Hematopoietic 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 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 mice. Enforced activation of the mTOR pathway by conditionally deleting significantly rescued HSCs and their gene expression in mice. intrinsically promoted mTOR activation in HSCs, and its expression diminished over time. Conditional deletion of further reduced mTOR activity and strongly exacerbated HSC depletion in mice. Therefore, HSCs temporally transition from intrinsic LIN28B-dependent to extrinsic TPO-dependent maintenance in the developing liver.