Tropomyosin 1 deficiency facilitates cell state transitions and enhances hemogenic endothelial cell specification during hematopoiesis.

Tropomyosins coat actin filaments to impact actin-related signaling and cell morphogenesis. Genome-wide association studies have linked Tropomyosin 1 (TPM1) with human blood trait variation. TPM1 has been shown to regulate blood cell formation in vitro, but it remains unclear how or when TPM1 affects hematopoiesis. Using gene-edited induced pluripotent stem cell (iPSC) model systems, we found that TPM1 knockout augmented developmental cell state transitions and key signaling pathways, including tumor necrosis factor alpha (TNF-α) signaling, to promote hemogenic endothelial (HE) cell specification and hematopoietic progenitor cell (HPC) production. Single-cell analyses revealed decreased TPM1 expression during human HE specification, suggesting that TPM1 regulated in vivo hematopoiesis via similar mechanisms. Analyses of a TPM1 gene trap mouse model showed that TPM1 deficiency enhanced HE formation during embryogenesis, without increasing the number of hematopoietic stem cells. These findings illuminate novel effects of TPM1 on developmental hematopoiesis.

Wilken MB ，Fonar G ，Qiu R ，Bennett L ，Tober J ，Nations C ，Pavani G ，Tsao V ，Garifallou J ，Petit C ，Maguire JA ，Gagne A ，Okoli N ，Gadue P ，Chou ST ，French DL ，Speck NA ，Thom CS ... -  《Stem Cell Reports》

Tropomyosin 1 deficiency facilitates cell state transitions to enhance hemogenic endothelial cell specification during hematopoiesis.

Wilken MB ，Fonar G ，Nations C ，Pavani G ，Tsao V ，Garifallou J ，Tober J ，Bennett L ，Maguire JA ，Gagne A ，Okoli N ，Gadue P ，Chou ST ，Speck NA ，French DL ，Thom CS ... -  《-》

GATA2 Is Dispensable for Specification of Hemogenic Endothelium but Promotes Endothelial-to-Hematopoietic Transition.

The transcriptional factor GATA2 is required for blood and hematopoietic stem cell formation during the hemogenic endothelium (HE) stage of development in the embryo. However, it is unclear if GATA2 controls HE lineage specification or if it solely regulates endothelial-to-hematopoietic transition (EHT). To address this problem, we innovated a unique system, which involved generating GATA2 knockout human embryonic stem cell (hESC) lines with conditional GATA2 expression (iG2-/- hESCs). We demonstrated that GATA2 activity is not required for VE-cadherin+CD43-CD73+ non-HE or VE-cadherin+CD43-CD73- HE generation and subsequent HE diversification into DLL4+ arterial and DLL4- non-arterial lineages. However, GATA2 is primarily needed for HE to undergo EHT. Forced expression of GATA2 in non-HE failed to induce blood formation. The lack of GATA2 requirement for generation of HE and non-HE indicates the critical role of GATA2-independent pathways in specification of these two distinct endothelial lineages.

Kang H ，Mesquitta WT ，Jung HS ，Moskvin OV ，Thomson JA ，Slukvin II ... -  《Stem Cell Reports》

Tropomyosin 1 genetically constrains in vitro hematopoiesis.

Thom CS ，Jobaliya CD ，Lorenz K ，Maguire JA ，Gagne A ，Gadue P ，French DL ，Voight BF ... -  《BMC BIOLOGY》

Specification and function of hemogenic endothelium during embryogenesis.

Gritz E ，Hirschi KK 《-》