Renal Klotho and inorganic phosphate are extrinsic factors that antagonistically regulate hematopoietic stem cell maintenance

The composition and origin of extrinsic cues required for hematopoietic stem cell (HSC) maintenance are incompletely understood. Here we identify renal Klotho and inorganic phosphate (Pi) as extrinsic factors that antagonistically regulate HSC maintenance in the bone marrow (BM). Disruption of the Klotho-Pi axis by renal Klotho deficiency or Pi excess causes Pi overload in the BM niche and Pi retention in HSCs, leading to alteration of HSC maintenance. Mechanistically, Pi retention is mediated by soluble carrier family 20 member 1 (SLC20A1) and sensed by diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) to enhance Akt activation, which then upregulates SLC20A1 to aggravate Pi retention and augments GATA2 activity to drive the expansion and megakaryocyte/myeloid-biased differentiation of HSCs. However, kidney-secreted soluble Klotho directly maintains HSC pool size and differentiation by restraining SLC20A1-mediated Pi absorption of HSCs. These findings uncover a regulatory role of the Klotho-Pi axis orchestrated by the kidneys in BM HSC maintenance.