Platelet activation triggered by CD39L1/NTPDase2 facilitates CD133+/CD45* stem cell mediated liver generation

肝损伤后CD133+祖细胞的归巢和隔离及其分化的机制尚不清楚。鉴于肝再生过程中血管重建需要外核酶，我们在第一年研究了CD133+/CD45+ BMSCs的功能是否由嘌呤能外核酶决定。我们可以证明CD39/NTPDase1（和CD39L1/NTPDase2）是由CD133+/CD45+ BMSCs表达的，嘌呤能信号在这些细胞的动员和功能促进肝脏再生中起着至关重要的作用。基于这些观察结果，我们计划在第二年研究由CD39L1/NTPDase2启动的adp相关血小板激活是否以及如何促进CD133+/CD45+干细胞介导的肝脏再生。我们将研究野生型、CD39L1/NTPDase2缺失和CD39/NTPDase1缺失小鼠在70%肝切除术后诱导血小板减少或血小板增多的肝脏再生情况。我们计划对野生型和命名敲除小鼠的CD133+/CD45+骨髓间充质干细胞进行静脉注射，以进一步研究外核苷酶局部表达的重要性。

Mechanisms underlying the process of homing and sequestration of CD133+ progenitor cells after liver injury and their differentiation remain unclear. Given the requirement of ectonucleotidases for vascular reconstitution during liver regeneration, we have examined within the first year whether CD133+/CD45+ BMSCs functions are dictated by purinergic ectoenzymes. We could show that CD39/NTPDase1 (and CD39L1/NTPDase2) are expressed by CD133+/CD45+ BMSCs and that purinergic signaling plays crucial roles in mobilization and function of these cells in boosting liver regeneration. Based on these observations, we plan to investigate in the second year whether and how ADP-associated platelet activation, initiated by CD39L1/NTPDase2, facilitates CD133+/CD45+ stem cell mediated liver regeneration. We will investigate liver regeneration in wild-type, CD39L1/NTPDase2 null and CD39/NTPDase1 null mice with induced thrombocytopenia or thrombocytosis following 70% hepatectomy. We plan to administer i.v. CD133+/CD45+ BMSCs from wild-type and named knock-out mice to further address the importance of local expression of ectonucleotidases.