The Lkb1 metabolic sensor maintains haematopoietic stem cell survival

Abstract

Haematopoietic stem cells (HSCs) can convert between growth states that have marked differences in bioenergetic needs. Although often quiescent in adults, these cells become proliferative upon physiological demand. Balancing HSC energetics in response to nutrient availability and growth state is poorly understood, yet essential for the dynamism of the haematopoietic system. Here we show that the Lkb1 tumour suppressor is critical for the maintenance of energy homeostasis in haematopoietic cells. Lkb1 inactivation in adult mice causes loss of HSC quiescence followed by rapid depletion of all haematopoietic subpopulations. Lkb1-deficient bone marrow cells exhibit mitochondrial defects, alterations in lipid and nucleotide metabolism, and depletion of cellular ATP. The haematopoietic effects are largely independent of Lkb1 regulation of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling. Instead, these data define a central role for Lkb1 in restricting HSC entry into cell cycle and in broadly maintaining energy homeostasis in haematopoietic cells through a novel metabolic checkpoint.The metabolic control systems in HSCs are poorly understood although these cells have been shown to be highly sensitive to energetic and oxidative stress and must be able to shift Author Information Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. Readers are welcome to comment on the online version of this article at www.nature.com/nature. NIH Public Access Author ManuscriptNature. Author manuscript; available in PMC 2011 March 1. Lkb1 mutant animals displayed progressive pancytopenia as well as rapid loss of bone marrow myeloid, B lymphoid and erythroid cells (Fig. 1c, d and Supplementary Fig. 2a), and markedly decreased cellularity of the thymus and spleen ( Supplementary Fig. 2c, d and data not shown). Notably, in the bone marrow and thymus, immature lymphoid cells declined at a faster rate than the more differentiated cells ( Supplementary Fig. 2b, c). The Lkb1 mutants also exhibited a pronounced loss of HSC and multipotent progenitor populations at day 5 after pIpC treatment (Fig. 1e, f and Supplementary Fig. 2f). Furthermore, Lkb1 mutant bone marrow cells formed fewer and smaller colonies in in vitro colony forming assays ( Fig. 1g and Supplementary Fig. 2e). Comparable in vivo and in vitro phenotypes were seen using a second model system in which Lkb1 was deleted using the tamoxifen-inducible Rosa26-creERt2 strain ( Supplementary Fig. 2g, h, and not shown). These results show that Lkb1 is critically required for haematopoiesis and for the maintenance of HSCs and progenitor cells. Lkb1 function in bone marrow is cell intrinsicBoth theMx1-cre and Rosa26-creERt2 systems induce Cre recombinase activity in many cell types; thus bone marrow transplants were used to determine whether Lkb1 has a cellautonomous role in haematopoiesis. We performed non-competitive transplants of CD45.1 whole bone marrow from contr...

Transplanted Mesoangioblasts Require Macrophage IL-10 for Survival in a Mouse Model of Muscle Injury

“…Stem cell survival represents a limiting step for the regeneration of various tissues (84)(85)(86)(87), particularly of skeletal muscle (88,89). Our results suggest that macrophages, a key element in muscle regeneration (8,12,13,16,60,61) known to deliver antiapoptotic and survival signals in other tissues (90)(91)(92)(93)(94)(95)(96), orchestrate the survival and eventually the differentiation of transplanted mesoangioblasts.…”

Signal Transduction by Mitochondrial Oxidants

“…This general theme has also been expanded by three recent studies in which the tumor suppressor and metabolic regulator LKB1 was shown to regulate HSC quiescence (51)(52)(53). In the absence of LKB1, stem cells appeared to proliferate initially, giving rise to increased progenitor cell number.…”

LKB1 couples glucose metabolism to insulin secretion in mice

“…However, targeting liver kinase B1 (LKB1) in the beta cell for the treatment of diabetes would be undesirable as knockout of Lkb1 in adult mice has a deleterious effect on haematopoietic stem cell maturation [20][21][22]. We and others have identified non-overlapping functions in beta cells for LKB1 targets, including MAP/microtubule affinityregulating kinase 2 (MARK2), salt-inducible kinase 2 (SIK2), brain-specific kinase 2 (BRSK2) as well as AMPactivated protein kinase (AMPK) itself [19,[23][24][25][26][27][28], underscoring the potential for identifying the minimal target(s) of LKB1 responsible for enhancing insulin secretion.…”