Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering disease resulting from a lack of type VII collagen production. Recent clinical trials have shown efficacy of bone marrow-derived mesenchymal stem cells (BM-MSCs) in the treatment of epidermolysis bullosa, including improved basement membrane restructuring and cutaneous wound healing. The mechanism as to how type VII collagen is transferred from donor stem cell to recipient RDEB cells has not been defined. Here, we submit the model that BM-MSC-derived extracellular vesicles serve at least two roles: 1) to help transport type VII collagen within the extracellular space; and 2) to feed RDEB fibroblasts with messenger RNA that codes for type VII collagen, resulting in COL7A1 translation and synthesis of type VII collagen alpha chain proteins by RDEB fibroblasts. Utilizing a chemoselective ligation detection method, we found RDEB cells that were treated simultaneously with BM-MSC EVs and an L-methionine analog, L-homopropargylglycine (HPG), synthesized collagen VII alpha chain protein that contained the alkyne group of HPG to react (i.e. undergo the Click-iT® reaction) with azide-modified Alexa 594, suggesting de novo synthesis of type VII collagen by RDEB fibroblasts. Thus, our results support a model in which BM-MSC EVs help increase type VII collagen levels available to recipient cells by 1) donating BM-MSC type VII collagen protein and 2) inducing RDEB fibroblasts to make their own type VII collagen protein. These findings allow us to hypothesize that the secretome of BM-MSCs could have therapeutic value in the treatment of RDEB-related skin disorders.

隐性营养不良性大疱性表皮松解症（RDEB）是由于缺乏VII型胶原蛋白产生而引起的严重水疱性疾病。最近的临床试验表明，骨髓间充质干细胞（BM-MSC）在治疗大疱性表皮松解中的功效，包括改善的基底膜结构和皮肤伤口愈合。关于VII型胶原如何从供体干细胞转移至受体RDEB细胞的机制尚未确定。在这里，我们提出了模型，即BM-MSC衍生的细胞外囊泡至少起两个作用：1）帮助在细胞外空间内运输VII型胶原。2）用编码VII型胶原的信使RNA为RDEB成纤维细胞喂食，从而产生COL7A1RDEB成纤维细胞翻译和合成VII型胶原α链蛋白。利用化学选择性连接检测方法，我们发现RDEB细胞同时用BM-MSC EV和L-蛋氨酸类似物L-高炔丙基甘氨酸（HPG）处理，合成的胶原VIIα链蛋白包含HPG炔基反应（即通过叠氮化物修饰的Alexa 594进行Click-iT®反应，这表明是从头开始的RDEB成纤维细胞合成VII型胶原。因此，我们的结果支持了一种模型，其中BM-MSC电动汽车通过1）捐赠BM-MSC VII型胶原蛋白和2）诱导RDEB成纤维细胞制造自己的VII型胶原蛋白，帮助增加受体细胞可利用的VII型胶原蛋白水平。这些发现使我们可以假设，BM-MSC的分泌组在治疗RDEB相关的皮肤疾病中可能具有治疗价值。