高迁移率蛋白-1对造血干细胞归巢的影响及机制

Hematopoietic stem cell transplantation is the only available therapeutic strategy that could cure many types of hematological malignancies. Umbilical cord hematopoietic stem cell transplantation is characterized by its high rate of successful match and low mobility and severity of GVHD after transplantation. However, the number of hematopoietic stem cells in umbilical cord blood is relatively low, and thus significantly affects the engraftment and elongates duration of hematopoietic reconstitution. This is a key unsolved clinical problem in the field. The engraftment of hematopoietic stem cells not only depends on the number of hematopoietic stem cells, but also is determined by its homing efficiency to the bone marrow. We recently found that hematopoietic stem cells from lupus mice have 13 times higher engraftment efficiency, as compared to the wild-type mice-derived hematopoietic stem cells. This phenomenon is closely associated with high levels of high mobility group box 1 protein (HMGB1) in the lupus mice’s serum. In the light of these findings, we assessed the effect of HMGB1 on the homing of hematopoietic stem cells, and found that exposure of hematopoietic stem cells to purified recombinant HMGB1 protein 6 times increased migration of hematopoietic stem cells. Thus, we postulate that pre-incubation of hematopoietic stem cells by HMGB1 could enhance the engraftment after umbilical cord hematopoietic stem cell transplantation. We next will test this working hypothesis by using mouse hematopoietic stem cell transplantation models, and study its underlying mechanisms.

造血干细胞移植是多种恶性血液病的根治手段。脐血造血干细胞移植具有配型成功率高、移植后GVHD发生率低且程度轻的特点。但脐血造血干细胞数量相对不足，影响了移植的植入率和延长了造血重建时间，是临床上亟待解决的问题。造血干细胞移植的植入率不仅依赖于造血干细胞的数量，而且取决于造血干细胞迁移至骨髓（“归巢”）的效率。我们最近发现：与正常小鼠造血干细胞相比，狼疮小鼠造血干细胞在数量相对不足的情况下能使移植的植入率提高13倍。该现象与狼疮小鼠血清中HMGB1蛋白的水平密切相关。我们随后检测了HMGB1对造血干细胞迁移能力的影响，发现：使用HMGB1纯化蛋白预孵育造血干细胞后能使该细胞的迁移能力增强6倍。基于上述发现，我们提出：使用HMGB1预孵育造血干细胞可能提高脐血造血干细胞移植的植入率。围绕上述科学假设，我们一方面将采用小鼠造血干细胞移植模型来验证该假说，另一方面将深入探讨其分子机制。

Caspase蛋白家族中的Caspase11近几年被发现是细菌内毒素的细胞内受体，介导细胞焦亡，从而引起花生酸类物质以及细胞因子如白介素1-a等的释放，过度活化Caspase11导致的细胞焦亡是内毒素血症休克发病机制的关键。但是内毒素血症以及脓毒症中内毒素进入细胞胞浆活化Caspase11的具体机制尚不明确。我们发现HMGB1蛋白可以与内毒素结合并介导其入胞。肝脏细胞释放的HMGB1，通过免疫细胞上的RAGE受体介导的胞吞作用进入溶酶体；在溶酶体的酸性环境中HMGB1可以破坏磷脂双层，进而内毒素被释放入细胞浆，从而活化非经典炎性小体Caspase-11并导致细胞焦亡。条件性敲除肝脏细胞HMGB1、抑制肝细胞释放HMGB1、中和循环中的HMGB1或者敲除RAGE受体都可以抑制细胞焦亡，降低内毒素血症及脓毒症模型动物死亡率。这些研究结果揭示了机体对细菌内毒素的应答机制，为感染性休克提供新的治疗思路。