Secreted factors from dental pulp stem cells improve Sjögren's syndrome via regulatory T cell-mediated immunosuppression.
Secreted factors from dental pulp stem cells improve Sjögren's syndrome via regulatory T cell-mediated immunosuppression.
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DOI：
10.1186/s13287-021-02236-6
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发表时间：
2021-03-16
影响因子：
7.5
通讯作者：
Nakamura S
中科院分区：
文献类型：
--
作者：
Matsumura-Kawashima M;Ogata K;Moriyama M;Murakami Y;Kawado T;Nakamura S
干燥综合征（SS）是一种慢性自身免疫性疾病，主要特征是唾液腺和泪腺炎症。活化的T细胞通过产生促炎性细胞因子，导致正反馈回路的建立，从而有助于疾病的发病机制。本研究旨在探讨牙髓干细胞（DPSCs）和骨髓间充质干细胞（BMMSCs）分泌因子对干燥综合征（SS）患者唾液分泌减少的影响及其机制。用无血清Dulbecco改良Eagle培养基补充80%汇合的干细胞并孵育48小时;随后，收集来自DPSC（DPSC-CM）和BMMSC（BMMSC-CM）的条件培养基。进行细胞因子阵列分析以评估培养基中存在的细胞因子的类型。进行流式细胞术分析以评估在DPSC-CM或BMMSC-CM中培养的活化T细胞的数目。随后，将DPSC-CM或BMMSC-CM施用于SS小鼠模型。将小鼠分为以下组（每组n = 6）：未处理组、Dulbecco改良Eagle培养基（-）组、BMMSC-CM组和DPSC-CM组。进行唾液腺的组织学分析。检测下颌下腺（SMG）中辅助性T细胞亚群相关细胞因子的基因和蛋白表达水平。DPSC-CM含有更多具有组织再生机制的分泌因子，如细胞增殖、抗炎作用和免疫调节作用。在流式细胞术分析中，DPSC-CM比其他组更有效地抑制活化的T细胞。与其他组相比，DPSC-CM组SS小鼠的刺激唾液流率增加。此外，给予DPSC-CM的小鼠的SMG中的炎症部位的数量低于其他组。DPSC-CM组IL-10和TGF-β1表达上调，IL-4和IL-17 a表达下调。与其他组相比，DPSC-CM给药组的调节性T（Treg）细胞百分比显著增加，17型Th（Th 17）细胞百分比显著降低。这些结果表明DPSC-CM通过促进小鼠脾脏Treg细胞分化和抑制Th 17细胞分化来改善SS。在线版本包含补充材料，可通过10.1186/s13287-021-02236-6获得。
Sjögren’s syndrome (SS) is a chronic autoimmune disease primarily characterized by inflammation in the salivary and lacrimal glands. Activated T cells contribute to disease pathogenesis by producing proinflammatory cytokines, which leads to a positive feedback loop establishment. The study aimed to evaluate the effects of secreted factors derived from dental pulp stem cells (DPSCs) or bone marrow mesenchymal stem cells (BMMSCs) on hyposalivation in SS and to investigate the mechanism involved. Eighty percent confluent stem cells were replenished with serum-free Dulbecco’s modified Eagle’s medium and incubated for 48 h; following which, conditioned media from DPSCs (DPSC-CM) and BMMSCs (BMMSC-CM) were collected. Cytokine array analysis was performed to assess the types of cytokines present in the media. Flow cytometric analysis was performed to evaluate the number of activated T cells cultured in DPSC-CM or BMMSC-CM. Subsequently, DPSC-CM or BMMSC-CM was administered to an SS mouse model. The mice were categorized into the following groups (n = 6 each): non-treatment, Dulbecco’s modified Eagle’s medium (−), BMMSC-CM, and DPSC-CM. Histological analysis of the salivary glands was performed. The gene and protein expression levels of cytokines associated with T helper subsets in the submandibular glands (SMGs) were evaluated. DPSC-CM contained more secreted factors with tissue-regenerating mechanisms, such as cell proliferation, anti-inflammatory effects, and immunomodulatory effects. DPSC-CM was more effective in suppressing the activated T cells than other groups in the flow cytometric analysis. The stimulated salivary flow rate increased in SS mice with DPSC-CM compared with that in the other groups. In addition, the number of inflammation sites in SMGs of the mice administered with DPSC-CM was lower than that in the other groups. The expression levels of interleukin (Il)-10 and transforming growth factor-β1 were upregulated in the DPSC-CM group, whereas those of Il-4 and Il-17a were downregulated. The DPSC-CM-administered group presented with a significantly increased percentage of regulatory T (Treg) cells and a significantly decreased percentage of type 17 Th (Th17) cells compared with the other groups. These results indicated that DPSC-CM ameliorated SS by promoting Treg cell differentiation and inhibiting Th17 cell differentiation in the mouse spleen. The online version contains supplementary material available at 10.1186/s13287-021-02236-6.
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