In patients with chronic aplastic anemia, bone marrow–derived MSCs regulate the Treg/Th17 balance by influencing the Notch/RBP-J/FOXP3/RORγt pathway

Abstract

The standard treatment for aplastic anemia (AA) in young patients is a matched sibling hematopoietic stem cell transplant. Transfusion of a chronic AA patient with allogeneic bone marrow–derived mesenchymal stromal cells (BMMSCs) is currently being developed as a cell-based therapy, and the safety and efficacy of such transfusions are being continuously improved. Nevertheless, the mechanisms by which BMMSCs exert their therapeutic effects remain to be elucidated. In this study, mesenchymal stromal cells (MSCs) obtained from bone marrow donors were concentrated and intravenously injected into 15 chronic AA patients who had been refractory to prior immunosuppressive therapy. We showed that BMMSCs modulate the levels of Th1, Th2, Th17 and Treg cells, as well as their related cytokines in chronic AA patients. Furthermore, the percentages of Th1 and Th17 cells among the H-MSCs decreased significantly, while the percentage Treg cells increased. The Notch/RBP-J/FOXP3/RORγt pathway was involved in modulating the Treg/Th17 balance after MSCs were transfused in vitro. Additionally, the role played by transfused MSCs in regulating the Treg/Th17 balance via the Notch/RBP-J/FOXP3/RORγt pathway was further confirmed in an AA mouse model. In summary, in humans with chronic AA, BMMSCs regulate the Treg/Th17 balance by affecting the Notch/RBP-J/FOXP3/RORγt pathway.

Mesenchymal Stem Cell Therapy for Aging Frailty

“…The tissue microenvironment into which MSCs migrate/are injected into also influences their immunosuppressive properties. MSCs located within an inflammatory microenvironment can suppress cytotoxic T cells ( 96 , 113 ), induce T regulatory cells ( 114 , 115 ), and stimulate macrophage polarization ( 116 ) (transition from an M1 to an M2 phenotype) thereby promoting an anti-inflammatory milieu. Furthermore, a recent study demonstrated that MSCs exert antibacterial effects ( 117 ) indicating that MSCs possess an immune function independent of the host's immune system.…”

Regulatory T cells and CD20+B cells in pediatric very severe aplastic anemia: possible clinical markers for evaluating the therapeutic efficacy and prognosis

“…Previous studies indicate Tregs function in the progression of some kind of autoimmune diseases like SAA [13][14][15], To our knowledge, blood Tregs are significantly decreased in AA patients than their counterparts in normal people [16]. Furthermore, Tregs can also regulate the function of B cells and other non-T cells diametrically.…”

Efficacy and safety of combined immunosuppressive therapy plus umbilical cord blood infusion in severe aplastic anemia patients: A cohort study

“…In addition, several previous studies have elucidated that treatment with CsA may increase the number of Tregs in patients with AA and other diseases ( 42 – 44 ). Previous studies have indicated good efficacy of CsA in the treatment of patients with AA, which may indicate that if it existed, the inhibition of Tregs by CsA may be limited and does not interfere with the treatment effect ( 1 , 45 – 47 ).…”