已证实MSCs具有免疫调节作用，这在治疗急性肝衰竭（AHF）中尤为重要。Kupffer细胞是肝巨噬细胞，司职天然免疫功能，是内毒素所致肝损伤进而肝衰竭的关键环节，MSCs治疗AHF应与Kupffer细胞有必然的联系。推测MSCs主要通过对Kupffer细胞功能的抑制作用，调节免疫失调，使AHF恢复。为验证此假说，拟首先进行在聚肌胞/内毒素脂多糖(LPS)刺激、损伤肝细胞条件下的MSCs和Kupffer细胞混合培养，观测细胞活性、PGE2、TNF-α等细胞因子变化，体外评价MSCs对Kupffer细胞的调节作用；在此基础上，制备抑制/耗竭Kupffer细胞的AHF小鼠模型，体内移植MSCs，观察Kupffer细胞对MSCs治疗AHF作用的影响；围绕LPS信号转导系统，挖掘关键的细胞因子和受体，利用对应的拮抗剂和增强剂进行干预，阐释MSCs通过调节Kupffer细胞治疗AHF的细胞与分子机制。

Mesenchymal stem cells (MSCs) are not only characterized as multipotent stromal cells with the capacity for both self-renewal and differentiation into mesodermal cell lineages, but also have immunomodulation potential by modulating both innate and adaptive immune responses. The immunoregulatory functions of MSCs should be more important for the treatment of acute hepatic failure（AHF）. It has been well know that Kupffer cells, the liver macrophagocyte, is a key link of endotoxin-induced liver injuries and hepatic failure, so we presume that the therapy of MSCs on AHF is results in the modulation of immune disturbance by inhibiting the functions of Kupffer cells. To validate the hypothesis, cell activity, cytokine, such as transforming growth factor beta (TGF-β), prostaglandin E2 (PGE2), necrosis factor-alpha (TNF-α), interferon-gamma（IFN-γ）, interleukin（IL）, will be examined in co-cultivation of MSCs, Kupffer cells and hepatocytes stimulated by polyinosinic acid:polycytidilic acid (poly i:c) or lipopolysaccharide (LPS) for the evaluation of regulation MSCs on Kupffer cells in vitro. Then, the Kupffer cell functional activity inhibition or cell exhaustion mouse AHF model will be prepared. MSCs will be transplanted in mice that with and without Kupffer cells exhaustion or functions inhibition to observe the effect of Kupffer cells for the treatment of MSCs on AHF. Further, some key cytokines and receptors related LPS signal transduction system will be investigated by antagonist or enhancement correspondingly. Final, we hope to explain the cell and molecule mechanism of MSCs for AHF therapy through Kupffer cells modulation and provide an immunoregulatory evidence of MSCs in the treatment of AHF.