Enhancement of bone healing based on ex vivo gene therapy using human muscle-derived cells expressing bone morphogenetic protein 2
Enhancement of bone healing based on ex vivo gene therapy using human muscle-derived cells expressing bone morphogenetic protein 2
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DOI：
10.1089/104303402320138989
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发表时间：
2002-07-01
影响因子：
4.2
通讯作者：
Huard, J
中科院分区：
文献类型：
--
作者：
Lee, JY;Peng, HR;Huard, J
分子生物学的进步已经允许在临床环境中使用基因治疗。此外，许多报道表明骨骼肌中存在可诱导的骨祖细胞。正因为如此，我们假设骨骼肌细胞可能是传递骨诱导因子的理想载体。采用体外基因转移方法，我们用腺病毒和逆转录病毒对新鲜分离的人骨骼肌细胞进行基因工程改造，使其表达人骨形态发生蛋白2（BMP-2）。然后将这些细胞植入严重联合免疫缺陷（SCID）小鼠的非愈合性骨缺损（颅骨缺损）中。大体和组织学监测缺损的闭合。接受BMP-2产生的人类肌肉衍生细胞的小鼠在移植后4至8周经历了缺损的完全闭合。在4至8周期间，新形成的骨的重塑在组织学上是明显的。当通过荧光原位杂交分析时，在新形成的骨中发现了一小部分移植的人肌源性细胞，骨细胞通常位于新形成的骨中。这些结果表明，基因工程的人肌源性细胞主要通过递送BMP-2来增强骨愈合，而一小部分细胞似乎分化成成骨细胞。
Molecular biological advances have allowed the use of gene therapy in a clinical setting. In addition, numerous reports have indicated the existence of inducible osteoprogenitor cells in skeletal muscle. Because of this, we hypothesized that skeletal muscle cells might be ideal vehicles for delivery of bone-inductive factors. Using ex vivo gene transfer methods, we genetically engineered freshly isolated human skeletal muscle cells with adenovirus and retrovirus to express human bone morphogenetic protein 2 (BMP-2). These cells were then implanted into nonhealing bone defects (skull defects) in severe combined immune deficiency (SCID) mice. The closure of the defect was monitored grossly and histologically. Mice that received BMP-2-producing human muscle-derived cells experienced a full closure of the defect by 4 to 8 weeks posttransplantation. Remodeling of the newly formed bone was evident histologically during the 4- to 8-week period. When analyzed by fluorescence in situ hybridization, a small fraction of the transplanted human muscle-derived cells was found within the newly formed bone, where osteocytes normally reside. These results indicate that genetically engineered human muscle-derived cells enhance bone healing primarily by delivering BMP-2, while a small fraction of the cells seems to differentiate into osteogenic cells.