Supplementary Material for: Mesenchymal stromal cell-secretome for therapeutic application in skin wound healing: a systematic review of preclinical studies

Non-healing skin wounds remain a challenge in the healthcare system. In this sense, it is suggested that the secretome of mesenchymal stromal cells (MSCs) can be effective as a therapeutic strategy for regenerative medicine. Therefore, this systematic review aimed to determine the effects of treatment with secretome derived from MSCs on the healing of skin wounds in preclinical model of rodents (mice and rats). Studies were systematically retrieved from six databases and grey literature that provided 1172 records, of which 25 met the inclusion criteria for qualitative analysis. Results revealed substantial heterogeneity among studies concerning experimental designs and methodologies, resulting in a high risk of bias. Together, the selected studies reported that treatment improved wound healing by (I) accelerating wound closure and improving skin repair quality; (II) reducing inflammation by decreasing the number of cells and inflammatory cytokines, accompanied by polarization of the M2 macrophage; (III) complete re-epithelialization and epidermal reorganization; (IV) neovascularization promoted by proliferation of endothelial cells (CD34+) and increased levels of pro-angiogenic mediators; (V) better scar quality promoted by increased expression of collagen types I and III, as well as improved deposition and remodeling of collagen fibers. In conclusion, despite the need for alignment of methodological protocols and transparent reports in future studies, results show that the secretome of MSCs from different tissue sources corresponds to a promising tool of regenerative medicine for the treatment of skin wounds.

难愈性皮肤创面仍是医疗保健系统面临的一大挑战。据此，有研究提出间充质基质细胞（mesenchymal stromal cells, MSCs）的分泌组（secretome）可作为再生医学领域的有效治疗策略。为此，本系统综述旨在探究间充质基质细胞来源分泌组对啮齿类动物（小鼠与大鼠）皮肤创面愈合的干预效果。
研究人员系统检索了6个数据库及灰色文献，共获取1172条记录，其中25条符合定性分析的纳入标准。结果显示，不同研究在实验设计与方法学层面存在显著异质性，由此带来较高的偏倚风险。
纳入的研究均表明，该干预可通过以下途径改善创面愈合：（1）加速创面闭合，提升皮肤修复质量；（2）通过减少炎症细胞与炎症细胞因子的水平缓解炎症，并伴随M2型巨噬细胞（M2 macrophage）极化；（3）实现完全上皮再生与表皮重塑；（4）通过内皮细胞（endothelial cell）增殖以及促血管生成介质水平升高，促进新生血管形成；（5）通过上调I型与III型胶原蛋白的表达，优化胶原纤维的沉积与重塑，从而提升瘢痕修复质量。
综上，尽管未来研究仍需统一方法学方案并提升报告透明度，但现有结果表明，不同组织来源的间充质基质细胞分泌组是一种极具应用前景的再生医学工具，可用于皮肤创面的治疗。