Exp Mol Med.  2014 Jan;46(1):e70. 10.1038/emm.2013.135.

Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages

• Cho DI
• Kim MR
• Jeong HY
• Jeong HC
• Jeong MH
• Yoon SH
• Kim YS
• Ahn Y

• KMID: 2155335
• DOI: http://doi.org/10.1038/emm.2013.135

Abstract

Mesenchymal stem cells (MSCs) have been widely studied for their applications in stem cell-based regeneration. During myocardial infarction (MI), infiltrated macrophages have pivotal roles in inflammation, angiogenesis and cardiac remodeling. We hypothesized that MSCs may modulate the immunologic environment to accelerate regeneration. This study was designed to assess the functional relationship between the macrophage phenotype and MSCs. MSCs isolated from bone marrow and bone marrow-derived macrophages (BMDMs) underwent differentiation induced by macrophage colony-stimulating factor. To determine the macrophage phenotype, classical M1 markers and alternative M2 markers were analyzed with or without co-culturing with MSCs in a transwell system. For animal studies, MI was induced by the ligation of the rat coronary artery. MSCs were injected within the infarct myocardium, and we analyzed the phenotype of the infiltrated macrophages by immunostaining. In the MSC-injected myocardium, the macrophages adjacent to the MSCs showed strong expression of arginase-1 (Arg1), an M2 marker. In BMDMs co-cultured with MSCs, the M1 markers such as interleukin-6 (IL-6), IL-1beta, monocyte chemoattractant protein-1 and inducible nitric oxide synthase (iNOS) were significantly reduced. In contrast, the M2 markers such as IL-10, IL-4, CD206 and Arg1 were markedly increased by co-culturing with MSCs. Specifically, the ratio of iNOS to Arg1 in BMDMs was notably downregulated by co-culturing with MSCs. These results suggest that the preferential shift of the macrophage phenotype from M1 to M2 may be related to the immune-modulating characteristics of MSCs that contribute to cardiac repair.

Keyword

immunologic environment; macrophage; mesenchymal stem cell; myocardial infarction

MeSH Terms

Animals
Biomarkers/metabolism
*Cell Differentiation
Cells, Cultured
Coculture Techniques
Culture Media, Conditioned/pharmacology
Humans
*Macrophage Activation
Macrophage Colony-Stimulating Factor/*pharmacology
Macrophages/drug effects/*immunology/metabolism
*Mesenchymal Stem Cell Transplantation
Mesenchymal Stromal Cells/*cytology/drug effects/metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Myocardial Infarction/surgery
Rats
Biomarkers
Culture Media, Conditioned
Macrophage Colony-Stimulating Factor