Department of Anesthesiology, Tulane University, New Orleans, Louisiana, USA.
PLoS One. 2010 Apr 26;5(4):e10088. doi: 10.1371/journal.pone.0010088.
Our laboratory and others reported that the stimulation of specific Toll-like receptors (TLRs) affects the immune modulating responses of human multipotent mesenchymal stromal cells (hMSCs). Toll-like receptors recognize "danger" signals, and their activation leads to profound cellular and systemic responses that mobilize innate and adaptive host immune cells. The danger signals that trigger TLRs are released following most tissue pathologies. Since danger signals recruit immune cells to sites of injury, we reasoned that hMSCs might be recruited in a similar way. Indeed, we found that hMSCs express several TLRs (e.g., TLR3 and TLR4), and that their migration, invasion, and secretion of immune modulating factors is drastically affected by specific TLR-agonist engagement. In particular, we noted diverse consequences on the hMSCs following stimulation of TLR3 when compared to TLR4 by our low-level, short-term TLR-priming protocol.
Here we extend our studies on the effect on immune modulation by specific TLR-priming of hMSCs, and based on our findings, propose a new paradigm for hMSCs that takes its cue from the monocyte literature. Specifically, that hMSCs can be polarized by downstream TLR signaling into two homogenously acting phenotypes we classify here as MSC1 and MSC2. This concept came from our observations that TLR4-primed hMSCs, or MSC1, mostly elaborate pro-inflammatory mediators, while TLR3-primed hMSCs, or MSC2, express mostly immunosuppressive ones. Additionally, allogeneic co-cultures of TLR-primed MSCs with peripheral blood mononuclear cells (PBMCs) predictably lead to suppressed T-lymphocyte activation following MSC2 co-culture, and permissive T-lymphocyte activation in co-culture with MSC1.
Our study provides an explanation to some of the conflicting reports on the net effect of TLR stimulation and its downstream consequences on the immune modulating properties of stem cells. We further suggest that MSC polarization provides a convenient way to render these heterogeneous preparations of cells more uniform while introducing a new facet to study, as well as provides an important aspect to consider for the improvement of current stem cell-based therapies.
我们的实验室和其他实验室的研究报告指出，特定 Toll 样受体 (TLR) 的刺激会影响人多能间充质基质细胞 (hMSC) 的免疫调节反应。Toll 样受体识别“危险”信号，其激活会导致深刻的细胞和全身反应，动员先天和适应性宿主免疫细胞。触发 TLR 的危险信号是在大多数组织病理学后释放的。由于危险信号招募免疫细胞到损伤部位，我们推断 hMSC 可能以类似的方式被招募。事实上，我们发现 hMSC 表达几种 TLR（例如 TLR3 和 TLR4），并且它们的迁移、侵袭和免疫调节因子的分泌受到特定 TLR 激动剂结合的显著影响。特别是，我们注意到在我们的低水平、短期 TLR 引发方案刺激 TLR3 时，hMSC 会产生与 TLR4 刺激时不同的后果。
在这里，我们扩展了我们对特定 TLR 引发的 hMSC 免疫调节影响的研究，并根据我们的发现，提出了一个新的 hMSC 范式，该范式从单核细胞文献中汲取了线索。具体来说，hMSC 可以通过下游 TLR 信号被极化为两种均质作用的表型，我们在这里将其分类为 MSC1 和 MSC2。这个概念来自于我们的观察，即 TLR4 引发的 hMSC，或 MSC1，主要产生促炎介质，而 TLR3 引发的 hMSC，或 MSC2，主要表达免疫抑制性介质。此外，TLR 引发的 MSC 与外周血单核细胞 (PBMC) 的异基因共培养可预测性地导致 MSC2 共培养后 T 淋巴细胞激活受到抑制，而 MSC1 共培养中 T 淋巴细胞激活允许。
我们的研究为一些关于 TLR 刺激的净效应及其对干细胞免疫调节特性的下游后果的相互矛盾的报告提供了解释。我们进一步表明，MSC 极化为这些异质细胞制剂提供了一种更均匀的方法，同时为研究提供了一个新的方面，并为改进当前基于干细胞的治疗提供了一个重要方面。
