Enhancement of stem cell regenerative properties by hydrogen sulfide: a novel wound dressing to augment stem cell therapies

摘要 尽管烧伤患者的护理有了显著改善，但仍有约40,000名患者 美国每年因严重烧伤而住院治疗，这是一种与慢性烧伤有关的伤害 康复和高昂的护理成本。因为伤口愈合的延迟延长了住院时间，增加了 对于感染，确定安全有效的促进伤口愈合的治疗方法将促进康复 并改善烧伤患者的预后。成体脂肪干细胞(ADSC)在临床中的应用 烧伤创面再生皮肤作为一种有效治疗方法的潜力越来越为人们所认识。 以加速愈合和恢复。然而，改善细胞对伤口的输送和ADSC活性的方法 而修复功能是提高这种正在开发的再生疗法的有效性所必需的。氢 硫化物(H_2S)是一种气态生物介体，在各种组织中具有广泛的作用。最近，它一直在 研究表明，硫化氢可以促进骨髓和脂肪来源的细胞的增殖、活性和功能 干细胞，由我们的初步数据证实。我们认为，局部硫化氢处理可以提高 ADSC治疗的再生特性和加速烧伤创面修复。然而，有效的应用 由于缺乏稳定的硫化氢供体或可局部使用的诱导剂，将硫化氢应用于伤口是具有挑战性的 以受控释放方式交付。一种基于透明质酸(HA)的生物相容水凝胶，负载了一种缓释剂. 释放硫化氢供体，已被开发并用作敷料，以促进非烧伤伤口愈合。此外，一个 研制了包埋MSC的HA-水凝胶。在本项目中，一种双负载HA水凝胶， 含有硫化氢供体和ADSC，将被开发并作为敷料应用于烧伤创面。我们 假设双负荷ADSC/H_2S释放敷料在烧伤创面中的应用将加速 硫化氢对ADSC存活、增殖和刺激营养因子产生的影响 治疗反应。这将通过以下目标进行测试：1)证明ADSC的改进 双负载ADSC-H_2S释放创面敷料对绵羊重症烧伤创面的治疗作用 损伤和自体移植；2)表征硫化氢对ADSC特性和功能的影响 在正常和低氧条件下(缺血创伤环境模型)促进伤口愈合；3) 证明硫化氢可提高人ADSC治疗烧伤创面的疗效。这 该项目不仅将确定一种新的伤口敷料来促进愈合，而且还将确立硫化氢作为一种 加强再生干细胞治疗烧伤和其他疾病的治疗 深入了解硫化氢对ADSC生物学的调控作用。

Abstract Despite significant improvements in the care of burn patients, approximately 40,000 patients are hospitalized yearly in the United States for the treatment of severe burns, an injury associated with slow recovery and high costs of care. Because delayed wound healing prolongs hospitalization and increases risk of infection, identification of safe and effective treatments that promote wound healing would facilitate recovery and improve outcomes for burn patients. The application of adult adipose-derived stem cells (ADSC) to regenerate skin in burn wounds is becoming increasingly recognized for its potential as an effective treatment to accelerate healing and recovery. However, methods to improve cell delivery to wounds, and ADSC viability and reparative functions are needed to increase the efficacy of this developing regenerative therapy. Hydrogen sulfide (H2S) is a gaseous biological mediator with a range of effects in various tissues. Recently it has been shown that H2S can increase the proliferation, viability and functions of bone marrow- and adipose-derived stem cells, confirmed by our preliminary data. We propose that local H2S treatment can enhance the regenerative properties of ADSC therapy and accelerate burn wound repair. However, the effective application of H2S to wounds is challenging due to a lack of stable H2S donors or inducing agents that can be topically delivered with controlled release. A biocompatible hyaluronic acid (HA)-based hydrogel, loaded with a slow- release H2S donor, has been developed and used as a dressing to enhance non-burn wound healing. Further, a HA-hydrogel with encapsulated MSC has been developed. In this project, a dual-loaded HA-based hydrogel, containing both an H2S donor and ADSC, will be developed and applied to burn wounds as a dressing. We hypothesize that application of a dual-loaded ADSC/H2S-releasing dressing to burn wounds will accelerate healing through effects of H2S on ADSC survival, proliferation and production of trophic factors that stimulate healing responses. This will be tested through the following aims: 1) To demonstrate improvement of ADSC wound therapy by H2S using dual-loaded ADSC-H2S releasing wound dressings in an ovine model of severe injury and autologous grafting.; 2) To characterize the effects of H2S on ADSC properties and functions that promote wound healing, under normal and hypoxic conditions (model of ischemic wound environment); 3) To demonstrate that H2S increases therapeutic efficacy of human ADSC for the treatment of burn wounds. This project will not only identify a novel wound dressing to improve healing, but it will also establish H2S as a treatment to augment regenerative stem cell therapies for the treatment of burns and other diseases and will provide insight into regulation of ADSC biology by H2S.