SPARC对B淋巴细胞发育和功能影响研究

The development of B lineage cells is a dynamic processs. B lineage cells in different development stages reside within distinct, specialized niches which comprise stromal cells including endosteal CXCL12-expressing osteoblasts and perivascular cells in bone marrow. The signals generated by stromal cells regulate B-cell development and trafficking. SPARC is highly expressed in osteoblasts and perivascular reticular stromal cells. However, it is unclear whether SPARC regulates B-cell development and trafficking. The expression level of SPARC is closely associated with carcinogenesis and progression; the loss of SPARC in SPARC-deficient mice accelerated the progression of some cancers and metastasis, and immune response was deregulated; we found in SPARC-null mice that B cells were remarkably decreased in bone marrow while significantly increased in peripheral blood, and B progenitors were impaired in bone marrow. Taken together, these data above suggest that SPARC is involved in the regulation of carcinogenesis and progression via affecting B cell development and function. Thus, in this study, we will use SPARC-null mice as an animal model to analyze the roles and mechanisms of SPARC in B lymphogenesis . This study will provide new thinkings and targets for preventation and therapy of cancers.

B淋巴细胞的发育是一个动力学过程，不同发育阶段的B细胞定位在由不同基质细胞形成的特定壁龛中，壁龛发出的信号控制了B细胞的发育和迁移。B细胞的壁龛细胞（CXCL12表达丰富的骨内膜成骨细胞、血管周网状基质细胞）高水平表达SPARC，但SPARC是否影响B细胞的发育和迁移尚不清楚。已知SPARC 表达水平与多种肿瘤的发生、发展密切相关；SPARC缺失小鼠，恶性肿瘤的发生和转移增加，免疫反应降低；在预实验中，我们发现SPARC缺失小鼠骨髓中B 细胞明显减少，而外周血中明显增加，骨髓中B祖细胞发育异常。提示SPARC可能通过影响B细胞的发育和功能，参与调节肿瘤的发生、发展。因此本课题拟用SPARC 缺失小鼠作为动物模型分析SPARC对B细胞发育的作用及机理。此研究将为某些恶性肿瘤的防治提供新的思路和靶点。

不同发育阶段的B细胞定位于由不同基质细胞形成的特定壁龛中，壁龛发出的信号控制了B细胞的发育和迁移。B细胞的壁龛细胞高水平表达SPARC，但SPARC是否影响B细胞的发育和迁移尚不清楚。本课题利用SPARC缺失小鼠研究SPARC对B细胞发育和动员的影响。发现SPARC缺失后，骨髓中pro-B、pre-B和immature B显著减少，pro-pro B没有明显改变，表明SPARC 缺失影响骨髓pre-pro-B 向pro-B的转化。AMD3100对野生型和缺失鼠的HSPC和B祖细胞的动员无显著差异。SPARC缺失导致脾脏中成熟B细胞（FOB和MZB）显著增加，外周血IgG和IgM水平显著提高，表明SPARC参与调控B细胞的分化成熟和抗体分泌功能。