Medical Scientist Training Program (MD/PhD), University of Minnesota, Minneapolis, Minnesota, USA.
Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.
Stem Cells. 2021 Jul;39(7):897-903. doi: 10.1002/stem.3356. Epub 2021 Mar 1.
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, incurable blistering skin disease caused by biallelic mutations in type VII collagen (C7). Advancements in treatment of RDEB have come from harnessing the immunomodulatory potential of mesenchymal stem cells (MSCs). Although human bone marrow-derived MSC (BM-MSC) trials in RDEB demonstrate improvement in clinical severity, the mechanisms of MSC migration to and persistence in injured skin and their contributions to wound healing are not completely understood. A unique subset of MSCs expressing ATP-binding cassette subfamily member 5 (ABCB5) resides in the reticular dermis and exhibits similar immunomodulatory characteristics to BM-MSCs. Our work aimed to test the hypothesis that skin-derived ABCB5+ dermal MSCs (DSCs) possess superior skin homing ability compared to BM-MSCs in immunodeficient NOD-scid IL2rgamma (NSG) mice. Compared to BM-MSCs, peripherally injected ABCB5+ DSCs demonstrated superior homing and engraftment of wounds. Furthermore, ABCB5+ DSCs vs BM-MSCs cocultured with macrophages induced less anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) production. RNA sequencing of ABCB5+ DSCs compared to BM-MSCs showed unique expression of major histocompatibility complex class II and Homeobox (Hox) genes, specifically HOXA3. Critical to inducing migration of endothelial and epithelial cells for wound repair, increased expression of HOXA3 may explain superior skin homing properties of ABCB5+ DSCs. Further discernment of the immunomodulatory mechanisms among MSC populations could have broader regenerative medicine implications beyond RDEB treatment.
隐性营养不良型大疱性表皮松解症（RDEB）是一种罕见的、无法治愈的水疱性皮肤病，由 VII 型胶原（C7）的双等位基因突变引起。RDEB 治疗的进展来自于利用间充质干细胞（MSCs）的免疫调节潜能。尽管 RDEB 中的人骨髓源性 MSC（BM-MSC）试验表明临床严重程度有所改善，但 MSCs 向损伤皮肤迁移和持续存在的机制及其对伤口愈合的贡献尚不完全清楚。一个独特的 MSC 亚群表达 ABC 转运蛋白家族成员 5（ABCB5），位于网状真皮中，表现出与 BM-MSCs 相似的免疫调节特征。我们的工作旨在检验以下假设：与 BM-MSCs 相比，皮肤来源的 ABCB5+真皮间充质干细胞（DSCs）在免疫缺陷 NOD-scid IL2rgamma（NSG）小鼠中具有更好的皮肤归巢能力。与 BM-MSCs 相比，外周注射的 ABCB5+DSCs 表现出更好的归巢和对伤口的植入能力。此外，与巨噬细胞共培养时，ABCB5+DSCs 比 BM-MSCs 诱导产生更少的抗炎性白细胞介素 1 受体拮抗剂（IL-1RA）。与 BM-MSCs 相比，ABCB5+DSCs 的 RNA 测序显示主要组织相容性复合体 II 和同源盒（Hox）基因，特别是 HOXA3 的独特表达。HOXA3 的表达增加对于诱导内皮细胞和上皮细胞迁移以修复伤口至关重要，这可能解释了 ABCB5+DSCs 具有更好的皮肤归巢特性。对 MSC 群体之间的免疫调节机制的进一步研究可能会对 RDEB 治疗以外的再生医学产生更广泛的影响。
