Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Tissue Eng Part A. 2010 Sep;16(9):2987-97. doi: 10.1089/ten.tea.2009.0731.
Due to their immunomodulatory functions, mesenchymal stem cells (MSCs) have great potential for clinical applications to prevent rejection in organ transplantation and to prevent graft-versus-host disease in hematopoietic stem cell (HSC) transplantation. Since dendritic cells (DCs) play an important role in modulating diverse T cell responses, including rejection and graft-versus-host disease, the goal of this study was to investigate whether MSCs modulate DC differentiation from HSCs and if this effect could be one of the mechanisms for MSCs' immune-modulating functions. Our results demonstrate that differentiation of HSCs into mature DCs is inhibited in the presence of MSCs. Similar frequency of dendritic precursors in the cultures, either with or without MSCs, suggests that the inhibition of MSCs on the differentiation of mature DCs from HSCs could be due to the arresting of maturation at the dendritic precursor step. Reduced levels of cyclic AMP, adenosine 3',5'-cyclic monophosphate (cAMP) and beta-catenin in DC-like cells from the cocultures are detected, suggesting that induction of apoptosis and inhibition of differentiation could be the basis for the inhibition of mature DCs from HSCs by MSCs. Further, our results demonstrate that DCs derived from HSCs in the presence of MSCs are functionally impaired, especially for those after direct contact with MSCs. To investigate the basis of functional impairment, our data show downregulated tumor necrosis factor-alpha and transforming growth factor-beta1 secretion and upregulated interleukin-6 (IL6) and IL1beta secretion in the cultures with MSCs. Together, MSCs can inhibit differentiation of mature DCs from HSCs by arresting them at the precursor stage and induce their apoptosis. Further, HSC-derived DCs in the presence of MSCs are functionally impaired, which could be partly due to the upregulation of IL6 secretion.
由于间充质干细胞 (MSCs) 具有免疫调节功能，因此它们在临床应用中具有很大的潜力，可用于预防器官移植中的排斥反应和造血干细胞 (HSC) 移植中的移植物抗宿主病。由于树突状细胞 (DCs) 在调节多种 T 细胞反应中起着重要作用，包括排斥反应和移植物抗宿主病，因此本研究的目的是研究 MSCs 是否调节 HSCs 分化为成熟 DCs，以及这种作用是否是 MSCs 免疫调节功能的一种机制。我们的研究结果表明，在 MSC 存在的情况下，HSCs 向成熟 DCs 的分化受到抑制。在有或没有 MSC 的情况下，树突状前体细胞的频率相似，这表明 MSC 对 HSCs 分化为成熟 DCs 的抑制作用可能是由于在树突状前体细胞阶段成熟被阻止。在共培养物中的 DC 样细胞中检测到环磷酸腺苷 (cAMP)、环磷酸腺苷 (adenosine 3',5'-cyclic monophosphate，cAMP) 和β-连环蛋白的水平降低，表明诱导凋亡和抑制分化可能是 MSC 抑制 HSCs 成熟 DCs 的基础。此外，我们的结果表明，在 MSC 存在的情况下，从 HSCs 衍生的 DCs 功能受损，特别是那些与 MSC 直接接触的 DCs。为了研究功能受损的基础，我们的数据表明，在有 MSC 的情况下，培养物中肿瘤坏死因子-α和转化生长因子-β1 的分泌减少，白细胞介素-6 (IL-6) 和白细胞介素-1β (IL-1β) 的分泌增加。总之，MSC 可通过阻止其在祖细胞阶段分化来抑制 HSCs 成熟 DCs 的分化，并诱导其凋亡。此外，在 MSC 存在的情况下，HSC 衍生的 DCs 功能受损，这可能部分是由于 IL-6 分泌的上调。
