Abstract
BackgroundMesenchymal stromal cells (MSCs), due to their regenerative and immunomodulatory properties, are therapeutically used for diseases, including heart failure. As early gestational-phase embryonic tissues exhibit extraordinary regenerative potential, fetal MSCs exposed to inflammation offer a unique opportunity to evaluate molecular mechanisms underlying preferential healing, and investigate their inherent abilities to communicate with the immune system during development. The principal aim of this study was to evaluate the effects of interferon-γ (IFNγ) on the immunomodulatory effects of first-trimester human fetal cardiac (hfc)-MSCs.MethodshfcMSCs (gestational week 8) were exposed to IFNγ, with subsequent analysis of the whole transcriptome, based on RNA sequencing. Exploration of surface-expressed immunoregulatory mediators and modulation of T cell responses were performed by flow cytometry. Presence and activity of soluble mediators were assessed by ELISA or high-performance liquid chromatography.ResultsStimulation of hfcMSCs with IFNγ revealed significant transcriptional changes, particularly in respect to the expression of genes belonging to antigen presentation pathways, cell cycle control, and interferon signaling. Expression of immunomodulatory genes and associated functional changes, including indoleamine 2,3-dioxygenase activity, and regulation of T cell activation and proliferation via programmed cell death protein (PD)-1 and its ligands PD-L1 and PD-L2, were significantly upregulated. These immunoregulatory molecules diminished rapidly upon withdrawal of inflammatory stimulus, indicating a high degree of plasticity by hfcMSCs.ConclusionsTo our knowledge, this is the first study performing a systematic evaluation of inflammatory responses and immunoregulatory properties of first-trimester cardiac tissue. In summary, our study demonstrates the dynamic responsiveness of hfcMSCs to inflammatory stimuli. Further understanding as to the immunoregulatory properties of hfcMSCs may be of benefit in the development of novel stromal cell therapeutics for cardiovascular disease.
Highlights
Co-ordination of the immune response in pregnancy is central to ensuring fetal survival and development
Flow cytometry analysis confirmed that human fetal cardiac Mesenchymal stromal cells (MSCs) (hfcMSCs) constitutively express IFNγ-receptor (R)1 (CD119; Fig. 1a) and that the level of expression, as assessed by median fluorescence intensity (MFI), significantly increased with prolonged, 7-day, exposure to IFNγ (Fig. 1b; IFNγ 2 days vs IFNγ 7 days; P < 0.01)
(See figure on previous page.) Fig. 1 Expression of cell-surface receptors upon stimulation with IFNγ. a Histograms showing antibody staining of cell surface-expressed IFNγ-R1 on hfcMSCs from one representative donor compared to IgG1 PE-negative controls
Summary
Co-ordination of the immune response in pregnancy is central to ensuring fetal survival and development. The expression of allogeneic paternal antigens by the fetus and evasion of an ensuing maternal immune response has been attributed to populations of trophoblasts at the maternal-fetal interface [1]. Pregnancy constitutes a challenge for the immune systems of the mother and fetus, and puts strict requirements on the fetal-maternal interface to prevent fetal rejection, while maintaining the capacity to combat infections. Trophoblasts at the fetal-maternal interphase have been thoroughly studied in this context, the forming fetal organs and tissues have not, and knowledge regarding the capacity of developing fetal tissues to generate and modulate immune responses is very limited [8]. As early gestational-phase embryonic tissues exhibit extraordinary regenerative potential, fetal MSCs exposed to inflammation offer a unique opportunity to evaluate molecular mechanisms underlying preferential healing, and investigate their inherent abilities to communicate with the immune system during development. The principal aim of this study was to evaluate the effects of interferon-γ (IFNγ) on the immunomodulatory effects of first-trimester human fetal cardiac (hfc)-MSCs
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