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Prevention of Burn Wound Progression by Mesenchymal Stem Cell Transplantation

Deeper Insights Into Underlying Mechanisms

Abbas, Ozan Luay, MD*; Özatik, Orhan, MD; Gönen, Zeynep Burçin, DDs, PhD; Öğüt, Serdal, PhD§; Entok, Emre, MD; Özatik, Fikriye Yasemin, MD; Bahar, Dilek, MSc; Bakir, Zehra Burcu, PhD#; Musmul, Ahmet, PhD**

doi: 10.1097/SAP.0000000000001620
Transplantation Surgery and Research

Introduction Burns are dynamic wounds that may present a progressive expansion of necrosis into the initially viable zone of stasis. Therefore, salvage of this zone is a major subject of focus in burn research. The beneficial effects of mesenchymal stem cells (MSCs) on the survival of the zone of stasis have been previously documented. However, many gaps still exist in our knowledge regarding the underlying protective mechanisms. Hence, this study was designed to evaluate the pathophysiological basis of MSCs in the prevention of burn wound progression.

Methods Wistar rats received thermal trauma on the back according to the “comb burn” model. Animals were randomly divided into sham, control, and stem cell groups with sacrifice and analysis at 72 hours after the burn. The stasis zones were evaluated using histochemistry, immunohistochemistry, biochemistry, real-time polymerase chain reaction assay, and scintigraphy to evaluate the underlying mechanisms.

Results Gross evaluation of burn wounds revealed that vital tissue percentage of the zone of stasis was significantly higher in the stem cell group. Semiquantitative grading of the histopathologic findings showed that MSCs alleviated burn-induced histomorphological alterations in the zone of stasis. According to CC3a staining and expression analysis of Bax (B-cell leukemia 2–associated X) and Bcl-2 (B-cell leukemia 2) genes, MSCs attenuated increases in apoptosis postburn. In addition, these transplants showed an immunomodulatory effect that involves reduced neutrophilic infiltration, down-regulation of proinflammatory cytokines (tumor necrosis factor α, interleukin 1β [IL-1β], and IL-6), and up-regulation of the anti-inflammatory cytokine IL-10 in the zone of stasis. Burn-induced oxidative stress was significantly relieved with MSCs, as shown by increased levels of malondialdehyde, whereas the expression and activity of the antioxidant enzyme superoxide dismutase were increased. Finally, MSC-treated interspaces had enhanced vascular density with higher expression levels for vascular endothelial growth factor A, platelet-derived growth factor, fibroblast growth factor, and transforming growth factor β. Gamma camera images documented better tissue perfusion in animals treated with MSCs.

Conclusions The protective effects of MSCs are mediated by the inhibition of apoptosis through immunomodulatory, antioxidative, and angiogenic actions.

From the Departments of *Plastic, Reconstructive and Aesthetic Surgery and

Histology and Embryology, Faculty of Medicine, Ahi Evran University, Kirşehir;

Gen Kök Genome and Stem Cell Center, Erciyes University, Kayseri;

§Department of Nutrition and Dietetics, Faculty of Health Science, Adnan Menderes University, Aydin;

Department of Nuclear Medicine, Faculty of Medicine, Osmangazi University, Eskişehir;

Department of Pharmacology, Faculty of Medicine, Ahi Evran University, Kirşehir;

#Department of Biology, Adnan Menderes University, Aydin; and

**Department of Biostatistics, Faculty of Medicine, Osmangazi University, Eskişehir, Turkey.

Received February 20, 2018, and accepted for publication, after revision July 12, 2018.

Author Contributions: All authors have made substantial contributions to the conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content, and final approval of the version to be submitted. O.L.A. is corresponding author; O.Ö.: histological and immunohistological analysis; Z.B.G.: stem cell isolation and characterization; S.Ö.: biochemical evaluation of oxidative stress; E.E.: nuclear imaging; F.Y.Ö.: surgical procedures and data analysis; D.B.: stem cell isolation and characterization; Z.B.B.: collagen assay analysis; A.M.: biostatistical analysis.

This study received approval of Osmangazi University Ethical Committee for Experimental Research on Animals and was supported by Ahi Evran University Research Fund (project TIP.A3.16.012).

Conflicts of interest and sources of funding: none declared.

Reprints: Ozan Luay Abbas, MD, Department of Plastic, Reconstructive and Aesthetic Surgery, Faculty of Medicine, Ahi Evran University, Postal code 40100, Kirşehir, Turkey. E-mail:

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