Attenuation of PKCδ enhances metabolic activity and promotes expansion of blood progenitors. (16th November 2018)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO journal. Volume 37:Number 24(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-11-16
• Subjects: hematopoietic stem and progenitors -- metabolism -- PKCδ -- regeneration -- signaling; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2018100409
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. Synopsis: Hematopoietic stem and progenitor cells (HSPC) exert critical roles in the cell expansion required during homeostasis and regeneration of the blood system. Here, the protein kinase C delta (PKCδ) is shown to limit mouse HSPC output by controlling energy metabolism and hematopoietic differentiation. PKCδ restricts HSPC pool size by restraining cell cycle progression and regulating apoptosis. PKCδ deletion enhances recovery of HSPCs in settings of BM transplant and myelosuppression. PKCδ deletion enhances metabolic activity of HSPCs. PKCδ sets a threshold for HSPC activation and coordinately regulates multiple targets within progenitor cell signaling. Abstract : The protein kinase C delta restricts primitive hematopoietic cell contribution to the blood system to set a threshold for proliferation and regeneration.