Bacteria Engineered to Deliver CXCL12 Accelerate Wound Healing in Mice

Researchers here report on an interesting approach used to deliver a therapeutic molecule into wounds, and thereby accelerate regeneration. They engineered a common bacterial species to produce the molecule of interest, CXCL12, which is implicated in the processes of wound healing. Those processes are an intricate dance between various types of immune cell, stem cell, senescent cell and somatic cells in the injured tissue. In recent years researchers have gained an increased understanding of the scope of involvement of immune cells known as macrophages; the participation of the immune system has turned out to be much more important to the quality and pace of regeneration than was thought a few decades ago. Macrophages can adopt different states, or polarizations. Of the two commonly observed polarizations, one is inflammatory and harmful to regeneration, while the other assists regeneration. There appears to be some potential in therapies that adjust the proportions of a macrophage population in injured tissue to favor the second type - and this is one of the goals that the researchers here aimed to achieve in their study.

During the inflammation phase of wound healing, immune cells accumulate in response to alarm signals, cytokines, and chemokines released by injured or activated cells. The chemokine CXCL12 (Stromal cell-Derived Factor 1α) is associated with beneficial effects in models of cutaneous wounds and binds CXCR4 expressed by immune cells and keratinocytes. Macrophages and neutrophils represent the major immune cell populations at the wound site, where they are essential for keeping invading microorganisms at bay and also for fueling the healing process by secreting additional chemokines, growth factors, and matrix digesting enzymes. During the course of healing, macrophages shift phenotype toward an anti-inflammatory one and subsequently promote tissue restitution. This shift is induced by macrophage phagocytosis of cell debris and by microenvironmental signals such as CXCL12.

Chronic wounds are often associated with underlying pathologic processes that increase susceptibility for acquiring wounds (e.g., peripheral neuropathies) and/or reduced healing abilities as seen in persons with arterial or venous insufficiencies. Several experimental and clinical trials have investigated the effects of local application of growth factors alone or coupled to different biomaterials on different types of chronic wounds, but with modest results so far.

This study aimed to accelerate wound healing by targeting the function of immune cells through local bioengineering of the wound microenvironment. To achieve this, a technology optimized to deliver chemokines directly to wounded skin was developed, whereby lactic acid bacteria were used as vectors. Lactobacillus reuteri bacteria were transformed with a plasmid encoding the chemokine CXCL12 previously associated with beneficial effects in models of healing and blood-flow restoration. Bacteria-produced lactic acid reduced the pH in the wound and thereby potentiated the effects of the produced CXCL12 by prolonging its bioavailability. The overall result of topical wound treatment with this on-site chemokine delivery system was strongly accelerated wound closure to an extent not reported before.

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.

Link: https://doi.org/10.1073/pnas.1716580115

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