Human MSC Suppression Correlates With Cytokine Induction of Indoleamine 2,3-Dioxygenase and Bystander M2 Macrophage Differentiation

By M. François, R. Romieu-Mourez, Mengyang Li, J. Galipeau. Molecular Therapy, 2012

665 citations recorded by the source corpus.

Clinical trials testing the use of either autologous or allogeneic human bone marrow-derived mesenchymal stromal cells (MSC) as a cell-based pharmaceutical for suppression of autoimmune and alloimmune ailments are underway. Reported results from completed trials vary in effectiveness within and between studies without any clear mechanistic explanation. We propose that these discrepancies may arise from intrinsic variability in the immunosuppressive potential of each MSC donor source. Here, we demonstrate that tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)-activated MSC derived from normal adult volunteers suppress T cell proliferation in vitro in a variegated manner, an observation linked to IFN-mediated indoleamine 2,3-dioxygenase (IDO) upregulation. We also demonstrate that MSC IDO activity is implicated in the differentiation of monocytes into interleukin (IL)-10-secreting M2 immunosuppressive macrophages (CD14+/CD206+). Those monocyte-derived M2 are in turn implicated in the suppression of T cell proliferation in an IL-10-independent manner, thus amplifying the immunosuppressive effect generated by MSC. In summary, the immune plasticity of IFN-γ and TNF-α licensed veto function of MSC vary among donors and defines a central role to inducible IDO activity and its bystander effect on lymphomyeloid immune effectors.

Subfields: Behavioral Neuroscience, Biological Psychiatry, Neurology

View Paper: https://www.semanticscholar.org/paper/71bd3926c77b17658e851f63677d84887a5134ab

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Citations in the corpus

Mesenchymal stromal cells: sensors and switchers of inflammation. (2013, positive): “In addition, murine and human MSCs employ different effector molecules (i.e., nitric oxide [NO] and indolamine 2,3 dioxygenase [IDO], respectively) for immune regulation, for example during suppression of T cell proliferation (Ren et al., 2008; Franç ois et al., 2012).”
Mesenchymal stromal cells: clinical challenges and therapeutic opportunities (2018, background): “However, when interrogating the functional response of MSCs to stimulatory cues, there can be substantial variance in the magnitude of expression of key effector pathways – such as IDO upregulation following interferon-γ stimulation(Francois et al., 2012) – suggesting that biomarker-driven donor scr”
The secretion profile of mesenchymal stem cells and potential applications in treating human diseases (2022, background): “MSCs also require IDO in promoting the differentiation of monocytes into immunosuppressive macrophages to ameliorate inflammatory responses.(196) However, KYNA limited IL-10 production via the increase of intracellular cAMP in BM-derived macrophages and predicted poor prognosis in atherosclerosis.”
Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer (2017, background): “Moreover, macrophages differentiated in GM-CSF, like in the present study, have been shown to express low levels of IL-10 after LPS treatment((45)).”
Mesenchymal stem cell-macrophage crosstalk and bone healing (2018, background): “demonstrated that human MSC exposed to IFN- and TNF- upregulated indoleamine 2,3-dioxygenase (IDO) expression, which was implicated in the polarization of monocytes into IL-10-secreting M2 macrophages and indirect suppression of T cell proliferation [64].”
Harnessing the Mesenchymal Stem Cell Secretome for the Treatment of Cardiovascular Disease (2012, background): “In addition, MSCs exert immunomodulatory effects by inducing neighboring cells to secrete relevant cytokines (Aggarwal and Pittenger, 2005; François et al., 2012; Németh et al., 2009; Prockop and Oh, 2012), which may be useful in inhibiting excessive inflammation and pathological remodeling under MI”