Physiological hematopoiesis is fueled by a hierarchically organized, broad basis of (almost) self-renewing stem and progenitor cells. (A) Relative compartment sizes of HSCs (Lin⁻Sca⁺Kit⁺CD150⁺CD48⁻), ST-HSCs (Lin⁻Sca⁺Kit⁺CD150⁻CD48⁻), and MPPs (Lin⁻Sca⁺Kit⁺CD150⁻CD48⁺) (all phenotypes according to Oguro et al¹⁵ ) are drawn to scale. Based on the measured output from Tie2⁺ HSCs,⁸  we estimated the frequencies of differentiating cells in each compartment, indicated by red circles (lower side, outgoing; upper side, incoming). The continuous but rare input from Tie2⁺ HSCs is greatly amplified in ST-HSCs and MPPs to sustain overall output (red arrows); to achieve this, the rates of self-renewing cell divisions also increase from HSCs to ST-HSCs to MPPs (black circle arrows). (B) Fate mapping data from Tie2^MeriCreMer knock-in mice,⁸  and the comprehensive functional characterization of Tie2⁺ vs Tie2⁻ HSCs in Tie2 reporter mice,²¹  indicate heterogeneity of the HSC compartment, with Tie2⁺ HSCs residing at the tip, differentiating, and self-renewing.