Reducing Inflammation Assists Stem Cells Therapies to Enhance Regeneration

The immune system is highly influential in the processes of regeneration. Inflammation is a key marker of the types of immune cell involved and the sort of activities they are undertaking, either helping or hindering regeneration, and greater levels of inflammation are usually a bad thing. Researchers have demonstrated enhanced healing by ensuring that fewer of the more aggressive and inflammatory class of macrophage cell are present in injured tissue, for example. Further, it is known that aspects of aging such as immune system dysfunction and the growth in number of senescent cells can disrupt regeneration, and inflammation appears to be an important component there also. Is inflammation a direct cause of failing regeneration, or is it more of a signal that other processes are at work, and those processes happen to coincide with greater inflammation?

In the paper here, researchers investigate this question in a subset of the broader problem. They are interested in the development of stem cell therapies as a treatment to accelerate wound healing. Wounds are inflammatory environments, however, and this isn’t helpful when it comes to the survival of transplanted cells. The researchers find that one approach to suppressing inflammation can be beneficial in this scenario; this extends the common theme of inflammation as a hindrance to healing found in other areas of research relevant to enhancing existing regenerative processes. We are probably going to see much more on this topic in the next few years, especially if other research groups can find ways to improve the outcome of cell therapies via similar methodologies. In the long run, however, more sophisticated means of suppressing inflammation may be of greater important when it comes to adjusting native cell behaviors and capacity for regeneration. This is very much needed in older individuals.

Reducing inflammation protects stem cells during wound repair

Inflammation is normal in wound healing. As wounds heal, white blood cells, such as those called macrophages, are attracted to the wound site and release substances called cytokines that cause an inflammatory response. At the wound site, enzymes such as cyclooxygenase-2 (COX-2) also become more active and contribute to the inflammation. This inflammation is important in the normal healing process, affecting tissue growth and blood flow changes that allow the tissue to heal; when the inflammation subsides, skin cells start growing to cover the wound and help the tissue knit together. In chronic wounds, however, inflammation can be more extensive and prolonged. This is bad news for any stem cells that might be injected into a chronic wound to help heal it. Stem cells are not like typical drugs – they are alive, and like all life forms, they can die in a hostile environment. The harsh inflammation in chronic wounds kills many of the injected cells, and this is one of the reasons why, so far, stem cells have not worked as a treatment for chronic wounds.

Researchers hypothesized that celecoxib, a common anti-inflammatory drug that selectively inhibits the pro-inflammatory enzyme COX-2, would improve stem cell survival and treatment outcomes for chronic wound therapy. To test their hypothesis, the group used an experimental wound model in mice. The researchers split the mice into four groups. They left a control group completely untreated and treated the second group using mouse stem cells from bone marrow, which they injected into the skin near the wound. They treated a third group orally using celecoxib, and the final group received celecoxib orally, as well as a stem cell injection into the skin near the wound. After a week, the scientists examined the wound tissue for healing and inflammation, and checked if the stem cells had survived.

As expected, the wounds showed an inflammatory response over the duration of the experiment. However, the mice treated using both celecoxib and stem cells showed better wound healing and more tissue growth a week later, compared with untreated mice or mice treated using stem cells or celecoxib alone. A significantly higher amount of stem cells had survived and integrated into the wound tissue in mice that had received celecoxib. So far so good, but did celecoxib have any direct effects on the stem cells themselves? The scientists found that celecoxib directly increased stem cell differentiation into keratinocytes – skin cells required for wound healing. By helping the stem cells to survive and encouraging them to differentiate into skin cells, celecoxib produced a two-pronged healing effect.

Cox-2 inhibition potentiates mouse bone marrow stem cell engraftment and differentiation-mediated wound repair

Engraftment of transplanted stem cells is often limited by cytokine and noncytokine proinflammatory mediators at the injury site. We examined the role of Cyclooxygenase-2 (Cox-2)-induced cytokine-mediated inflammation on engraftment of transplanted bone marrow stem cells (BMSCs) at the wound site. BMSCs isolated from male C57/BL6J mice were transplanted onto excisional splinting wounds in presence or absence of celecoxib, a Cox-2 specific inhibitor, to evaluate engraftment and wound closure. Celecoxib administration led to a significantly high percent of wound closure, cellular proliferation, collagen deposition, BMSCs engraftment and re-epithelialization at the wound site. Thus celecoxib protects transplanted BMSCs from Cox-2/IL-17-induced inflammation and increases their engraftment, differentiation into keratinocytes and re-epithelialization thereby potentiating wound tissue repair.

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