Medial HOXA genes demarcate haematopoietic stem cell fate during human development

被引：77

作者：

Dou, Diana R. ^{[1
,2
,3
]}

Calvanese, Vincenzo ^{[1
,2
]}

Sierra, Maria I. ^{[1
,2
]}

Nguyen, Andrew T. ^{[1
]}

Minasian, Arazin ^{[1
,2
]}

Saarikoski, Pamela ^{[1
,2
]}

Sasidharan, Rajkumar ^{[1
,2
]}

Ramirez, Christian M. ^{[4
]}

Zack, Jerome A. ^{[2
,5
,6
]}

Crooks, Gay M. ^{[1
,2
,7
]}

Galic, Zoran ^{[2
,5
]}

Mikkola, Hanna K. A. ^{[1
,2
,3
]}

机构：

[1] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, Dept Microbiol Mol Genet & Immunol, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

来源：

NATURE CELL BIOLOGY | 2016年 / 18卷 / 06期

关键词：

RETINOIC ACID; PROGENITOR CELLS; DIFFERENTIATION CULTURES; MYELOID-LEUKEMIA; YOLK-SAC; RNA-SEQ; EXPRESSION; BLOOD; ENDOTHELIUM; GENERATION;

D O I：

10.1038/ncb3354

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Pluripotent stem cells (PSCs) may provide a potential source of haematopoietic stem/progenitor cells (HSPCs) for transplantation; however, unknown molecular barriers prevent the self-renewal of PSC-HSPCs. Using two-step differentiation, human embryonic stem cells (hESCs) differentiated in vitro into multipotent haematopoietic cells that had the CD34(+)CD38(-/lo)CD90(+)CD45(+) GPI-80(+) fetal liver (FL) HSPC immunophenotype, but exhibited poor expansion potential and engraftment ability. Transcriptome analysis of immunophenotypic hESC-HSPCs revealed that, despite their molecular resemblance to FL-HSPCs, medial HOXA genes remained suppressed. Knockdown of HOXA7 disrupted FL-HSPC function and caused transcriptome dysregulation that resembled hESC-derived progenitors. Overexpression of medial HOXA genes prolonged FL-HSPC maintenance but was insufficient to confer self-renewal to hESC-HSPCs. Stimulation of retinoic acid signalling during endothelial-to-haematopoietic transition induced the HOXA cluster and other HSC/definitive haemogenic endothelium genes, and prolonged HSPC maintenance in culture. Thus, medial HOXA gene expression induced by retinoic acid signalling marks the establishment of the definitive HSPC fate and controls HSPC identity and function.

引用

页码：595 / +

页数：22

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