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科學家繪制造血干細胞擴增組織的3D轉錄組圖譜

文章來源:動物研究所   發布時間:2019-05-10  【字號:     】  

  血液系統中貯藏著一種具有自我更新、分化成各種血細胞潛能的成體干細胞,稱為造血干細胞,它能夠維持機體長久造血和組織穩態。造血干細胞移植是惡性血癌的有效治療手段,但干細胞來源不足成為限制該治療廣泛應用的瓶頸。因此,造血干細胞的發育,尤其是造血干細胞擴增的研究備受關注。然而,現在的研究主要集中在特定細胞群體或關鍵因子的“線性化”或“平面化”解析,缺乏全面“立體化”的分析。從系統生物學角度解析擴增性造血器官,將為造血干細胞擴增的機制研究提供更多的啟示。鑒于造血發育過程的高度保守性,中國科學院動物研究所劉峰研究組及合作者以斑馬魚尾部造血組織(在功能上類似于哺乳動物的胎肝,為造血干細胞擴增及分化提供了特定的微環境)為研究對象,利用多重轉錄組測序的方法,繪制了擴增性造血器官的3D轉錄組圖譜,闡釋了造血干細胞和微環境細胞之間的分子調控網絡。

  首先,為了系統性地研究斑馬魚尾部造血組織如何支持造血干細胞擴增、分化的機制,劉峰實驗室利用三種轉錄組測序方法,特定類型群體細胞轉錄組、空間轉錄組和單細胞轉錄組,詳細解析了斑馬魚尾部造血組織的時空特性。不同發育時期特定細胞群體的轉錄組測序分析表明,造血干細胞與相應微環境細胞具有協同發育和共享基因表達的特點。空間轉錄組測序反映細胞位置信息,揭示了多種微環境因素對造血干細胞的不同調控方式,并實現了三維轉錄組重構斑馬魚造血器官。單細胞轉錄組數據更精細闡釋尾部造血組織細胞類群、細胞特征及細胞間分子調控,并發現造血干祖細胞分化和細胞周期存在一定的關聯性。多重轉錄組測序綜合分析揭示了造血干細胞在尾部造血組織的擴增受到內源性和外源性信號的共同調控,鑒定了新的造血干細胞的標記基因,發現了影響造血干細胞擴增的信號通路,完善了造血干細胞-微環境細胞間分子調控網絡。例如,染色質結構維持蛋白smchd1,通過調節造血干細胞增殖促進其擴增;微環境細胞來源的Integrin 信號通路負向調控造血干細胞擴增。同時此項工作還構建了斑馬魚尾部造血組織多重轉錄組數據庫(http://www.picb.ac.cn/hanlab/ichtatlas/Home),可以檢索任何基因在造血組織的表達譜,包括基因表達的時間、細胞類型及相對空間位置。

  該工作不僅發現了造血干細胞特征基因、細胞狀態與細胞分化的關系,闡釋了微環境和造血干細胞互作的調控網絡,更為血液系統研究提供了豐富的數據資源;同時,也將為造血干細胞的體外擴增和造血類器官的體外組裝提供理論指導。該研究論文“A 3D atlas of hematopoietic stem and progenitor cell expansion by multi-dimensional RNA-seq analysis430日在線發表于Cell Reports

  動物所博士研究生薛媛媛和中科院計算生物學研究所博士研究生劉登輝為文章共同第一作者,動物所研究員劉峰和計算生物學所研究員韓敬東為文章共同通訊作者。中科院生物化學與細胞生物學研究所研究員景乃禾與中科院廣州生物醫藥與健康研究院研究員彭廣敦在空間轉錄組測序方面提供了大力支持。該研究得到國家自然科學基金委、國家重點基礎研究發展計劃和中科院器官重建與制造戰略性先導科技專項的資助。

 

  圖1:多重轉錄組測序解析斑馬魚造血器官。多重轉錄組測序,包括:特定類型群體細胞轉錄組測序、空間轉錄組測序和單細胞轉錄組測序,揭示斑馬魚尾部造血組織的時空特性。

 

圖2:斑馬魚造血器官轉錄組數據庫 




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