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Attenuation of PKC δ enhances metabolic activity and promotes expansion of blood progenitors
Author(s) -
Rao Tata Nageswara,
Gupta Manoj K,
Softic Samir,
Wang Leo D,
Jang Young C,
Thomou Thomas,
Bezy Olivier,
Kulkarni Rohit N,
Kahn C Ronald,
Wagers Amy J
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018100409
Subject(s) - stem cell , progenitor cell , gerontology , biology , transplantation , medicine , physiology , genetics
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 ( HSPC s). Here, we report that protein kinase C delta ( PKC δ) is a critical regulator of adult HSPC number and function that couples the proliferative and metabolic activities of HSPC s. PKC δ‐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. PKC δ‐deficient HSPC s 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 PKC δ acts in a hematopoietic cell‐intrinsic manner to restrict HSPC number and bone marrow regenerative function. Mechanistically, PKC δ regulates HSPC energy metabolism and coordinately governs multiple regulators within signaling pathways implicated in HSPC homeostasis. Together, these data identify PKC δ as a critical regulator of HSPC signaling and metabolism that acts to limit HSPC expansion in response to physiological and regenerative demands.