Macrophages inhibit adipogenic differentiation of adipose tissue derived mesenchymal stem/stromal cells by producing pro-inflammatory cytokines

Abstract

Background: Mesenchymal stem/stromal cells (MSCs) and macrophages are critical components in many tissue microenvironments, including that in adipose tissue. The close interaction between MSCs and macrophages modulates various adipose-related disease development. However, the effects of macrophages on the fate of MSCs remain largely elusive. We here studied the effect of macrophages on the adipogenic differentiation of MSCs. Methods: Macrophages were obtained from THP-1 cells treated with phorbol-12-myristate-13-acetate (PMA). The induced matured macrophages were then induced to undergo classically activated macrophage (M1) or alternatively activated macrophage (M2) polarization with Iipopolysaccharide (LPS)/interferon (IFN)-γ and interleukin (IL)-4/IL-13, respectively. The supernatants derived from macrophages under different conditions were applied to cultured human adipose tissue-derived mesenchymal stem/stromal cells (hADSCs) undergoing adipogenic differentiation. Adipogenic differentiation was evaluated by examining Oil Red O staining of lipid droplets and the expression of adipogenesisrelated genes with real-time quantitative polymerase chain reaction (Q-PCR) and western blot analysis. Results: The adipogenic differentiation of hADSCs was impaired when treated with macrophage-derived supernatants, especially that from the M1-polarized macrophage (M1-sup). The inhibitory effect was found to be mediated by the inflammatory cytokines, mainly tumor necrosis factor-α (TNF-α) and IL-1β. Blocking TNF-α and IL-1β with neutralizing antibodies partially alleviated the inhibitory effect of M1-sup. Conclusion: Macrophage-derived supernatants inhibited the adipogenic differentiation of hADSCs in vitro, irrespective of the polarization status (M0, M1 or M2 macrophages). M1-sup was more potent because of the higher expression of pro-inflammatory cytokines. Our findings shed new light on the interaction between hADSCs

Mesenchymal Stem Cell-Macrophage Crosstalk and Maintenance of Inflammatory Microenvironment Homeostasis

“…Enhanced osteogenesis was also observed by several groups, they demonstrated that M1 macrophages promote osteogenesis in MSCs via the COX-2-PGE2 pathway (Guihard et al, 2012;Lu et al, 2017;Zhang et al, 2017;Nathan et al, 2019;Tang et al, 2019). Recently, the Shi group reported that macrophage-derived supernatants can inhibit the adipogenic differentiation of human adiposederived mesenchymal stem cells (hADSCs) in vitro, irrespective of the polarization status (M0, M1, or M2 macrophages) (Ma et al, 2020). In summary, macrophages also have an important influence on the differentiation ability of MSCs.…”

Adipose-Derived Stem Cells Secretome and Its Potential Application in “Stem Cell-Free Therapy”

“…Adipose-derived stem cells produce many molecules responsible for cell signaling, such as cytokines [29,74], growth factors [28,75], morphogens [76], chemokines [27,77], and extracellular vesicles [78][79][80], improving various cellular mechanisms. Interestingly, compared to BM-MSCs-the second most frequently considered MSCs for stem cell therapy-ASCs secrete more growth factors, and this feature increases their regenerative capacity [2,81].…”

“…In addition to bifunctional IL-2 and IL-6, adipose-derived stem cells secrete other cytokines with a well-defined pro-inflammatory (IL-7, IL-8, IL-9, IL-11, IL-12, IL-15, IL-17, interferon-gamma IFN-γ, IL-1β, and tumor necrosis factor-alpha TNF-α) or antiinflammatory (IL-1Ra, IL-4, IL-10, and IL-13) properties [29,44,89]. It has been shown that TNF-α and IL-1β secretion by macrophages mediates the inhibitory effect on ASCs adipogenesis, and also that combination of TNF-α or IL-1β with IFN-γ can enhance the immunomodulatory properties of ASCs mainly dependent on indoleamine 2, 3-dioxidase (IDO) or inducible nitric oxide synthase (iNOS) [74]. IFN-γ triggers ASCs to elicit immunosuppressive factors [90].…”

Macrophages, as a Promising Strategy to Targeted Treatment for Colorectal Cancer Metastasis in Tumor Immune Microenvironment

“…They produce various molecules that interact with other immune cells and tumor cells and further affect the progression in CRC (38). Under the influence of different cytokines and exosomes, three types of macrophages can be identified: naive M0, the M1 subtype with pro-inflammatory effects, and the M2 subtype with immunosuppressive effects (39,40), which promote or inhibit the progression of CRC.…”