CD133+ adult bone marrow stem cells to promote liver regeneration - the role of platelets for hepatic homing and analyses of released factors for differentiation as well as proliferation subsequent to clinical hepatic resection

最初的临床经验表明，在8名计划扩大右肝切除的患者中，采用促进肝再生的新概念后，在门静脉栓塞右肝叶的同时，应用CD133+骨髓干细胞(BMSC)后，左肝段的增殖率增加了2.5倍。为了深入了解CD133+BMSC应用于改善生理性肝再生过程的信念和机制，将采用CD133+BMSC与原代肝细胞或分离的肝窦内皮细胞(SEC)的2D细胞共培养模型和2种全肝灌流模型。结合异种临床前小动物模型(与我们的临床概念类似)以及临床实验研究，我们将探索血小板和血小板衍生微粒(PMP)促进CD133+BMSC参与肝脏再生的潜力以及相应的治疗方案。在肝切除术后的患者中，细胞因子、生长因子和血小板激活水平将与外周血CD133+细胞动员、肝实质丢失水平和肝功能相关，并研究它们与原代肝细胞共培养时调节CD133+BMSC分化/增殖的能力。这些研究将有助于理解和改进使用CD133+骨髓间充质干细胞促进肝脏再生的治疗概念。除了有广泛肝部分切除指征的肿瘤患者的外科治疗外，这些研究得出的结果可能会对在其他急性和慢性肝损伤情况下促进器官再生的治疗产生影响。

Initial clinical experience with a novel concept to promote liver regeneration in 8 patients, scheduled for extended right liver resection, demonstrated a 2.5-fold increase of proliferation rates of left liver lobe segments subsequent to application of CD133+ bone marrow stem cells (BMSC) in addition to portal venous embolization of the right liver lobe. To gain insight in faith and mechanisms of CD133+BMSC applied to improve physiological liver regeneration processes 2D-cell co-culture models of CD133+BMSC with either primary liver cells or isolated sinusoidal endothelial cells (SEC) and 2 whole liver perfusion models will be utilized. In concert with a xenogeneic pre-clinical small animal model - analogue to our clinical concept – as well as clinical experimental studies, the potential of platelets and platelet derived microparticles (PMP) to promote CD133+BMSC participation in liver regeneration with consequent therapeutic options will be explored. In patients subsequent to liver resection, cytokines, growth factors and levels of platelet activation will be correlated with peripheral CD133+ cell mobilisation, levels of hepatic parenchymal loss and liver function and investigated for their capacity to modulate differentiation/ proliferation of CD133+BMSC in co-culture with primary liver cells. These studies will help to understand and improve a therapeutic concept using CD133+BMSC to promote liver regeneration. Beyond the surgical treatment of oncological patients with an indication for extensive partial hepatectomy the findings derived from these studies may have an impact on therapeutic promotion of organ regeneration following other scenarios of acute and chronic liver damage.