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bioRxiv · 10.1101/2021.09.20.461098

Progenitor-intrinsic Metabolic Sensing Promotes Hematopoietic Homeostasis

Pizzato, H. A.·Wang, Y.·Wolfgang, M.·Finck, B.·Patti, G. J.·Bhattacharya, D.
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Abstract

Hematopoietic homeostasis is maintained by stem and progenitor cells in part by extrinsic feedback cues triggered by mature cell loss. We demonstrate a different mechanism by which hematopoietic progenitors intrinsically anticipate and prevent the loss of mature progeny through metabolic switches. We examined hematopoiesis in mice conditionally deficient in long-chain fatty acid oxidation (carnitine palmitoyltransferase 2, Cpt2), glutaminolysis (glutaminase, Gls), or mitochondrial pyruvate import (mitochondrial pyruvate carrier 2, Mpc2). While genetic ablation of Cpt2 or Gls minimally impacted most blood lineages, deletion of Mpc2 led to a sharp decline in mature myeloid cells. However, MPC2-deficient myeloid cells rapidly recovered due to a transient increase in myeloid progenitor proliferation. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was intrinsic to MPC2-deficient progenitors and accompanied by a metabolic switch to glutaminolysis. Thus, hematopoietic progenitors intrinsically adjust to metabolic perturbations independently of feedback from downstream mature cells to maintain homeostasis.

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Pizzato, H. A., Wang, Y., Wolfgang, M., Finck, B., Patti, G. J., Bhattacharya, D.. 2021-09-20. Progenitor-intrinsic Metabolic Sensing Promotes Hematopoietic Homeostasis. https://doi.org/10.1101/2021.09.20.461098

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