Wang Wei, Chen Liang, Zhang Yuxin, Wang Heng, Dong Dong, Zhu Jingjing, Fu Wei, Liu Tianyi
Department of Plastic and Aesthetic Surgery Huadong Hospital, Shanghai Medical College, Fudan University Shanghai China.
Institute of Pediatric Translational Medicine, Shanghai Institute of Pediatric Congenital Heart Disease, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University Shanghai China.
Bioeng Transl Med. 2023 Nov 10;9(2):e10620. doi: 10.1002/btm2.10620. eCollection 2024 Mar.
Skin wound healing often leads to scar formation, presenting physical and psychological challenges for patients. Advancements in messenger RNA (mRNA) modifications offer a potential solution for pulsatile cytokine delivery to create a favorable wound-healing microenvironment, thereby preventing cutaneous fibrosis. This study aimed to investigate the effectiveness of human adipose-derived stem cells (hADSCs) enriched with -methylpseudouridine (m1ψ) modified transforming growth factor-β3 (TGF-β3) and interleukin-10 (IL-10) mRNA in promoting scar-free healing in preclinical models. The results demonstrated that the modified mRNA (modRNA)-loaded hADSCs efficiently and temporarily secreted TGF-β3 and IL-10 proteins. In a dorsal injury model, hADSCs loaded with modRNA TGF-β3 and IL-10 exhibited multidimensional therapeutic effects, including improved collagen deposition, extracellular matrix organization, and neovascularization. In vitro experiments confirmed the ability of these cells to markedly inhibit the proliferation and migration of keloid fibroblasts, and reverse the myofibroblast phenotype. Finally, collagen degradation mediated by matrix metalloproteinase upregulation was observed in an ex vivo keloid explant culture model. In conclusion, the synergistic effects of the modRNA TGF-β3, IL-10, and hADSCs hold promise for establishing a scar-free wound-healing microenvironment, representing a robust foundation for the management of wounds in populations susceptible to scar formation.
皮肤伤口愈合通常会导致瘢痕形成，给患者带来生理和心理挑战。信使核糖核酸（mRNA）修饰技术的进步为脉冲式细胞因子递送提供了一种潜在解决方案，以创造有利的伤口愈合微环境，从而预防皮肤纤维化。本研究旨在探讨富含N6-甲基假尿苷（m1ψ）修饰的转化生长因子-β3（TGF-β3）和白细胞介素-10（IL-10）mRNA的人脂肪来源干细胞（hADSCs）在临床前模型中促进无瘢痕愈合的有效性。结果表明，负载修饰mRNA（modRNA）的hADSCs能有效且暂时地分泌TGF-β3和IL-10蛋白。在背部损伤模型中，负载modRNA TGF-β3和IL-10的hADSCs表现出多维度治疗效果，包括改善胶原沉积、细胞外基质组织和新血管形成。体外实验证实这些细胞能够显著抑制瘢痕疙瘩成纤维细胞的增殖和迁移，并逆转肌成纤维细胞表型。最后，在体外瘢痕疙瘩外植体培养模型中观察到基质金属蛋白酶上调介导的胶原降解。总之，modRNA TGF-β3、IL-10和hADSCs的协同作用有望建立无瘢痕的伤口愈合微环境，为易形成瘢痕人群的伤口管理奠定坚实基础。
