Transforming growth factor-β1 regulates the nascent hematopoietic stem cell niche by promoting gluconeogenesis

The understanding of hematopoietic stem cell (HSC) emergence is important to generate HSCs from pluripotent precursors. However, integrated signaling network that regulates the niche of nascent HSCs remains unclear. Herein, we uncovered a novel role of TGF-β1 in the metabolic niche of HSC emergence using the tgf-β1b^-/- zebrafish. Our findings first showed that Tgf-β1 transcripts were enriched in the nascent HSCs. Loss of tgf-β1b caused a decrease of nascent HSCs within the aorta-gonad-mesonephros. Moreover, tgf-β1b⁺ cells were runx1⁺ HSCs and underwent an endothelial-to-hematopoietic-transition process. Although the autocrine of Tgf-β1 in HSCs rather than endothelial cells was highly demanded to regulate HSC generation, we found that tgf-β1b promoted HSC emergence through the endothelial c-Jun N-terminal kinase/c-Jun signaling. Chromatin immunoprecipitation (ChIP)-sequencing data showed that tgf-β1b/c-Jun targeted g6pc3 of FoxO signaling to promote gluconeogenesis and maintain a high glucose level in the niche. Furthermore, loss of tgf-β1b increased the endoplasmic-reticulum stress and oxidative stress by disturbing metabolic homeostasis. Adding a low dose of TGF-β1 protein could promote the differentiation of mouse embryonic stem cells towards HSCs in vitro. Altogether, our study provided insights into a new feature of TGF-β1 in the regulation of glucose metabolism and nascent HSC niche, which may contribute to therapies of hematological malignancies.