Kaundal Urvashi, Rakha Aruna
Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160012, India.
Scleroderma Genomics and Health Disparities Unit, NIAMS, NIH, Bethesda, USA.
Biochem Biophys Rep. 2024 Aug 10;39:101809. doi: 10.1016/j.bbrep.2024.101809. eCollection 2024 Sep.
Mesenchymal stromal cells (MSCs) have evolved as an invaluable therapeutic cell type due to their broad therapeutic properties. Bone marrow-derived MSCs are currently being applied in numerous clinical trials, and the initial results have been encouraging. However, heterogeneous responsiveness amongst patients is also being experienced; therefore, the efficacy of MSCs is still debatable. Host microenvironment plays an essential role in determining the fate of MSCs . Recent studies have indicated the role of toll-like receptors (TLR) in modulating the biological properties of MSCs. TLRs are expressed by MSCs, and activation of TLR3 and TLR4 can alter the functionality of MSCs. While MSCs can suppress the effector and memory T cell function by promoting regulatory T cells, the effect of TLR activation on MSC-mediated immune cell induction is still not well understood. This study was performed to understand the TLR licensing of MSCs and its impact on MSC-mediated immunomodulation. We found that TLR3 mediated activation of MSCs (TLR3-MSCs) increased the expression of G-CSF & IL-10 while TLR4-mediated activation of MSCs led to an increase in CXCL-1, CXCL-10, and CXCL-12. To study the immunological aspect, an co-culture model was established-to imitate the brief interaction of MSCs and immune cells. We found that TLR3-MSCs led to increase in CD4 and CD8 naive T (T) cells and vice versa for effector (T) and memory T (T) cells, while TLR4-MSCs did not show any effect. Moreover, only TLR3-MSCs led to a non-significant increase in the regulatory T cells (T) and Double negative regulatory cells. No change in B cell profile was evident while TLR3-MSCs depicted an increasing trend in regulatory B cells which was not statistically significant. TLR3 MSCs also inhibited the T cell proliferation in our setup. Our data indicate that TLR3 priming may regulate the function of MSCs through immunomodulation. Understanding the role of TLRs and other microenvironmental factors causing subdued responses of MSCs would allow the uninhibited use of MSCs for many diseased conditions.
间充质基质细胞（MSCs）因其广泛的治疗特性已发展成为一种极具价值的治疗性细胞类型。骨髓来源的MSCs目前正在众多临床试验中应用，初步结果令人鼓舞。然而，患者之间也存在异质性反应；因此，MSCs的疗效仍存在争议。宿主微环境在决定MSCs的命运中起着至关重要的作用。最近的研究表明了Toll样受体（TLR）在调节MSCs生物学特性中的作用。MSCs表达TLRs，TLR3和TLR4的激活可改变MSCs的功能。虽然MSCs可通过促进调节性T细胞来抑制效应性和记忆性T细胞功能，但TLR激活对MSCs介导的免疫细胞诱导的影响仍未完全了解。进行本研究以了解MSCs的TLR许可及其对MSCs介导的免疫调节的影响。我们发现TLR3介导的MSCs激活（TLR3-MSCs）增加了G-CSF和IL-10的表达，而TLR4介导的MSCs激活导致CXCL-1、CXCL-10和CXCL-12增加。为了研究免疫学方面，建立了共培养模型以模拟MSCs与免疫细胞的短暂相互作用。我们发现TLR3-MSCs导致CD4和CD8初始T（T）细胞增加，而效应性（T）和记忆性T（T）细胞则相反，而TLR4-MSCs没有显示任何影响。此外，只有TLR3-MSCs导致调节性T细胞（T）和双阴性调节细胞非显著性增加。B细胞谱没有明显变化，而TLR3-MSCs显示调节性B细胞有增加趋势，但无统计学意义。在我们的实验设置中，TLR3 MSCs也抑制了T细胞增殖。我们的数据表明，TLR3启动可能通过免疫调节来调节MSCs的功能。了解TLRs和其他导致MSCs反应减弱的微环境因素的作用将使MSCs能够不受限制地用于许多疾病状况。
