with voluntary wheel running, significantly increased the density of perfused microvessels by greater than 3-fold, in comparison to treatment with scaffolds without IGF-1. Enhanced myogenesis was also observed in animals treated with the IGF-1-laden scaffolds combined with exercise, compared to control scaffolds transplanted into mice that did not receive exercise. Furthermore, the abundance of mature neuromuscular junctions was greater by approximately 2-fold in muscles treated with IGF-1-laden scaffolds, when paired with exercise, in comparison to the same treatment without exercise. These findings demonstrate that voluntary exercise improves the regenerative effect of growth factor-laden scaffolds by augmenting neurovascular regeneration, and have important translational implications in the design of off-the-shelf therapeutics for the treatment of traumatic muscle injury.
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3.3
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