Induction of immunomodulatory monocytes by human mesenchymal stem cell-derived hepatocyte growth factor through ERK1/2

Abstract

Monocytes are a population of leukocytes that terminally differentiate into macrophages and DCs. Whereas these differentiated progeny have inflammatory and resident--which are more immunomodulatory--phenotypes, less has been reported on the plasticity of monocytes themselves. We found that MSCs, a population of somatic stem cells, can rapidly induce human and murine monocytes through secretion of HGF to acquire an immunomodulatory phenotype to suppress T cell effector function. MSCs are multilineage postnatal progenitor cells with strong immunomodulatory effects toward T lymphocytes, NK lymphocytes, and DCs, but less is known regarding their interactions with monocytes. We found that CD14(+) human monocytes express c-Met, the receptor for HGF, and both depletion of HGF-treated CD14(+) monocytes and knockdown of HGF secretion in MSCs abrogate the suppression of anti-CD3/28-activated T cell proliferation. HGF-treated monocytes remain undifferentiated and can alter activated T cell cytokine expression from a Th1 toward Th2 profile. Moreover, monocytes cocultured with MSCs or treated with HGF alone can produce high levels of IL-10, a potent immunomodulatory cytokine. Injection of HGF to WT mice also results in an increase in IL-10(+)-expressing monocytes from the spleen, a known reservoir for circulating monocytes. Mechanistically, HGFs modulate IL-10 production in monocytes through the ERK1/2 pathway. Our data demonstrate further the pleomorphic nature of MSC immunomodulation, as well as highlight the important role of immunomodulatory monocytes in altering T cell effector function.

Transplantation of Human Placenta-Derived Multipotent Stem Cells Reduces Ischemic Brain Injury in Adult Rats

“…Moreover, the presence of interferon-g (IFN-g), a proinflammatory cytokine, enhances the immunosuppressive properties of hPDMCs (8). hPDMCs enhance immunomodulatory leukocytes of the innate immune system, increasing the number of myeloid-derived suppressor cells and modulating monocytes into an immunosuppressive phenotype (10,33). Furthermore, hPDMCs, but not BMMSCs, upregulated the immunomodulatory molecule human leukocyte antigen (HLA)-G upon exposure to IFN-g and reduced natural killer lymphocyte (NK)/interleukin (IL)-2-mediated apoptosis (21).…”

Acute Genotoxic Stress-Induced Senescence in Human Mesenchymal Cells Drives a Unique Composition of Senescence Messaging Secretome (SMS)

“…The increase in secretion of MMP1, MMP3 and MMP9 and absence of their inhibitors TIMPs might directly trigger ECM degradation [41][42][43]45]. In hADSCs SMS, the presence of mitogenic growth factors such as transforming growth factors (TGF β1 and β2), basic Fibroblast Growth Factor (FGF-6), Hepatocyte Growth Factor (HGF), Vascular Endothelial Growth Factor (VEGF), Insulinlike Growth Factor -1 (IGF-1), and Platelet-derived Growth Factors (PDGF) as well as number of cytokines (shown in Figure 3) suggests that the senescence-triggered cellular communication could result in an increase in fibroblasts, keratinocytes, epithelial and endothelial cell division, migration or differentiation, thus triggering ECM remodeling [46][47][48][49][50].…”

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

“…At clinical diagnosis, AML cells may also induce heterogeneous mesenchymal BM stroma alterations that significantly affect the clinical course of the disease [59]. After initial treatment, a high MSC number predicts a poor prognosis that might not only be due to their immunosuppressive/ anti-inflammatory [61,121,122] and angiogenic properties [60], but also to the activation of the Gas6/Axl paracrine axis that can be targeted with BGB324, a small Axl inhibitor [123]. In addition, MSC exposure to toll-like ligand receptor-2 (TLR2) (peptidoglycan), the activation of TLR4 (lipopolysaccharide) [61] and exposure to platelet lysate supplemented media [124] might polarize microenvironmental MSCs toward a proinflammatory phenotype, but it is still doubtful whether this type of priming might be truly effective.…”