Cell size is a determinant of stem cell potential during aging (HSC size-fractionation RNA-seq dataset)
Stem cells are remarkably small in size. Human hematopoietic stem cells (HSCs) measure a mere 7 µm in diameter. Whether small size is important for stem cell function is unknown. We find that murine HSCs enlarge under conditions known to decrease stem cell function. This decreased fitness of large HSCs is due to reduced proliferative potential. We further show that preventing HSC enlargement by inhibiting macromolecule biosynthesis or reducing the size of large HSCs by shortening G1 averts the loss of stem cell potential. Naturally large HSCs also exhibit decreased stem cell potential indicating that large size characterizes exhausted HSCs under physiological conditions. Finally, we show that our findings are relevant to aging. A fraction of murine and human HSCs enlarge during aging. Preventing this age-dependent enlargement improves HSC function. We conclude that small cell size is important for stem cell function and propose that stem cell enlargement contributes to their functional decline during aging. Overall design: Two replicates each of RNA isolated from small (XS-HSCs), medium (M-HSCs) and large (XL-HSCs) hematopoetic stem cells. Four replicates each of RNA isolated from Hematopoetic Stem Cells isolated from mice treated with vehicle, PD, rapamycin and PD+rapamycin.