再生障碍性贫血造血干细胞向巨核细胞分化功能异常及机制研究

Incomplete recovery of platelet and megakaryopoieis is the bottleneck in aplastic anemia (AA) after treatment. Grounded on the clinical hotspot, we hypothesize that there is an impairment of hematopoietic stem cell (HSC) differentiation towards megakaryocyte in AA. On the cutting-edge knowledge of megakaryopoiesis, we schedule a program focusing on key points: 1) to definite the abnormalities of surface receptors specific for megakaryocyte in HSC population; 2) to identify megakaryopoiesis impairment occurring at which stage of HSC; 3) to illuminate dysfunction of lineage-committed transcriptional factors in HSC priming and differentiation into megakaryocyte; 4) to explore the signal pathways booming megakaryocytic differentiation by eltrombopag. In accord with translation medicine principle, the project originates from bedside and solves a scientific issue, for the purpose of screening small molecules with clinical potential that facilitate HSC differentiation down the megakaryocyte lineage. By the virtue of single-cell technique, our work breaks through method barriers in the field of HSC in AA, broadens the core knowledge of pathophysiological mechanisms, and pushes forward the translation progress in solving the bottleneck in AA.

巨核细胞造血及血小板数难以恢复是再生障碍性贫血（AA）治疗疗效瓶颈。基于此临床问题，我们提出科学假设：AA患者造血干细胞（HSC）向巨核细胞分化功能异常。结合HSC向巨核细胞分化基础研究前沿发展，利用单细胞技术平台，我们重点开展以下研究工作：①明确巨核细胞特异性分子在HSC表达的异常变化；②揭示AA 哪个阶段的HSC向巨核细胞分化功能有异常；③阐明核心转录因子导致巨核细胞分化功能异常的机制；④探索信号通路激活促进巨核细胞分化功能的机制。本研究秉承转化医学宗旨，立题来源于临床问题，通过基础研究解决关键科学问题，为下一步筛选有临床应用潜能的小分子化合物，促进HSC向巨核细胞分化成熟，提供科学研究基础。本研究利用单细胞技术特色优势，突破既往AA HSC研究领域的技术屏障，扩展了AA病理机制核心环节的研究，对于解决AA治疗疗效的瓶颈问题有重要的转化医学意义。

骨髓衰竭性疾病是骨髓造血干/祖细胞（Hematopoietic stem/progenitor cell，HSPC）功能和数量异常所致的外周血一系或多系血细胞减少。近两年，再生障碍性贫血患者经免疫抑制治疗后发生克隆性演变的临床与基础研究证实，患者造血干细胞（Hematopoietic stem cell，HSC）存在克隆性造血，骨髓衰竭性疾病患者HSC的生物学功能异常。因巨核细胞分化困难以及产血小板障碍所引起的血小板减少是临床治疗中的“瓶颈”。得益于单细胞技术的进步，最新研究表明，HSC是一群异质性细胞群体，部分HSC具有直接分化为巨核系细胞倾向。因此，我们筛选对于HSC具有扩增作用的小分子化合物，探索其对HSC向巨核系分化的作用，并对其机制进行初步研究。

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