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

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

Research output: Contribution to journalArticle

45 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1895-1900
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number8
DOIs
Publication statusPublished - 20 Feb 2018

Bibliographical note

Copyright © 2018 the Author(s). Published by PNAS.

Keywords

  • Animals
  • Cell Proliferation
  • Chemokine CXCL12/administration & dosage
  • Gene Expression Regulation
  • Genetic Therapy
  • Humans
  • Lactobacillus reuteri/genetics
  • Macrophages/metabolism
  • Mice
  • Plasmids
  • Skin
  • Tissue Culture Techniques
  • Transforming Growth Factor beta/metabolism
  • Wound Healing
  • Wounds and Injuries/therapy

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