Human Adipose-Derived Stromal/Stem Cells Induce Functional CD4⁺CD25⁺FoxP3⁺CD127⁻Regulatory T Cells Under Low Oxygen Culture Conditions

Abstract

Human adipose tissue stromal/stem cells (ASCs) are known to induce proliferation of resting T cells under ambient (21%) O 2 conditions; however, ASCs exist physiologically under lower oxygen (5% O 2 ) conditions in adipose tissue. The effects of low oxygen levels on ASC immunomodulation of T cells are unknown. In this study, we show that ASCs stimulated proliferation of naive CD4+ T cells and the percentage of CD25 + T cells was significantly increased under both low and ambient O 2 . Forkhead box P3 (FoxP3) and transforming growth factor beta (TGF-b) mRNA expression were significantly increased when ASCs were cocultured with CD4 + T cells under low compared with ambient O 2 conditions. The low O 2 -induced regulatory T cells (iT regs ) exhibited functionality when added to mixed lymphocyte reactions as demonstrated by inhibition of peripheral blood mononuclear cell proliferation, and by > 300-fold increase in FoxP3 mRNA, and > 2-fold increase in TGF-b mRNA expression. These results demonstrate that under physiologically relevant low O 2 conditions, direct contact of human ASCs with naive CD4 + T cells induced functional iT regs .

Enhanced Immunosuppression of T Cells by Sustained Presentation of Bioactive Interferon-γ Within Three-Dimensional Mesenchymal Stem Cell Constructs

“…Despite the extensive use of biomaterials with specific biophysical and biochemical properties and ability to deliver biochemical stimuli to direct differentiation of MSCs, similar approaches have largely been unexplored for directing the immunomodulatory paracrine activity and broader trophic effects of MSCs. Numerous studies have demonstrated that MSC paracrine factor secretion is modulated in response to environmental cues in addition to the local cytokine milieu, including matrix composition, mechanics, and topography , , as well as oxygen tension . Furthermore, environmental stimuli are highly amenable to manipulation via biomaterials to specifically define the microenvironment of stem cells and direct their function .…”

Immunoevasive Pericytes From Human Pluripotent Stem Cells Preferentially Modulate Induction of Allogeneic Regulatory T Cells

“…TGF‐β has a central role in maintenance and induction of FoxP3 expression in vitro, activating signaling pathways involving SMADs and NFAT, which bind the TGF‐β sensitive element (enhancer) within the FoxP3 locus [52, 53]. In accordance with this, we demonstrate here that inhibition of TGF‐β signaling was accompanied with a parallel and significant reduction in the frequency of two T‐cell subpopulations, CD4 + CD25 − Foxp3 + and CD4 + CD25 high Foxp3 + , implying that the first may represent a subset of TGF‐β‐dependent Treg precursors.…”

Intravenous Administration of Bone Marrow-Derived Mesenchymal Stem Cell, but not Adipose Tissue-Derived Stem Cell, Ameliorated the Neonatal Hypoxic-Ischemic Brain Injury by Changing Cerebral Inflammatory State in Rat

“…The beneficial effect of MSC transplantation is related to their potency to differentiate into multiple lineages ( 18 ). Their administration has been shown to improve the tissue environment via endocrine/paracrine effects ( 19 , 20 ) and have immunosuppressive effects ( 21 , 22 ).…”