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MACROPHAGE POLARIZATION IN SKIN WOUNDS TREATED WITH A DERMAL SUBSTITUTE ASSOCIATED WITH MESENCHYMAL STEM CELLS
Large skin wounds such as burns lead to secondary disorders and death if not quickly stabilized. Therefore, novel strategies combining cell therapy, tissue engineering and regenerative medicine have been developed to treat these challenging wounds. Currently, the gold standard treatment involves the use of dermal templates, such as Integra™ matrix, a dermal substitute composed of collagen and chondroitin sulfate. In contrast, mesenchymal stem cells (MSCs) shows wide range of therapeutic applications due their differentiation potential and paracrine effects. Recent studies suggest that MSCs induces the shift of macrophages from pro-inflamatory phenotype (M1) to pro-healing phenotype (M2).
Objetivos - Metodologia - Resultados - Discussão dos Resultados/Objectives - Methodology - Results - Discussion of Results/Objetivos - Metodología - Resultados - Discusión de los resultados
The aim of this study was to verify the macrophage polarization in skin wounds treated with Integra™ matrix associated with human MSCs. Dermal and adipose derived mesenchymal stem cells (DSC and ASC, respectively), were isolated from human abdominoplasties discards. The MSCs were characterized with regard to their immunophenotype and mesodermal differentiation potential and associated with the Integra matrix. Wounds were induced in the back of C57bl/6 mice and treated with Integra™ (control group), Integra™ with DSC or Integra™ with ASC. Wounds were measured over time and samples were harvested after 3 and 21 days for immunohistochemistry evaluation of F4/80 (macrophage marker), iNOS (M1 marker) and MMR (M2 marker). DSC and ASC expressed mesenchymal markers (CD90, CD73 and CD105 and do not express hematopoietic markers (CD45 and CD34) and both MSCs were able to generate adipocytes, osteocytes and chondrocytes. DSC and ASC were adequately associated with Integra™ in vitro and promoted higher closure (90.27% ± 18.78 SD and 86.88% ± 24.5 SD, respectively) of skin wounds after 21 days than control (55.78% ± 29.06 SD). At day 3, there were more macrophages in the control group than MSCs groups (60.81% ± 7.1 SD versus 45.32% ±9.0 in DSC and 40.29% ± 5.63 SD in ASC), but the percentage of macrophages was similar between control and cell groups after 21 days (43.33% ±4.27 SD in control group, 44.91% ±3.87 SD in DSC and 46.93% ±7.9 SD in ASC). The percentage of macrophages decreased from day 3 to 21 in control group, while it remained stable in the cell groups, suggesting an anti-inflammatory effect of MSCs in the inflammatory phase of healing. Accordingly, at both 3 and 21 days, there were significantly more iNOS (M1) macrophages and less MMR (M2) in the control group than DSC and ASC groups (3 days: 83.27% ±5.34 SD iNOS in control versus 65.95% ±6.36 SD in DSC and 64.53% ±12.79 SD in ASC and 45% ±6.63 SD MMR in control versus 68.59% ±9.49 SD in DSC and 62.02% ±10.35 SD in ASC; 21 days: 68.83% ±5.15 SD iNOS in control versus 42.30% ±11.25 SD in DSC and 46.44% ±12.68 SD in ASC and 51.76% ±7.93 SD MMR in control versus 66.69% ± 9.85 SD in DSC and 63.91% ± 8.52 SD in ASC). The percentage of iNOS in each group decreased over time, but the percentage of MMR remained similar. Togheter, these results demonstrate the immunomodulatory and anti-inflammatory effects of DSC and ASC in skin wound healing and highlights both types of MSCs as promissing sources of cells for future therapies.
Considerações Finais/Final considerations/Consideraciones finales
The association of Integra™ matrix with mesenchymal stem cells promote faster wound closure and an immunomodulation by the shift of macrophages polarization from a pro-inflammatory phenotype to a pro-healing phenotype.
Support: CNPq, CAPES / PDSE, MCTIC, INCT-REGENERA and CDI.
Palavras-chave/Key words/Palabras clave
cutaneous repair, mesenchymal stromal cells, MSC, translational research, inflammation, immunomodulation.
HELENA DEBIAZI ZOMER, Talita da Silva Jeremias, Buddy Ratner, Andrea Gonçalves Trentin