Attenuation of PKCδ enhances metabolic activity and promotes expansion of blood progenitors

• Tata Nageswara Rao ^[2] ; Manoj K Gupta ^[3] ; Samir Softic ^[1] ; Leo D Wang ^[4] ; Young C Jang ^[5] ; Thomas Thomou ^[6] ; Olivier Bezy ^[7] ; Rohit N Kulkarni ^[3] ; C Ronald Kahn ^[6] ; Amy J Wagers ^[8]
  1. [1] Boston Children's Hospital

     Boston Children's Hospital

     City of Boston, Estados Unidos

     
  2. [2] 1 Department of Stem Cell and Regenerative Biology Harvard Stem Cell Institute Harvard University Cambridge MA USA; 2 Section on Islet Cell and Regenerative Biology Joslin Diabetes Center Boston MA USA; 6Present address: Department of Biomedicine, Experimental Hematology University Hospital Basel and University of Basel Basel Switzerland
  3. [3] 2 Section on Islet Cell and Regenerative Biology Joslin Diabetes Center Boston MA USA
  4. [4] 1 Department of Stem Cell and Regenerative Biology Harvard Stem Cell Institute Harvard University Cambridge MA USA; 2 Section on Islet Cell and Regenerative Biology Joslin Diabetes Center Boston MA USA; 5 Division of Pediatric Hematology/Oncology/Stem Cell Transplantation Dana‐Farber/Boston Children's Center for Cancer and Blood Disorders Boston MA USA; 7Present address: Departments of Immunooncology and Pediatrics Beckman Research Institute, City of Hope Duarte CA USA
  5. [5] 1 Department of Stem Cell and Regenerative Biology Harvard Stem Cell Institute Harvard University Cambridge MA USA; 2 Section on Islet Cell and Regenerative Biology Joslin Diabetes Center Boston MA USA; 8Present address: Georgia Institute of Technology School of Biological Sciences Parker H. Petit Institute for Bioengineering and Bioscience Atlanta GA USA
  6. [6] 3 Section on Integrative Physiology and Metabolism Joslin Diabetes Center Boston MA USA
  7. [7] 3 Section on Integrative Physiology and Metabolism Joslin Diabetes Center Boston MA USA; 9Present address: Internal Medicine Research Unit Pfizer Inc. Cambridge MA USA
  8. [8] 1 Department of Stem Cell and Regenerative Biology Harvard Stem Cell Institute Harvard University Cambridge MA USA; 2 Section on Islet Cell and Regenerative Biology Joslin Diabetes Center Boston MA USA

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 24, 2018
• Idioma: inglés
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  • A finely tuned balance of self‐renewal, differentiation, proliferation, and survival governs the pool size and regenerative capacity of blood‐forming hematopoietic stem and progenitor cells (HSPCs). Here, we report that protein kinase C delta (PKCδ) is a critical regulator of adult HSPC number and function that couples the proliferative and metabolic activities of HSPCs. PKCδ‐deficient mice showed a pronounced increase in HSPC numbers, increased competence in reconstituting lethally irradiated recipients, enhanced long‐term competitive advantage in serial transplantation studies, and an augmented HSPC recovery during stress. PKCδ‐deficient HSPCs also showed accelerated proliferation and reduced apoptosis, but did not exhaust in serial transplant assays or induce leukemia. Using inducible knockout and transplantation models, we further found that PKCδ acts in a hematopoietic cell‐intrinsic manner to restrict HSPC number and bone marrow regenerative function. Mechanistically, PKCδ regulates HSPC energy metabolism and coordinately governs multiple regulators within signaling pathways implicated in HSPC homeostasis. Together, these data identify PKCδ as a critical regulator of HSPC signaling and metabolism that acts to limit HSPC expansion in response to physiological and regenerative demands.