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

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.

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In Figure 1 H, Limiting dilution analysis (LDA) Engraftment data shown at 14--weeks post--BMT A recipient mouse was considered positive if donor multilineage engraftment (CD45.2+ blood nucleated cells) exceeded 1% in recipient peripheral blood. Plots show the percentages of recipient mice containing less than 1% CD45.2+ blood nucleated cells. Dotted lines represent the 95% confidence interval of the same (p=0.0005). For the other experiments, no exclusion criteria was applied.

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All experiments involving mice were performed in accordance with the guidelines set by the Institutional Animal Care and Use Committees (IACUC) of Joslin Diabetes Center and Harvard University.

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All experiments involving mice were performed in accordance with the guidelines set by the Institutional Animal Care and Use Committees (IACUC) of Joslin Diabetes Center and Harvard University.
NO human subjects were used in this study NO human subjects were used No human or genomic data sets were included in this study.

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No computational large data sets were included in this study.
All the experiments reported in this study were performed in accordance with the guidelines set by the Institutional Animal Care and Use Committees (IACUC) of Joslin Diabetes Center and Harvard University.
NO human subjects were used NO human subjects were used NO human subjects were used NO human subjects were used