Atypical protein kinase C (aPKCζ and aPKλ) is dispensable for mammalian hematopoietic stem cell activity and blood formation

摘要

The stem-cell pool is considered to be maintained by a balance between symmetric and asymmetric division of stem cells. The cell polarity model proposes that the facultative use of symmetric and asymmetric cell division is orchestrated by a polarity complex consisting of partitioning-defective proteins Part and Par6, and atypical protein kinase C (aPKCζ and aPKCλ), which regulates pla nar symmetry of dividing stem cells with respect to the signaling microenvironment. However, the role of the polarity complex is unexplored in mammalian adult stem-cell functions. Here we re port that, in contrast to accepted paradigms, polarization and ac tivity of adult hematopoietic stem cell (HSC) do not depend on either aPKCζ or aPKCλ or both in vivo. Mice, having constitutive and hematopoietic-specific (Vav1-Cre) deletion of aPKCζ and aPKCλ, respectively, have normal hematopoiesis, including normal HSC self-renewal, engraftment, differentiation, and interaction with the bone marrow microenvironment. Furthermore, inducible complete deletion of aPKCλ (Mx1-Cre) in aPKCζ～(-/-) HSC does not affect HSC polarization, self-renewal, engraftment, or lineage repo pulation. In addition, aPKCζ- and aPKλ-deficient HSCs elicited a normal pattern of hematopoietic recovery secondary to myeloabla tive stress. Taken together, the expression of aPKCζ, aPKCλ, or both are dispensable for primitive and adult HSC fate determination in steady-state and stress hematopoiesis, contrary to the hypothesis of a unique, evolutionary conserved aPKCζ/λ-directed cell polarity signaling mechanism in mammalian HSC fate determination.