Lin-Sca-1+c-Kit low干细胞亚群的鉴定及其功能研究

p18INK4C(p18) plays a crucial role in regulating hematopoietic stem cell (HSC) self-renew and differentiation, p18 deletion will result in a variety of hematologic malignancies (such as T-ALL, T cell lymphoma, multiple myeloma). However, the molecular mechanism of p18 regulates HSC differentiation and related blood diseases is still unknown. Our latest research found a new distinct stem cell subpopulation in p18-/- mice bone marrow (LSKlow), which is different from LSK（Lin-Sca-1+c-kit+）, and the emergence of this distinct stem cell subpolulation associated with increased bone marrow pre-B cells and peripheral reduction in mature B cells, meanwhile, this group of cells can be differentiated into B and T cells in vitro. These data suggesting that this group of new stem cell subsets may be related to the lymphoid lineage developmental abnormalities and diseases occurrence. Whereas, there has not been report about this cell subpopulation in and out abroad so far. In our study, we use flow cytometry, single cell technologies,bone marrow transplantation and genomics analysis to study the biological characteristics ,functions and the relationship with the clinical blood diseases of this new stem cell subsets. We hope through our research, we can get new breakthroughs in the HSC research field, moreover, also for the possible mechanisms lead to the occurrence of malignant blood diseases.

p18INK4C（p18）在造血干细胞（HSC）自我更新及分化中起重要的调控作用，p18缺失会导致多种恶性血液病（如T-ALL，T细胞淋巴瘤，MM等）的发生。但p18调控HSC分化及其在相关血液肿瘤发生作用中的具体分子机制尚不明确。我们最新研究发现，在p18-/-小鼠骨髓中出现了一群有别于HSCs（Lin-Sca-1+c-Kit+）的独特的干细胞亚群（LSK low），这群细胞的出现伴随着骨髓中pre-B的增加和外周成熟B细胞的减少，同时这群细胞体外诱导可向B和T细胞分化，提示LSKlow细胞亚群可能与淋系发育异常及相关疾病的发生密切相关。关于这群细胞国内外尚未见报道。 本研究主要运用流式、单细胞、组学等多种技术系统全面的研究这群新干细胞亚群的生物学特性、功能以及与临床血液疾病发生的关系，期望在HSC研究领域获得新突破，同时也为p18异常调控HSC而导致恶性血液疾病的发生提出新的可能机制。

细胞周期依赖性蛋白激酶抑制剂CDKN2C（p18INK4c）抑制造血干细胞（HSC）的自我更新并参与淋巴细胞的发育成熟。P18的异常或缺失与小鼠或人类血液系统恶性肿瘤如白血病、多发性骨髓瘤等的发生密切相关。然而，p18调控HSCs到淋巴细胞的分化还知之甚少。在这项研究中我们发现在p18缺失的小鼠骨髓中，出现了一群干租细胞样（lsklow）亚群，具有淋系分化潜能，但不能向髓系分化。体内功能显示该细胞群不能长期自我更新，具有短期向淋巴细胞B和T细胞分化的能力，但分化的B细胞带有异常高表达的B系基因谱；LSKlow细胞的出现依赖于p18缺失的细胞而非p18缺失的造血微环境；p18的过表达可在一定程度逆转B细胞分化降低的表型，LSKlow细胞的异常出现为淋巴细胞恶性疾病的肿瘤发发病机制提供了潜在靶点。该项目执行期间，共计发表一作/通讯文章7篇，其中包括一作/通讯作者的SCI论文4篇，如Blood和Leukeima等高水平论文，并发表特邀英文综述一篇。