Researchers at U of T have determined that immunosuppressants used with transplant recipients slow wound repair by inhibiting the growth of cells adjacent to wounds. They have found ways to restore rapid wound repair in an in vivo animal model.
Prof Rodrigo Fernandez-Gonzalez in the Institute of Biomedical Engineering studies wound repair in the fruit fly embryo. In humans, wound repair is slowed by the immunosuppressant rapamycin, so Dr Gordana Scepanovic in his lab probed the effect of rapamycin on wound healing focusing on the protein target of rapamycin (TOR).
Scepanovic looked at two processes that happen in wound repair; the edges of the wound must be drawn together like a purse string and at the same time the cells around the wound must swell to take up the missing space from the wound.
Scepanovic found that disrupting TOR signalling with rapamycin did not affect the edges of the wound being drawn together. Instead, disrupting TOR prevented cell swelling and slowed down wound repair. Scepanovic used live microscopy and quantitative image analysis to measure wound healing dynamics and cell swelling.
In the absence of a wound, cells constantly digest and recycle small internal particles called lysosomes in a process known as autophagy. Scepanovic found that with normal TOR signalling autophagy was turned down upon wounding. Disrupting TOR signalling caused autophagy to go ahead at its normal level, inducing the cell to consume the materials that should have been used to swell the cell.
Rodrigo Fernandez-Gonzalez recognized the importance of this research from talks with colleagues at the Ted Rogers Centre for Heart Research. “When we first moved here, heart clinicians told me that surgical patients who were treated with rapamycin have difficulty healing their wounds.
“Immunosuppressants are important to prevent rejection of transplants, but transplant recipients sustain a wound from the surgical procedure, and this wound must heal rapidly to prevent infection. So how can we reactivate wound healing even in the presence of immunosuppressants?”
Fernandez-Gonzalez’ lab was able to return rapamycin-inhibited wound repair to normal levels by reducing the levels of proteins related to autophagy using RNA interference in their fly embryos.
They also saw promising results in inhibiting autophagy using the drug bafilomycin, which is known to inhibit maturation of lysosomes into autophagosomes.
The researchers’ detailed analysis of the downstream effects of the immunosuppressant rapamycin on wound healing show promise for applications to improve transplant efficacy.
These important results have been published in the journal Developmental Cell as “mTor limits autophagy to facilitate cell volume expansion and rapid wound repair in Drosophila embryos”.