The interaction between mesenchymal stromal/stem cells and macrophages in the process of wound healing
The interaction between mesenchymal stromal/stem cells and macrophages in the process of wound healing
Kianush Charoghdoozi,1Mojgan Mohammadi,2Mahvash Sadeghi,3Jalil Tavakol Afshari,4Sajad Dehnavi,5,*
1. Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 2. Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 3. Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 4. Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 5. Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Introduction: Wound healing is the process of restoring tissue to its normal state after infection or mechanical trauma and involves a series of coordinated steps. Mesenchymal stromal/stem cells (MSC) are present in almost all tissues and play a key role in tissue repair. They are attracted to sites of tissue damage and interact with inflammatory cells such as macrophages to influence tissue repair processes.
Methods: A comprehensive search of electronic databases, including PubMed, Google Scholar, Medline, Scopus, and Web of Science, was conducted to identify relevant studies investigating the interaction between MSCs and macrophages in the context of wound healing. The search strategy used a combination of keywords, including "wound healing," "mesenchymal stromal/stem cell," "macrophage," and "inflammation". The selected studies were subjected to a comprehensive review in order to elucidate the underlying mechanisms.
Results: Macrophage polarity can either promote or inhibit the inflammatory phase of wound repair. The M1 macrophages are able to recognize damage-associated molecular patterns (DAMP), including extracellular high mobility group box-1 (HMGB-1), DNA, RNA, and ATP, which are produced as a result of cell death. They can also recognize pathogen-associated molecular patterns (PAMP) on the surface of bacteria or fungi. To eliminate pathogens and cell debris and to promote the proliferation of wound cells such as fibroblasts and keratinocytes, M1 macrophages produce matrix metalloproteinase 12 (MMP12), nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory cytokine and chemokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, IL-12, CXCL9, and CXCL10. These molecules enable macrophages to control the subsequent phase of the repair process. The transition from the inflammatory to the proliferative phase is characterized by the repolarization of M1 macrophages to the M2 phenotype in response to downstream signals from cytokines, including IL-4, IL-13, IL-10, IL-33, and transforming growth factor-beta (TGF-β). Efferocytosis, or the phagocytosis of apoptotic cells, is a crucial process in the transition of M2 macrophages. The M2 phenotype is a healing-associated macrophage with downregulated inflammatory factors and ROS levels and upregulated anti-inflammatory cytokines and growth factors, such as IL-10, IL-1RA, and IL-1 type II decoy receptor. M2 macrophages stimulate neo-angiogenesis, cellular proliferation, and, in the case of severe injury, the activation and differentiation of tissue-resident stem and progenitor cells through the synthesis of numerous growth factors, including platelet-derived growth factor (PDGF), TGF- β1, insulin-like growth factor (IGF)-1, and vascular endothelial growth factor (VEGF). In addition, M2 macrophages secrete soluble mediators (IL-13, TGF-β1) that induce fibroblasts to differentiate into myofibroblasts. Myofibroblasts facilitate wound contraction and closure by increasing the production of extracellular matrix (ECM) components. In addition, ECM-degrading MMPs (MMP2, MMP9, and MMP13) are secreted by anti-inflammatory M2 macrophages, which also inhibit fibrosis.
Phagocytic activity, immunomodulatory potential, and recruitment of macrophages expressing low levels of IL-12, TNF-α, IL-1β, CD86, MHC-II, and high levels of IL-10 by macrophages, have all been found to be influenced by MSCs.
During the early stages of tissue healing, MSCs support the phagocytic activities of M1 macrophages. In the latter stages of tissue healing, MSCs can switch macrophages from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype by decreasing pro-inflammatory cytokines and increasing anti-inflammatory cytokines. This switch may be mediated by MSC-derived exosomes, TSG-6, PGE2, IL-4, IL1RA, and IL-6, through activation of NF-kB, STAT-3, and interferon-gamma (IFN-γ) mediated indoleamine 2, 3-dioxygenase (IDO) activation. Some studies have suggested that MSC metabolites play a role in MSC immunomodulation. Evidence suggests that lactate produced by MSCs alters mitochondrial activity through metabolic reprogramming, thereby promoting monocyte differentiation to M2. Chemokines serve as a link between MSCs and macrophages. MSC-derived CCL2 attracts macrophages and monocytes while interacting with CXCL12 to stimulate IL-10 production and M2-like macrophage polarization. Additionally, chemokines such as CXCL12, CCL4, and CCL5 can enhance the anti-inflammatory potential of macrophages in conjunction with CCL2.
Conclusion: Recent evidence suggests that MSCs have the ability to modulate the immune system, making them promising candidates for regenerative therapy. The current data on the coordinated effects of inflammatory cytokines, chemokines, and effector molecules in MSC-mediated immunosuppression suggest that interactions between macrophages and MSCs in the tissue environment may influence the efficacy of MSC-based therapy for wound healing.