Mesenchymal stem cells increase T-regulatory cells and improve healing following trauma and hemorrhagic shock

Abstract

Background Rodent lungs undergo full histologic recovery within one week following unilateral lung contusion (LC). However, when LC is followed by hemorrhagic shock (HS), healing is impaired. We hypothesize that the intravenous administration of mesenchymal stem cells (MSC) to animals undergoing combined LC followed by HS (LCHS) will improve wound healing. Methods Male Sprague-Dawley rats (n=5-6/group) were subjected to LCHS with or without the injection of a single iv dose of 5 × 106 MSCs following return of shed blood after HS. Rats were sacrificed seven days following injury. Flow cytometry was used to determine the T regulatory (Treg) cell population in peripheral blood (PB). Lung histology was graded using a well-established lung injury score (LIS). Components of the LIS include average inflammatory cells/high power field (hpf) over 30 fields, interstitial edema, pulmonary edema, and alveolar integrity with total scores ranging from 0-11. Data analyzed by ANOVA followed by Tukey's multiple comparison test, expressed as mean ± SD. p<0.05 considered significant. Results Seven days following isolated LC animals demonstrate lung healing with a LIS unchanged from naive. The addition of HS results in a persistently elevated LIS score, whereas addition of MSC to LCHS decreased the LIS score back to naïve levels. The change in LIS was driven by a significant decrease in edema scores. In rats undergoing LC alone, 10.5 ± 3.3% of CD4+ cells were Tregs. The addition of HS caused no significant change in Treg population (9.3±0.7%), whereas LCHS+MSC significantly increased the population to 18.2±6.8% in PB (p<0.05 vs LCHS). Conclusion Impaired wound healing following trauma and hemorrhagic shock is improved by a single dose of MSCs given immediately after injury. This enhanced healing is associated with an increase in the T regulatory cell population and a significant decrease in lung edema score as compared to animals undergoing LCHS. Further study into the role of Tregs in MSC-mediated wound healing is warranted.

Mesenchymal stem cells enhance lung recovery after injury, shock, and chronic stress

“…We have previously shown that MSCs enhance healing after LC, resulting in complete healing at five days post-injury 17 . More recently, we reported the benefit of MSCs in healing when LC was combined with either HS or CS 15,18 , however, it was unknown if MSCs retained their therapeutic effect in this most severe injury model, LCHS/CS. We demonstrated that a single dose of MSCs given immediately after the resuscitation period reversed this HS- and CS-induced healing impairment.…”

Wound healing and fibrosis: current stem cell therapies

“…Mortality from ARDS ranges from 20% to 40% . Studies utilizing MSCs for ARDS have shown good therapeutic tolerance, as well as improved recovery from ventilator‐associated pulmonary injury, decreased pulmonary edema, and increased presence of peripheral regulatory T cells . Given that cell engraftment of MSCs appears to be very low, therapeutic efficacy is believed to result from anti‐inflammatory cytokines or paracrine signals produced by MSCs .…”

Efficacy of erythropoietin-pretreated mesenchymal stem cells in murine burn wound healing: possible in vivo transdifferentiation into keratinocytes

“…Concordantly, it had been demonstrated that at early time points post-burn, rats treated with MSCs have decreased circulating levels of TNF-a, IL-6, white blood cells and C-reactive protein as compared to the control group [35]. In addition, MSCs have also demonstrated the ability to attenuate T cell activation and proliferation, decrease cytotoxic T cells, and increase immunosuppressive regulatory T cells [8]. Also, murine MSCs were injected intradermally in a rat burn model resulting in an increase in anti-inflammatory cytokines TGF-b and IL-10 in the blood and reduction of CD4+ and CD8+ cells in the spleen as compared to control PBS-treated rats [3].…”