2. Academic Validation
  3. Renal Klotho and inorganic phosphate are extrinsic factors that antagonistically regulate hematopoietic stem cell maintenance

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

  • Cell Rep. 2022 Feb 15;38(7):110392. doi: 10.1016/j.celrep.2022.110392.
Changhong Du 1,  Xinmiao Wang 1,  Yiding Wu 1,  Weinian Liao 1,  Jiachuan Xiong 2,  Yingguo Zhu 2,  Chaonan Liu 1,  Wenhao Han 2,  Yue Wang 2,  Songling Han 1,  Shilei Chen 1,  Yang Xu 1,  Song Wang 1,  Fengchao Wang 1,  Ke Yang 3,  Jinghong Zhao 4,  Junping Wang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China.
  • 2 Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Kidney Center of PLA, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China.
  • 3 Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Kidney Center of PLA, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China. Electronic address: [email protected].
  • 4 Department of Nephrology, Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Kidney Center of PLA, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: [email protected].
PMID: 35172146 DOI: 10.1016/j.celrep.2022.110392
Abstract

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.

Keywords

Klotho; bone marrow; hematopoietic stem cell; inorganic phosphate; kidney; megakaryocyte/myeloid-biased differentiation.

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