Immunomodulatory effect of human umbilical cord mesenchymal stem cells on T lymphocytes in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease which is lack of effective therapies. Abnormal activation, proliferation, and differentiation of T lymphocytes are closely related to RA. Mesenchymal stem cells (MSCs) can be used for RA treatment due to their immunoregulatory effects. However, the specific molecular mechanisms have not been fully elucidated and the therapeutic effect has been inconsistent. This study investigated the immunomodulatory effect of human umbilical cord MSCs (hUCMSCs) on T lymphocytes in collagen-induced arthritis (CIA) rats and RA patients to clarify the possible mechanism of hUCMSCs in RA treatment. The effects of hUCMSCs on arthritis index, radiological and synovial pathological changes, T lymphocyte proliferation and apoptosis, RORγt and Foxp3 expression, Th17 and Treg cell ratios, and IL-17 and TGF-β levels were assessed in CIA rats. Further, we verified the effect of hUCMSCs in RA patients, and compared the effect of hUCMSCs with that of hUCMSC derived extracellular vesicles (EVs). The results showed that hUCMSCs inhibited the proliferation and promoted apoptosis in T lymphocytes, downregulated RORγt mRNA and protein expression, decreased Th17 cell ratio, upregulated Foxp3 mRNA and protein expression, and increased Treg cell ratio in the spleen. Furthermore, they downregulated RORγt and Foxp3 expression in the joints, and inhibited IL-17 and promoted TGF-β expression in the serum, thereby improving arthritis, delaying radiological progression, and inhibiting synovial hyperplasia in CIA rats. In vitro the effects of hUCMSCs and EVs were consistent with those in vivo. Therefore, hUCMSCs may be expected to serve as a new therapy for RA.

Ma D ，Xu K ，Zhang G ，Liu Y ，Gao J ，Tian M ，Wei C ，Li J ，Zhang L ... -  《-》

Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorate collagen-induced arthritis via immunomodulatory T lymphocytes.

Rheumatoid arthritis (RA) is an autoimmune disease for which there are currently no effective therapies. Although mesenchymal stem cells (MSCs) can prevent arthritis through immunomodulatory mechanisms, there are several associated risks. Alternatively, MSC-derived small extracellular vesicles (sEVs) can mimic the effects of MSCs, while reducing the risk of adverse events. However, few studies have examined sEVs in the context of RA. Here, we evaluate the immunomodulatory effects of human umbilical cord MSC (hUCMSC)-derived sEVs on T lymphocytes in a collagen-induced arthritis (CIA) rat model to elucidate the possible mechanism of sEVs in RA treatment. We then compare these mechanisms to those of MSCs and methotrexate (MTX). The arthritis index and synovial pathology were assessed. T lymphocyte proliferation and apoptosis, Th17 and Treg proportions, and interleukin (IL)-17, IL-10, and transforming growth factor (TGF)-β expression were detected using flow cytometry. Retinoic acid receptor-related orphan receptor gamma t (RORγt) and forkhead box P3 (FOXP3), which are master transcriptional regulators of Th17 and Treg differentiation, were also assessed using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). sEV treatment ameliorated arthritis and inhibited synovial hyperplasia in a dose-dependent manner. These effects were mediated by inhibiting T lymphocyte proliferation and promoting their apoptosis, while decreasing Th17 cell proportion and increasing that of Treg cells in the spleen, resulting in decreased serum IL-17, and enhanced IL-10 and TGF-β expression. Transcriptionally, sEVs decreased RORγt and increased FOXP3 expression in the spleen, and decreased RORγt and FOXP3 expression in the joints. In some aspects sEVs were more effective than MSCs and MTX in treating CIA. hUCMSC-derived sEVs ameliorate CIA via immunomodulatory T lymphocytes, and might serve as a new therapy for RA.

Xu K ，Ma D ，Zhang G ，Gao J ，Su Y ，Liu S ，Liu Y ，Han J ，Tian M ，Wei C ，Zhang L ... -  《-》

Bone marrow CD11b(+)F4/80(+) dendritic cells ameliorate collagen-induced arthritis through modulating the balance between Treg and Th17.

Tolerogenic dendritic cells (DCs) are well-known to show an immunosuppressive function. In this study we determine the therapeutic effects and potential mechanisms of transferred bone marrow (BM) CD11b(+)F4/80(+) DCs on collagen-induced arthritis (CIA) in mice. Murine BM CD11b(+)F4/80(+) DCs were generated under the stimulation of GM-CSF and IL-4, and the function of BM CD11b(+) F4/80(+) DCs was identified by measuring the levels of IL-10, TGF-beta and indoleamine 2,3-dioxygenase (IDO). BM CD11b(+)F4/80(+) DCs were transferred to CIA mice by intravenous injections. The histopathology of joint and spleen were evaluated. T lymphocyte proliferation, Treg and Th17 subsets were analyzed. The expressions of Foxp3, Helios and RORγt in T lymphocytes co-cultured with BM CD11b(+)F4/80(+) DCs were measured in vitro. We found that BM CD11b(+)F4/80(+) DCs induced by GM-CSF and IL-4 could express high levels of IL-10, TGF-beta and IDO. BM CD11b(+)F4/80(+) DCs significantly reduced the pathologic scores in joints and spleens, which correlated significantly with the reduced T lymphocyte proliferation and Th17 cell number, and with the increased Tregs number. In vitro, OVA-pulsed BM CD11b(+)F4/80(+) DCs promoted Treg cell expansion, enhanced IL-10 and CTLA-4 protein expression, augmented Foxp3 and Helios mRNA expression, and inhibited RORγt and IL-17 mRNA expression. Taken together, BM CD11b(+)F4/80(+) DCs are able to ameliorate the development and severity of CIA, at least partly by inducing Foxp3(+) Treg cell expansion and suppressing Th17 function. The BM CD11b(+)F4/80(+) DCs might have a promising immunotherapeutic potential for autoimmune arthritis.

Zhang L ，Fu J ，Sheng K ，Li Y ，Song S ，Li P ，Song S ，Wang Q ，Chen J ，Yu J ，Wei W ... -  《-》

Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis.

Liu Y ，Mu R ，Wang S ，Long L ，Liu X ，Li R ，Sun J ，Guo J ，Zhang X ，Guo J ，Yu P ，Li C ，Liu X ，Huang Z ，Wang D ，Li H ，Gu Z ，Liu B ，Li Z ... -  《-》

Human umbilical cord mesenchymal stem cells improve the immune-associated inflammatory and prothrombotic state in collagen type-Ⅱ-induced arthritic rats.

Gu J ，Gu W ，Lin C ，Gu H ，Wu W ，Yin J ，Ni J ，Pei X ，Sun M ，Wang F ，Li Z ，Cai X ，Ren M ，Yu Z ，Gu X ... -  《-》