造血干细胞发育的分子机制 - CAS

1 : 2016 46 1 : 16 ~ 24 SCIENTIA SINICA Vitae : , , .. : , 2016, 46: 16 24 Wang L, Zhang C X, Liu F. Molecular regulation of hematopoietic stem cell development. Sci Sin Vitae, 2016, 46: 16 24, doi: 2016 SCIENCE CHINA PRESS , , * , , 100101 * , E-mail: : 2015-07-23; : 2015-08-20 ( : 31271570, 31425016) , . , . ( ) , , . , , , , (hematopoietic stem cells, HSCs) , , [1]. , . , .. 1 : / (primitive or embryonic hematopoiesis) / (definitive or adult hematopoiesis)[1].

2 (yolk sac) (blood island) . (primitive erythrocytes) (primitive myeloid cells). , . , . , - (erythromyeloid progenitor, EMP), , [2~6].. - - (aorta-gonad-mesonephros, AGM) [1,7~9]. , : 2016 46 1 17 (Mus musculus) [10,11] [9] [12] . , , [13]. , ( 1)[14]. (Barchydanio rerio var) , , [1,15~17]. / [18,19], , (intermediate cell mass, ICM), (erythroid); , (myeloid). , ICM .. AGM , (ventral wall of dorsal aorta). AGM.

3 , (caudal hematopoietic tissue, CHT), , . , 3~5 , , T [20]. , , . ( 1)[15,17,21]. 2 , (hemangio- blast)[22], . Etv2(Er71/Etsrp) , . , Etv2 FLK1 [23]; , Etv2 flk1 [24]. Etv2 BMP, Notch Wnt [25]. , , VEGF . Kdrl , VEGFa , ERK [26]. ERK . ERK , [27]; ERK , ESAM , , [28]. , 1 , . ; , - , , : 18 , ERK.

4 , ETS Fev BMP- Smad1/5 ERK , ERK , [27,28]. VEGFa- ERK Notch . vegfa , Notch [29]. Notch DeltaC Delta like 4, Notch1 Notch3 Notch Hey2 , Notch , , Notch [30,31]. VEGF-Notch hedgehog , shh gli2 , vegfa [29,32]. , hedgehog -Notch , , Scl [33]. , hedgehog Crlra(calcitonin receptor- like receptor) Notch , , VEGF [34]. 3 , HSCs (hemogenic endothelium, HE), . Eilken [35] , , . Lancrin [36] . (live imaging) - (endothelial-hematopoietic transition, EHT) HSCs[37~41].

5 AGM - , , [38]; , , [37,39]. EHT , 3 ( 2). scl [42,43]. scl , . , Scl [43~45]. scl : scl scl , scl EHT , scl . , scl , scl ; scl [44,45]. 2 , , . , , : 2016 46 1 19 runx1 , , , EHT runx1. runx1 , runx1 [46]; runx1 , [46,47].. Kissa Herbomel[39] kdrl-GFP EHT , runx1 , , EHT , . runx1 EHT.

6 , Gata2 ; gata2 (E10) , gata2 . Gata2 AGM (+ ), AGM (runx1 scl) , EHT [48]. gata2 , , , gata2 EHT [49,50]. Runx1 EHT , GATA2 EHT [50]. , , scl, runx1 , . Gata2 ETS Fli1 Elf1 , scl . Pimanda [51] Gata2, Fli1, Scl , AGM . , Gata2, Scl ETS Fli1, Elf1, runx1 [52]. EHT HSC . HoxA3 EHT , [53]. , gfi1 Runx1 , EHT [54]; F2r-ZO1 ESAM EHT [28,55]. , EHT , ( 3).

7 , [56,57]. (1) Notch . Notch . hsp70:gal4;uas:NICD , , Notch Runx1 [58]. , Jagged1 Notch1 Gata2 , [59]. , , Notch . , runx1 , Notch , Notch , [60]. , Ncor2 Notch [61]. Notch , Notch , , . (2) Wnt . Wnt/ -catenin . Wnt DKK Axin , , PGE2 -catenin Wnt , [62]. Wnt BMP Cdx-Hox [63]. Wnt [64]. -catenin EHT , -catenin , : 20 3 , hedgehog -Vegf-Notch.

8 , Notch Wnt/ - catenin , BMP-Smad1/5 . , Notch, -catenin ERK , EHT , Wnt/ -catenin [64]. -catenin EHT , , . , (RA) /Pre-HSC Wnt [65]. Wnt . , wnt16 , Notch DeltaC DeltaD , deltaC deltaD [66]. Wnt16 Notch . (3) BMP . , BMP , BMP4, , BMP4 . , scl runx1 BMP4[67]. , BMP , , BMP . BMP4 [68,69]. , BMP Smad1/5 Smad4 [28,70,71]. : 2016 46 1 21 BMP.

9 , BMP BMP Smad1 runx1 [72], . , , [60,73]; BMP , EHT , [34]. 4 , , . , .. , , .. (induced pluripotent stem cells, iPS cells) [74,75]. [76,77]. , , , . 1 Orkin S H, Zon L I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell, 2008, 132: 631 644 2 Bertrand J Y, Giroux S, Golub R, et al. Characterization of purified intraembryonic hematopoietic stem cells as a tool to define their site of origin. Proc Natl Acad Sci USA, 2005, 102: 134 139 3 Yokota T, Huang J, Tavian M, et al.

10 Tracing the first waves of lymphopoiesis in mice. Development, 2006, 133: 2041 2051 4 Bertrand J Y, Kim A D, Violette E P, et al. Definitive hematopoiesis initiates through a committed erythromyeloid progenitor in the zebrafish embryo. Development, 2007, 134: 4147 4156 5 Palis J, Robertson S, Kennedy M, et al. Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development, 1999, 126: 5073 5084 6 Yoder M C, Hiatt K, Mukherjee P. In vivo repopulating hematopoietic stem cells are present in the murine yolk sac at day postcoitus. Proc Natl Acad Sci USA, 1997, 94: 6776 6780 7 Kumaravelu P, Hook L, Morrison A M, et al. Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver.