转化的乳酸菌能加速伤口愈合

Title：
Accelerated wound healing in mice by on-site production and delivery of CXCL12 by transformed lactic acid bacteria

DOI：
10.1073/pnas.1716580115

Abstract：
Impaired wound closure is a growing medical problem associated with metabolic diseases and aging. Immune cells play important roles in wound healing by following instructions from the microenvironment. Here, we developed a technology to bioengineer the wound microenvironment and enhance healing abilities of the immune cells. This resulted in strongly accelerated wound healing and was achieved by transforming Lactobacilli with a plasmid encoding CXCL12. CXCL12-delivering bacteria administrated topically to wounds in mice efficiently enhanced wound closure by increasing proliferation of dermal cells and macrophages, and led to increased TGF-β expression in macrophages. Bacteria-produced lactic acid reduced the local pH, which inhibited the peptidase CD26 and consequently enhanced the availability of bioactive CXCL12. Importantly, treatment with CXCL12-delivering Lactobacilli also improved wound closure in mice with hyperglycemia or peripheral ischemia, conditions associated with chronic wounds, and in a human skin wound model. Further, initial safety studies demonstrated that the topically applied transformed bacteria exerted effects restricted to the wound, as neither bacteria nor the chemokine produced could be detected in systemic circulation. Development of drugs accelerating wound healing is limited by the proteolytic nature of wounds. Our technology overcomes this by on-site chemokine production and reduced degradation, which together ensure prolonged chemokine bioavailability that instructed local immune cells and enhanced wound healing.

All Authors：
Evelina Vågesjö,Emelie Öhnstedt,Anneleen Mortier,Hava Lofton,Fredrik Huss,Paul Proost,Stefan Roos,Mia Phillipson

First Authors：
Evelina Vågesjö

Correspondence：
Mia Phillipson

摘要：

     将编码趋化因子CXCL12（基质细胞衍生因子1α）的质粒转化到罗伊氏乳杆菌中， 将转化菌使用在小鼠伤口部位，观察发现可促进伤口处表皮细胞和巨噬细胞增殖，并增加后者的TGF-β表达，有效改善伤口愈合；分析发现是转化菌产生的乳酸降低伤口局部pH，抑制了肽酶CD26，从而增加CXCL12的生物利用度；在人类皮肤模型和高血糖症或外周局部缺血的小鼠模型中，转化菌也能改善伤口愈合；另外，该方法安全性良好，影响仅限于伤口部位而不会进入循环系统。