Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Research Residency Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Sci Transl Med. 2017 Jan 4;9(371). doi: 10.1126/scitranslmed.aaf8611.
Chronic nonhealing venous leg ulcers (VLUs) are widespread and debilitating, with high morbidity and associated costs; about $15 billion is spent annually on the care of VLUs in the United States. Despite this, there is a paucity of treatments for VLUs because of the lack of pathophysiologic insight into ulcer development as well as the lack of knowledge regarding biologic actions of existing VLU-targeted therapies. The bioengineered bilayered living cellular construct (BLCC) skin substitute is a U.S. Food and Drug Administration-approved biologic treatment for healing VLUs. To elucidate the mechanisms through which the BLCC promotes healing of chronic VLUs, we conducted a clinical trial (NCT01327937) in which patients with nonhealing VLUs were treated with either standard of care (compression therapy) or the BLCC together with standard of care. Tissue was collected from the VLU edge before and 1 week after treatment, and the samples underwent comprehensive microarray mRNA and protein analyses. Ulcers treated with the BLCC skin substitute displayed three distinct transcriptomic patterns, suggesting that BLCC induced a shift from a nonhealing to a healing tissue response, involving modulation of inflammatory and growth factor signaling, keratinocyte activation, and attenuation of Wnt/β-catenin signaling. In these ways, BLCC application orchestrated a shift from the chronic nonhealing ulcer microenvironment to a distinctive healing milieu resembling that of an acute, healing wound. Our findings provide in vivo evidence in VLU patients of pathways that can be targeted in the design of new therapies to promote healing of chronic VLUs.
慢性非愈合性静脉下肢溃疡（VLUs）广泛存在且使人虚弱，发病率高，相关费用高；美国每年在 VLUs 的治疗上花费约 150 亿美元。尽管如此，由于对溃疡发展的病理生理学缺乏了解，以及对现有 VLU 靶向治疗的生物学作用缺乏认识，VLUs 的治疗方法仍然很少。生物工程双层活细胞构建体（BLCC）皮肤替代物是美国食品和药物管理局批准的治疗 VLUs 愈合的生物治疗方法。为了阐明 BLCC 促进慢性 VLUs 愈合的机制，我们进行了一项临床试验（NCT01327937），其中患有非愈合性 VLUs 的患者接受标准护理（压迫疗法）或 BLCC 联合标准护理。在治疗前和治疗后 1 周从 VLU 边缘采集组织，对样本进行了全面的微阵列 mRNA 和蛋白质分析。用 BLCC 皮肤替代物治疗的溃疡显示出三种不同的转录组模式，这表明 BLCC 诱导了从非愈合到愈合组织反应的转变，涉及炎症和生长因子信号、角质形成细胞激活以及 Wnt/β-连环蛋白信号的衰减的调节。通过这种方式，BLCC 的应用协调了从慢性非愈合性溃疡微环境向类似于急性愈合性伤口的独特愈合环境的转变。我们的研究结果为 VLU 患者提供了体内证据，证明可以针对新疗法的设计来靶向这些途径，以促进慢性 VLUs 的愈合。
