Alterations of mesenchymal stem cells on regulating Th17 and Treg differentiation in severe aplastic anemia

Abstract

Immune-mediated hematopoietic destruction is a key factor in idiopathic severe aplastic anemia (SAA). With great immunomodulatory functions, mesenchymal stem cells (MSCs) are important for bone marrow niche. While the underlying etiology of immunologic changes in SAA bone marrow remains unknown, dysfunctional MSCs are implicated as a major cause. To provide evidence for their defects in immunomodulation, alterations of SAA MSCs in regulating T cell differentiation were determined. During differentiation from CD4+ T cells into T helper 17 (Th17) cells under polarization conditions, impaired inhibition on IL-17 and IL-1β production was noted when cocultured with SAA MSCs compared to control MSCs (P < 0.05). After stimulation of Th17 activation, the percentage of IL-17-secreting cells was significantly increased in the SAA group (9.1 ± 1.5% vs 6.6 ± 0.4%, P < 0.01). Under regulatory T (Treg) polarization, a higher percentage of CD4+CD25+FoxP3+ Treg cells was detected when cocultured with SAA MSCs compared to control MSCs (8.1 ± 0.5% vs 5.8 ± 0.8%, P < 0.01). Inconsistently, transforming growth factor-β (TGF-β) concentrations in the culture supernatant were decreased and IL-1β concentrations were elevated in the SAA group. Our data indicated impaired inhibition of SAA MSCs on Th17 activation and aberrant regulation of SAA MSCs on Treg differentiation. Increased IL-17 and IL-1β levels with decreased TGF-β levels in the supernatant suggested the potential of SAA MSCs for triggering a hyperinflammatory environment. Dysfunctional MSCs could contribute to the lack of immunoprotection in the bone marrow, which may be associated with SAA.

Altered Expression of microRNAs Implicated in Hematopoietic Dysfunction in the Extracellular Vesicles of Bone Marrow-Mesenchymal Stromal Cells in Aplastic Anemia

“…Data from our and other labs have confirmed that BM-MSC of AA patients have cellular and molecular defects, implying a possible role of these defects being responsible for their reduced ability in sustaining HSPC functions when compared to their normal counterparts 4,[7][8][9][10][11][12] . However, the mechanism by which BM-MSC impart their functional effect on HSPC in AA remains elusive.…”

Exploring the mechanism by which Angelica sinensis improves haematopoietic function in aplastic anaemia

“…The hyperinflammatory environment in severe AA is triggered by increased levels of IL-17 and IL-1β, along with decreased levels of TGF-β [16,17]. Furthermore, the single-cell profiling revealed the population of Th17-polarized CD4+CAMK4+ naïve T cells that exhibit activation of the IL-6/JAK3/STAT3 pathway, indicating a predisposition to proinflammatory pathogenesis in severe AA [18].…”

Formononetin reverses Treg/Th17 imbalance in immune-mediated bone marrow failure mice by regulating the PI3K/Akt signaling pathway

“…There are increasing evidences indicating that the balance between Treg cells and Th17 cells assumes a crucial role in the maintenance of immune homeostasis [ 11 ]. In patients with SAA, the immunomodulatory activity of Treg cells is impaired, whereas Th17 cells are excessively activated [ 12 , 13 ]. Thus, restoring the balance of Treg/Th17 cells can mitigate immune hyperactivity in SAA patients.…”