biostudies-literatureLee YNHLBI NIH HHSNCI NIH HHSeabm7688https://www.ebi.ac.uk/biostudies/studies/S-EPMC8926339biostudies-literatureUnknown8(11)Tissue stem cells temporally change intrinsic mechanisms to meet physiological demands. However, little is known whether and how stem cells rely on distinct extrinsic maintenance mechanisms over time. Here, we found that hematopoietic stem cells (HSCs) temporally transition to depend on thrombopoietin (TPO), a key extrinsic factor, from E16.5 onward in the developing liver. Deletion of <i>Tpo</i> reduced mTOR activity, induced differentiation gene expression, and preferentially depleted metabolically active HSCs. Ectopic activation of the JAK2 or MAPK pathway did not rescue HSCs in <i>Tpo^-/-</i> mice. Enforced activation of the mTOR pathway by conditionally deleting <i>Tsc1</i> significantly rescued HSCs and their gene expression in <i>Tpo^-/-</i> mice. <i>Lin28b</i> intrinsically promoted mTOR activation in HSCs, and its expression diminished over time. Conditional deletion of <i>Lin28b</i> further reduced mTOR activity and strongly exacerbated HSC depletion in <i>Tpo^-/-</i> mice. Therefore, HSCs temporally transition from intrinsic LIN28B-dependent to extrinsic TPO-dependent maintenance in the developing liver.Science advancesHematopoietic stem cells temporally transition to thrombopoietin dependence in the fetal liver.PMC8926339R01 HL153487R01 HL132074R01 HL155868P30 CA013696Leslie JDiMaulo-Milk ELee YDing LfalseHematopoietic stem cells temporally transition to thrombopoietin dependence in the fetal liver.Tissue stem cells temporally change intrinsic mechanisms to meet physiological demands. However, little is known whether and how stem cells rely on distinct extrinsic maintenance mechanisms over time. Here, we found that hematopoietic stem cells (HSCs) temporally transition to depend on thrombopoietin (TPO), a key extrinsic factor, from E16.5 onward in the developing liver. Deletion of <i>Tpo</i> reduced mTOR activity, induced differentiation gene expression, and preferentially depleted metabolically active HSCs. Ectopic activation of the JAK2 or MAPK pathway did not rescue HSCs in <i>Tpo^-/-</i> mice. Enforced activation of the mTOR pathway by conditionally deleting <i>Tsc1</i> significantly rescued HSCs and their gene expression in <i>Tpo^-/-</i> mice. <i>Lin28b</i> intrinsically promoted mTOR activation in HSCs, and its expression diminished over time. Conditional deletion of <i>Lin28b</i> further reduced mTOR activity and strongly exacerbated HSC depletion in <i>Tpo^-/-</i> mice. Therefore, HSCs temporally transition from intrinsic LIN28B-dependent to extrinsic TPO-dependent maintenance in the developing liver.2022-01-01T00:00:00Z2022 Mar2024-11-09T04:32:46.615Z2024-11-09T04:32:46.615ZS-EPMC89263393529422810.1126/sciadv.abm7688