Inflammation interferes with the healing of diabetic ulcers
Researchers from the Indian Institute of Chemical Technology (CSIR-IICT) have developed a new method of protecting bone marrow stem cells used for wound healing from the effects of severe inflammation. They suggest using the anti-inflammatory drug celexosib, which is widely used in clinical practice, for this purpose.
In patients with diabetes mellitus, chronic non–healing wounds can lead to the development of serious complications and, in some cases, to amputation of the affected limbs. According to the head of the study, Dr. Amitava Das, the treatment of chronic wounds in patients with diabetes mellitus, as well as undergoing chemotherapy and radiotherapy is a constant problem.
Traditional methods of treatment are often ineffective, so specialists are looking for alternative approaches. One of these approaches involves the introduction of stem cells into the wound that can differentiate into other types of cells, such as skin cells keratinocytes, which contribute to the healing process. However, the effectiveness of this method is limited by the aggressive microenvironment of wounds, in many cases inflamed.
Inflammation is a normal component of the wound healing process. Immune cells, leukocytes, are attracted to the healing zone, which release biologically active substances that cause inflammation, known as cytokines. The activation of inflammatory enzymes, such as cyclooxygenase-2 (COX-2), also increases in the damaged area. This inflammatory reaction affects the process of tissue growth and alters blood flow, facilitating the healing process. When the inflammation subsides, the skin cells begin to divide and cover the surface of the wound. However, in the case of chronic wounds, inflammation can be more pronounced and prolonged, which can be detrimental to stem cells injected into the wound to accelerate its healing.
The authors hypothesized that the popular anti-inflammatory drug celexosib, selectively inhibiting the pro-inflammatory enzyme cyclooxygenase-2, can increase the survival rate of stem cells injected into the wound and the effectiveness of therapy.
To test this hypothesis, they used an experimental mouse model. The animals were divided into 4 groups. The control group was not subjected to any treatment, mice of the second group were injected with bone marrow stem cells intradermally around the wound, the third group received oral celexosib, and the fourth received oral celexosib in combination with intradermal injections of stem cells. A week later, the researchers analyzed the level of healing and inflammation in the wound area, as well as the number of surviving stem cells.
As expected, during the experiment, signs of inflammation were recorded in the wounds. At the same time, the most effective healing and formation of new tissue was observed in the group whose animals received combined therapy with stem cells and celexosib. In the wounds of these mice, a significantly larger number of stem cells remained viable, which successfully integrated into the tissues. In addition, fewer white blood cells and lower levels of pro-inflammatory cytokines, including interleukin-17-alpha, were recorded in such wounds.
In order to find out how celexosib improves stem cell survival and wound healing, the researchers conducted a series of experiments to identify cytokines or enzymes that directly or indirectly influence this process. Using macrophages and stem cells cultured in laboratory conditions, they demonstrated that interleukin-17-alpha causes activation of macrophages, which ultimately can lead to the destruction of stem cells in the wound. By inhibiting cyclooxygenase-2 and subsequent inhibition of interleukin-17-alpha, celexosib is able to indirectly prevent the destruction of injected stem cells by macrophages, allowing them to participate in wound healing.
In addition, it turned out that celexosib directly stimulates the differentiation of stem cells into skin cells, kertinocytes, necessary for wound healing. Thus, this drug had a bilateral positive effect on the healing process of chronic wounds.
The data obtained by the authors indicate that the common anti-inflammatory drug celexosib can bring the introduction of stem cell therapy into clinical practice closer. The discovery of molecular targets responsible for its ability to improve the healing process will help develop new drugs with similar effects.
Article by Ramasatyaveni Geesala et al. Cox-2 inhibition potentials mouse bone marrow stem cell engraftment and differentiation-mediated wound repair is published in the journal Cytotherapy.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on Elsevier: Reducing inflammation protects stem cells during wound repair.
26.07.2017