骨髓微环境在范可尼贫血中的作用机制研究

Fanconi anemia (FA)is a representative inherited disorder in which multiple organ systems are involved including bone marrow failure. Many studies are focusing on hematopoietic cells instead of microenvironment. We have previously found that mesenchymal stem/progenitor(MSC) cells from wild type but not from Fancg-/- mice promoted the reconstitution of exogenous hematopietic stem cells in Fancg-/- mice in vivo and MSC from Fancg-/- mice appeared to be defect in vairous abilities. This result lead us to hypothesize that a common abnormal bone marrow microenvironment existing in FA and MSC co-transplanted can correct this defect and promote the reconstitution of hematopoietic cells. In this study, we will utilize a conditional knock-out mouse model to recapitulate another FA subtype FA-D1 in which a FANCD1/BRCA2 gene is knocked out in cells of bone marrow microenvironment but not in hematopoietic cells. With this specific model, we will unravel whether abnormal bone microenvironment is a common phenomenon and study the molecular mechanism of MSC in promoting the hematopoietic reconstitution in FA.These data will provide us scientific evidence for choosing cell sources in transplantation for FA. In addition, our study might inspire the research on the relation between microenvironment and some diseases, especially in tumor occurring and progressing.

范可尼贫血（FA）是一种典型的、累及多个系统的遗传性疾病，而骨髓造血功能衰竭最为突出。传统研究主要集中在造血细胞本身的病理变化，对造血微环境的病理作用认识不足。我们最近工作发现，正常小鼠间充质干细胞（MSC）促进造血细胞植入Fancg-/-小鼠，而Fancg-/-小鼠MSC却无此功能；该小鼠MSC各种功能异常。我们推测，FA骨髓微环境存在缺陷，MSC可能纠正这种缺陷而促进造血细胞植入。为进一步探讨FA微环境异常的分子机制，我们选取一代表性的FA-D1亚型，利用条件性基因敲除技术，特异性地敲除微环境细胞的FANCD1/BRCA2基因，而保留造血细胞中的该基因。藉此独特的FA模型，我们将探讨正常和基因缺陷MSC对造血植入的影响和机制。该研究成果将为FA移植治疗细胞选择提供科学依据；也将为微环境与疾病的关系，尤其是肿瘤的发生、发展提供重要启示。

范可尼贫血是一种由于FA基因突变而导致的异质性遗传疾病，发育异常和骨髓造血功能衰竭是其最主要的临床表现。本研究的开展主要是为了研究骨髓间充质干细胞的异常是否参与了此类疾病的发生和发展。我们首先利用FA基因双敲除小鼠系统研究了FA基因缺陷对造血微环境间充质干细胞的生物学特性的影响，并确证了FA基因缺陷导致骨髓间充质干细胞成骨分化能力降低、衰老增加、炎症因子分泌增加、对造血干祖细胞的支持能力降低；我们还利用利用患者原代细胞进行了相应的转化医学研究，FA患者来源的MSCs也存在着类似的衰老比例增加，分化异常，造血支持能力减弱等特点；利用Fancg基因敲除小鼠模型发现微环境中IL-8/KC细胞因子的分泌降低，可能是FA患者HSCs对G-CSF反应能力减弱的重要原因；建立和优化了一系列体内外实验模型，为进一步研究FA基因缺陷在疾病发生中的作用提供了重要工具。