Friedman Ryan M, Brown Elizabeth A, Bonelli Hannah M, Gupta Yashna, Aronson Matthew R, McDaid Kendra, Oh Hannah M, Bandora Eiman Abu, Zur Karen B, Gottardi Riccardo
Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
Division of Otolaryngology, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
bioRxiv. 2025 Jun 28:2025.06.25.661429. doi: 10.1101/2025.06.25.661429.
Vocal fold (VF) scarring is a leading cause of poor voice, yet no therapies exist to prevent its progression. Current treatments, such as intracordal steroid injections, offer limited efficacy and carry significant off-target toxicities. To identify targeted anti-scarring strategies, we performed transcriptomics of human VF myofibroblasts, the cellular drivers of VF scarring, and identified the proteoglycan decorin (DCN) as downregulated in activated myofibroblasts. We also show a time-dependent decrease in DCN during fibrotic wound healing in a preclinical rat model of VF scarring. Administration of DCN suppressed VF myofibroblast activation by reducing pro-fibrotic gene expression, α-smooth muscle actin (α-SMA) levels, and cell contractility. DCN was encapsulated in hyaluronic acid microgels for sustained protein release for 3-4 weeks. In a rat model of VF scarring, DCN-loaded microgels prevented hallmark features of scarring, including collagen deposition and myofibroblast activation. These findings highlight DCN as a promising therapeutic and provide a sustained delivery platform with translational potential against VF scarring.
声带瘢痕是嗓音不佳的主要原因，但目前尚无预防其进展的治疗方法。目前的治疗方法，如声带内类固醇注射，疗效有限且具有显著的非靶向毒性。为了确定有针对性的抗瘢痕策略，我们对人声带肌成纤维细胞（声带瘢痕形成的细胞驱动因素）进行了转录组学分析，并确定蛋白聚糖核心蛋白聚糖（DCN）在活化的肌成纤维细胞中表达下调。我们还在声带瘢痕形成的临床前大鼠模型中显示，在纤维化伤口愈合过程中DCN呈时间依赖性下降。给予DCN可通过降低促纤维化基因表达、α平滑肌肌动蛋白（α-SMA）水平和细胞收缩性来抑制声带肌成纤维细胞活化。DCN被包裹在透明质酸微凝胶中，可实现3-4周的持续蛋白质释放。在声带瘢痕形成的大鼠模型中，负载DCN的微凝胶可预防瘢痕形成的标志性特征，包括胶原沉积和肌成纤维细胞活化。这些发现突出了DCN作为一种有前景的治疗方法，并提供了一个具有转化潜力的针对声带瘢痕形成的持续递送平台。
