Manipal Institute of Regenerative Medicine, Constituent Institute of Manipal University, Bangalore, Karnataka, India.
PLoS One. 2010 Feb 2;5(2):e9016. doi: 10.1371/journal.pone.0009016.
Wharton's jelly derived stem cells (WJMSCs) are gaining attention as a possible clinical alternative to bone marrow derived mesenchymal stem cells (BMMSCs) owing to better accessibility, higher expansion potential and low immunogenicity. Usage of allogenic mesenchymal stem cells (MSC) could be permissible in vivo only if they retain their immune properties in an inflammatory setting. Thus the focus of this study is to understand and compare the immune properties of BMMSCs and WJMSCs primed with key pro-inflammatory cytokines, Interferon-gamma (IFNgamma) and Tumor Necrosis Factor-alpha (TNFalpha).
METHODOLOGY/PRINCIPAL FINDINGS: Initially the effect of priming on MSC mediated suppression of alloantigen and mitogen induced lymphoproliferation was evaluated in vitro. Treatment with IFNgamma or TNFalpha, did not ablate the immune-suppression caused by both the MSCs. Extent of immune-suppression was more with WJMSCs than BMMSCs in both the cases. Surprisingly, priming BMMSCs enhanced suppression of mitogen driven lymphoproliferation only; whereas IFNgamma primed WJMSCs were better suppressors of MLRs. Further, kinetic analysis of cytokine profiles in co-cultures of primed/unprimed MSCs and Phytohematoagglutinin (PHA) activated lymphocytes was evaluated. Results indicated a decrease in levels of pro-inflammatory cytokines. Interestingly, a change in kinetics and thresholds of Interleukin-2 (IL-2) secretion was observed only with BMMSCs. Analysis of activation markers on PHA-stimulated lymphocytes indicated different expression patterns in co-cultures of primed/unprimed WJMSCs and BMMSCs. Strikingly, co-culture with WJMSCs resulted in an early activation of a negative co-stimulatory molecule, CTLA4, which was not evident with BMMSCs. A screen for immune suppressive factors in primed/unprimed WJMSCs and BMMSCs indicated inherent differences in IFNgamma inducible Indoleamine 2, 3-dioxygenase (IDO) activity, Hepatocyte growth factor (HGF) and Prostaglandin E-2 (PGE2) levels which could possibly influence the mechanism of immune-modulation.
CONCLUSION/SIGNIFICANCE: This study demonstrates that inflammation affects the immune properties of MSCs distinctly. Importantly different tissue derived MSCs could utilize unique mechanisms of immune-modulation.
由于更容易获得、具有更高的扩增潜力和较低的免疫原性，Wharton 胶衍生的干细胞（WJMSCs）作为骨髓间充质干细胞（BMMSCs）的一种可能的临床替代物而受到关注。只有在炎症环境中保留其免疫特性的情况下，同种异体间充质干细胞（MSC）的使用才可能是允许的。因此，本研究的重点是了解和比较经关键促炎细胞因子干扰素-γ（IFNγ）和肿瘤坏死因子-α（TNFα）预刺激的 BMMSCs 和 WJMSCs 的免疫特性。
方法/主要发现：最初，在体外评估了预刺激对 MSC 介导的同种异体抗原和丝裂原诱导的淋巴增殖抑制作用的影响。用 IFNγ 或 TNFα 处理并没有消除两种 MSC 引起的免疫抑制。在这两种情况下，WJMSCs 的免疫抑制程度都高于 BMMSCs。令人惊讶的是，预刺激 BMMSCs 仅增强了对丝裂原驱动的淋巴增殖的抑制作用；而 IFNγ 预刺激的 WJMSCs 是更好的 MLR 抑制剂。此外，还评估了在预刺激/未预刺激 MSC 和植物血球凝集素（PHA）激活的淋巴细胞共培养物中的细胞因子谱的动力学分析。结果表明促炎细胞因子水平降低。有趣的是，仅在 BMMSCs 中观察到白细胞介素-2（IL-2）分泌的动力学和阈值的变化。在 PHA 刺激的淋巴细胞上分析激活标记物表明，在预刺激/未预刺激的 WJMSCs 和 BMMSCs 的共培养物中存在不同的表达模式。引人注目的是，与 BMMSCs 相比，共培养物中 CTLA4 的负共刺激分子的早期激活，这在 WJMSCs 中并不明显。对预刺激/未预刺激的 WJMSCs 和 BMMSCs 中的免疫抑制因子进行筛选表明，IFNγ 诱导的吲哚胺 2,3-双加氧酶（IDO）活性、肝细胞生长因子（HGF）和前列腺素 E-2（PGE2）水平存在固有差异，这可能影响免疫调节机制。
结论/意义：本研究表明炎症会显著影响 MSC 的免疫特性。重要的是，不同组织来源的 MSC 可能利用独特的免疫调节机制。
