The immune system plays a key role in tissue regeneration, and the various types of immune cells, such as macrophages, can help or hinder that repair process.
Inflammation is part of the immune response, but with aging that immune response becomes deregulated and the inflammation becomes excessive. Excessive levels of inflammation generally speaking inhibit tissue regeneration, and when that inflammation is continual, as it often is in aging, this leads to a breakdown in the ability to heal injuries.
As well as a deregulated and dysfunctional immune system, aging also sees rising numbers of senescent cells which also cause inflammation. The immune system fails as we age and stops clearing away these cells, leading to a downward spiral of inflammation and increasingly poor tissue repair.
The manipulation of the types (polarization) of macrophages has been enjoying great popularity recently; we talked about it in previous articles here, here, here and here. The new research we are about to discuss is very much related to this topic. Improving healing by reducing the numbers of more aggressive and inflammatory types of macrophages present at the site of injury does appear to be a viable approach.
Reducing inflammation aids transplanted stem cell survival
In this new paper, the researchers set out to see if they could use stem cell therapies as a treatment to accelerate chronic wound healing . Chronic wounds are wounds that do not heal quickly and are sites of extreme and prolonged inflammation.
By their very nature, wound sites are an inflammatory environment; unfortunately, inflammation does not facilitate the survival of transplanted cells. The researchers hoped to inject stem cells into an injury site in order to encourage regeneration, but they knew inflammation was a barrier to this working, as inflammation kills the cells.
The researchers showed that suppressing inflammation with an anti-inflammatory drug was helpful for the survival of these transplanted stem cells, which serves to reinforce the idea that inflammation hinders tissue regeneration and healing.
The researchers wanted to find out if celecoxib, a common anti-inflammatory drug that blocks the proinflammatory enzyme COX-2 secreted by macrophages, would improve stem cell survival at chronic injury sites.
To test this they used an experimental wound model mouse. They divided the mice into four groups: a control group which received no treatment; a group injected with bone marrow stem cells near the wound; a third group were given celecoxib orally; and a fourth group were given celecoxib orally, plus stem cells were injected near the wound.
After a week, the team inspected the wound tissue. As they hoped, whilst the wounds showed an inflammatory response throughout the duration of the experiment, the mice treated with both celecoxib and stem cells showed better wound healing and more tissue growth a week later compared to the other test groups.
A significantly higher number of stem cells were also reported to have survived and successfully integrated with the wound tissue. There were also fewer numbers of proinflammatory immune cells present at the wound site and lower levels of inflammatory cytokines such as interleukin-17A.
So, how does it work?
The researchers wanted to find out how celecoxib improved the survival of stem cells and boosted wound healing, so they ran a series of tests to identify the cytokines and enzymes involved in the process.
By using stem cells and macrophages in a dish, the team demonstrated that interleukin-17a was responsible for activating macrophages that could then potentially kill the stem cells. By blocking the COX-2 enzyme using celecoxib, they inhibited the expression of interleukin-17a and prevented the macrophages from attacking the stem cells and killing them. This resulted in the stem cells being able to help heal the wound.
Ok, so great, but what does celecoxib do to the stem cells? The researchers finally went on to demonstrate that celecoxib not only inhibited macrophages but also increased the differentiation of the stem cells into keratinocytes – a type of skin cell needed for wound repair. So great news for boosting wound healing.
These results open the door for researchers to explore and refine therapies that reduce inflammation to improve stem cell transplant success for the treatment of chronic wounds. It is very likely we will see an increase in research efforts in this direction in the next year or so as other groups join the search for ways to improve stem cell therapy outcomes.
 Geesala, R., Dhoke, N. R., & Das, A. (2017). Cox-2 inhibition potentiates mouse bone marrow stem cell engraftment and differentiation-mediated wound repair. Cytotherapy, 19(6), 756-770.