Transcriptional regulation of human HSC specification and maintenance
| Human HSC transcriptional regulators . | Role in hematopoiesis . | Functional validation . | References . |
|---|---|---|---|
| HSC specification | |||
| SCL/TAL1 | Promotes HE establishment and suppresses cardiac fate during mesoderm specification. Augments hematopoietic specification in hPSC cultures. | Mouse KO, mESC KO differentiation, and hESC OE model | 69,70-72 |
| SOX17 | Essential for establishment of arterial identity, definitive HE specification, and EHT. Marks definitive HE during hPSC differentiation. | Mouse KO, mESC KO differentiation, hESC reporters, and loss of function/OE models. | 63,73-76 |
| Medial HOXA genes | HOXA5, 7, and 9 are landmarks of specification to definitive hematopoietic fate in vitro and in vivo, HOXA9 associates with HSC proliferation and HOXA7 with suppressing primitive hematopoiesis associated programs in human fetal HSCs | Mouse KO and human FL-HSC KD/OE | 15,62,63,74,77-80 |
| RUNX1 | Necessary for IAHC formation in both HSC-independent and HSC-forming EHT. Indicates HE specification during human development and in hPSC cultures. | Mouse KO, mESC differentiation, and hESC reporters | 15,63,73,81 |
| MYB | Required during definitive hematopoiesis for HSC self-renewal and suppression of differentiation programs | Mouse KO and hESC reporters | 16,82,83 |
| GFI1/GFI1B | Promote hematopoietic identity by suppressing endothelial program and inducing quiescence | Mouse KO and small molecule inhibitors during hESC differentiation | 84-87 |
| HSC maintenance | |||
| MLLT3 | Essential for human HSC self-renewal. Sustains HSC transcriptional network via DOT1L. Expressed from pre-HE stage onwards. Levels increase during human HSC maturation. Expands functional HSCs. | KD and OE in human FL HSCs and CB-HSCs | 15,88 |
| HLF | Defines undifferentiated HSPC and promotes HSC quiescence. Highly specific for undifferentiated HSPC but expressed also in some second wave progenitors in human, although not observed in mouse erythromyeloid progenitors. Essential for human HSC function. | Mouse KOs, mouse reporters, and human CB HSC reporters. KD in human FL HSCs | 15,88-92 |
| MECOM | Maintains HSC proliferation in a dosage-dependent manner. Expressed highly in EC throughout EHT and HSCs. High expression levels define LT-HSC lineage. Essential for human HSC function. | Mouse KOs, mouse reporters. KD in human FL HSCs | 15,88,91,93,94 |
| MSI2 | Promotes human HSC expansion through AHR signaling inhibition | Mouse KO, human HSC KD/OE | 95,96 |
| Human HSC transcriptional regulators . | Role in hematopoiesis . | Functional validation . | References . |
|---|---|---|---|
| HSC specification | |||
| SCL/TAL1 | Promotes HE establishment and suppresses cardiac fate during mesoderm specification. Augments hematopoietic specification in hPSC cultures. | Mouse KO, mESC KO differentiation, and hESC OE model | 69,70-72 |
| SOX17 | Essential for establishment of arterial identity, definitive HE specification, and EHT. Marks definitive HE during hPSC differentiation. | Mouse KO, mESC KO differentiation, hESC reporters, and loss of function/OE models. | 63,73-76 |
| Medial HOXA genes | HOXA5, 7, and 9 are landmarks of specification to definitive hematopoietic fate in vitro and in vivo, HOXA9 associates with HSC proliferation and HOXA7 with suppressing primitive hematopoiesis associated programs in human fetal HSCs | Mouse KO and human FL-HSC KD/OE | 15,62,63,74,77-80 |
| RUNX1 | Necessary for IAHC formation in both HSC-independent and HSC-forming EHT. Indicates HE specification during human development and in hPSC cultures. | Mouse KO, mESC differentiation, and hESC reporters | 15,63,73,81 |
| MYB | Required during definitive hematopoiesis for HSC self-renewal and suppression of differentiation programs | Mouse KO and hESC reporters | 16,82,83 |
| GFI1/GFI1B | Promote hematopoietic identity by suppressing endothelial program and inducing quiescence | Mouse KO and small molecule inhibitors during hESC differentiation | 84-87 |
| HSC maintenance | |||
| MLLT3 | Essential for human HSC self-renewal. Sustains HSC transcriptional network via DOT1L. Expressed from pre-HE stage onwards. Levels increase during human HSC maturation. Expands functional HSCs. | KD and OE in human FL HSCs and CB-HSCs | 15,88 |
| HLF | Defines undifferentiated HSPC and promotes HSC quiescence. Highly specific for undifferentiated HSPC but expressed also in some second wave progenitors in human, although not observed in mouse erythromyeloid progenitors. Essential for human HSC function. | Mouse KOs, mouse reporters, and human CB HSC reporters. KD in human FL HSCs | 15,88-92 |
| MECOM | Maintains HSC proliferation in a dosage-dependent manner. Expressed highly in EC throughout EHT and HSCs. High expression levels define LT-HSC lineage. Essential for human HSC function. | Mouse KOs, mouse reporters. KD in human FL HSCs | 15,88,91,93,94 |
| MSI2 | Promotes human HSC expansion through AHR signaling inhibition | Mouse KO, human HSC KD/OE | 95,96 |
Key transcription factors functionally implicated in human HSC development in vivo or in vitro and their major roles are indicated.
AHR, aryl hydrocarbon receptor; CB, cord blood; ESC, embryonic stem cells; h, human; KD, knockdown; KO, knockout; m, murine; OE, overexpression.