Interrogation of RDEB Epidermal Allografts after BMT Reveals Coexpression of Collagen VII and Keratin 15 with Proinflammatory Immune Cells and Fibroblasts.
Interrogation of RDEB Epidermal Allografts after BMT Reveals Coexpression of Collagen VII and Keratin 15 with Proinflammatory Immune Cells and Fibroblasts.
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DOI：
10.1016/j.jid.2022.01.034
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发表时间：
2022-09
影响因子：
6.5
通讯作者：
Tolar, Jakub
中科院分区：
文献类型：
--
作者：
Riedl, Julia A.;Riddle, Megan;Xia, Lily;Eide, Cindy;Boull, Christina;Ebens, Christen L.;Tolar, Jakub
隐性营养不良性大疱性表皮松解症 (RDEB) 是一种破坏性的遗传性皮肤病，其特征是 VII 型胶原蛋白功能失调，导致皮肤、粘膜和胃肠道上皮起泡。 RDEB 无法治愈，但通过骨髓移植 (BMT) 和随后来自 BMT 供体的同种异体表皮移植已经实现了临床表型的改善。这些患者的同种异体表皮移植在治疗后长达三年内减少了伤口表面积。本研究旨在确定负责伤口愈合和皮肤完整性持久性的表皮同种异体移植细胞的表型。我们发现表皮同种异体移植物提供了共表达胶原蛋白 VII 和基底干细胞标志物角蛋白 15 的基底角质形成细胞。通过单细胞 RNA 测序对 RDEB 全层皮肤活检进行表征，发现了可能由 RDEB 皮肤局部环境驱动的促炎免疫和成纤维细胞表型。肌成纤维细胞群的存在进一步凸显了这一点，而在健康对照人类皮肤中尚未描述过这种情况。最后，我们发现表达促纤维化基因骨膜素（POSTN）的炎症成纤维细胞，这可能与鳞状细胞癌的发展有关，鳞状细胞癌是 RDEB 的一种常见致命并发症，缺乏治疗方法。总之，这项研究为未来 RDEB 研究和治疗提供了见解和目标。
Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis characterized by dysfunctional collagen VII protein resulting in epithelial blistering of the skin, mucosa, and gastrointestinal tract. There is no cure for RDEB, but improvement of clinical phenotype has been achieved with bone marrow transplant (BMT) and subsequent epidermal allografting from the BMT donor. Epidermal allografting of these patients has decreased wound surface area for up to three years post treatment. This study aimed to determine the phenotype of the epidermal allograft cells responsible for durable persistence of wound healing and skin integrity. We found that epidermal allografts provide basal keratinocytes co-expressing collagen VII and basal stem cell marker keratin 15. Characterization of RDEB full-thickness skin biopsies with single-cell RNA sequencing uncovered pro-inflammatory immune and fibroblast phenotypes potentially driven by the local environment of RDEB skin. This is further highlighted by the presence of a myofibroblast population, which has not been described in healthy control human skin. Finally, we found inflammatory fibroblasts expressing pro-fibrotic gene periostin (POSTN), which may have implications in development of squamous cell carcinoma, a common, lethal complication of RDEB that lacks curative treatment. In conclusion, this study provides insights and targets for future RDEB studies and treatments.
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