MC1R reduces scarring and rescues stalled healing in a novel preclinical chronic wound model
MC1R reduces scarring and rescues stalled healing in a novel preclinical chronic wound model
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MC1R 在新型临床前慢性伤口模型中减少疤痕并挽救停滞的愈合
DOI：
10.1101/2022.11.30.518516
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Rocliffe H
中科院分区：
文献类型：
--
作者：
Rocliffe H
皮肤伤口愈合通常导致疤痕；然而，慢性伤口是一种全球性的、不断升级的健康负担，造成大量发病率和死亡率。据估计，每年的医疗保险费用高达968亿美元，而且由于严重缺乏有效的治疗方法，迫切需要新的干预措施来提高治疗效果。在这项研究中，我们使用选择性激动剂BMS-470539 （MC1R- ag）评估了操纵黑素皮质素1受体（MC1R）对急性伤口愈合的影响。MC1R激动作用可在野生型小鼠中加速伤口愈合和再上皮化，而MC1Re/e小鼠则不然，因为MC1R /e小鼠含有一个无功能受体。MC1R-Ag通过促进血管生成和淋巴管生成、减少局部氧化应激和炎症以及减少疤痕的连锁效应来改善伤口灌注和淋巴引流。为了评估是否操纵MC1R将有利于病理愈合，我们开发了一种新的小鼠慢性皮肤伤口模型。由于高龄和局部氧化应激升高，这些因素在大多数人类创伤中都存在，无论其类别如何，由此产生的伤口扩大到周围组织的5倍，产生渗出液并产生脱落。与人类CWs的组织学比较显示了人类疾病的特征，包括增生性表皮、纤维性渗出物和血管炎。至关重要的是，我们的模型促进了候选疗法的体内研究，以挽救脱轨的愈合反应。我们已经发现，在使用MC1Re/e小鼠时，MC1R信号的消除会加剧CWs，并伴有渗出物和NETosis的增强。相比之下，溃疡清创后局部使用MC1R激动剂可以挽救愈合反应，这突出了MC1R激动剂作为人类CWs的候选治疗方法。我们预计我们独特的模型将成为阐明溃疡发展和持续机制的有价值的工具。
Cutaneous wound healing typically results in scarring; however, chronic wounds (CWs) represent a global and escalating health burden causing substantial morbidity and mortality. Estimated to cost Medicare up to $96.8 billion pa and with a profound paucity of effective therapeutics, novel interventions to improve healing are urgently needed. In this study, we assess the impact of manipulating the melanocortin 1 receptor (MC1R) on acute wound healing using a selective agonist, BMS-470539 (MC1R-Ag). MC1R agonism resulted in accelerated wound closure and reepithelialisation in wildtype but not MC1Re/e mice, which harbour a non-functional receptor. MC1R-Ag improved wound perfusion and lymphatic drainage by promoting angiogenesis and lymphangiogenesis, reducing local oxidative stress and inflammation with a knock-on effect of reduced scarring. To assess whether manipulating MC1R would be of benefit in pathological healing, we developed a novel murine model of chronic cutaneous wounds. By combining advanced age and locally elevated oxidative stress, factors shown to be present in most human CWs regardless of their category, resultant wounds expand 5-fold into the surrounding tissue, produce exudate and generate slough. Histological comparisons to human CWs demonstrate robust recapitulation of the hallmarks of human disease, including hyperproliferative epidermis, fibrinous exudate and vasculitis. Crucially, our model facilitates thein vivostudy of candidate therapies to rescue derailed healing responses. We have identified that abrogation of MC1R signalling, using MC1Re/e mice, exacerbates CWs with enhanced exudate and NETosis. In contrast, topical administration of an MC1R agonist following ulcer debridement rescues the healing response, highlighting MC1R agonism as a candidate therapeutic approach for human CWs. We anticipate that our unique model will become a valuable tool to elucidate mechanisms of ulcer development and persistence.
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影响因子：
16.6
作者：
Jiang D;Christ S;Correa-Gallegos D;Ramesh P;Kalgudde Gopal S;Wannemacher J;Mayr CH;Lupperger V;Yu Q;Ye H;Mück-Häusl M;Rajendran V;Wan L;Liu J;Mirastschijski U;Volz T;Marr C;Schiller HB;Rinkevich Y
通讯作者：
Rinkevich Y
影响因子：
2.9
作者：
Goh OQ;Ganesan G;Graves N;Ng YZ;Harding K;Tan KB
通讯作者：
Tan KB
影响因子：
3.1
作者：
Moore, Keith;Huddleston, Elizabeth;Harding, Keith G
通讯作者：
Harding, Keith G
影响因子：
3.7
作者：
Dhall S;Do D;Garcia M;Wijesinghe DS;Brandon A;Kim J;Sanchez A;Lyubovitsky J;Gallagher S;Nothnagel EA;Chalfant CE;Patel RP;Schiller N;Martins-Green M
通讯作者：
Martins-Green M