Losing Sense of Self and Surroundings: Hematopoietic Stem Cell Aging and Leukemic Transformation  Evgenia V. Verovskaya, Paul V. Dellorusso, Emmanuelle Passegué  Trends in Molecular Medicine  Volume 25, Issue 6, Pages 494-515 (June 2019) DOI: 10.1016/j.molmed.2019.04.006 Copyright © 2019 Terms and Conditions

Figure 1 Changes in Metabolism and Epigenetics during Hematopoietic Stem Cell (HSC) Activation and Aging. (A) In young HSCs, quiescence is maintained by a hardwired transcriptional regulatory network promoting anaerobic glycolysis and limiting the entry of pyruvate into the tricarboxylic acid (TCA) cycle. Low aerobic flux and fatty acid oxidation (FAO) also provide important substrates that participate in metabolic and epigenetic regulation and help to maintain quiescence. In response to activation signals, HSCs engage oxidative phosphorylation (OXPHOS), which is coupled with mitochondrial biogenesis, mTOR activation, and transcriptional reprogramming. This metabolic switch promotes reactive oxygen species (ROS) production and MAPK activation and stimulates HSC differentiation. When the needs of the hematopoietic system are met, HSCs engage autophagy to clear metabolically activated mitochondria and suppress oxidative metabolism to return to quiescence. (B) With age, old HSCs face challenges with the suppression of basal oxidative metabolism and maintenance of effective quiescence as a result of altered transcriptional regulatory networks and changes to cell-surface signaling, including exposure to higher levels of proinflammatory cytokines. This promotes stem cell exhaustion and blood aging phenotypes. ETC, electron transport chain. Trends in Molecular Medicine 2019 25, 494-515DOI: (10.1016/j.molmed.2019.04.006) Copyright © 2019 Terms and Conditions

Figure 2 Molecular Mechanisms Underlying Loss of Hematopoietic Stem Cell (HSC) Fitness with Age. (A) Model of HSC cell cycle and environmental activation signals driving context-dependent and age-related epigenetic drift. (B) Aging is associated with an expanded HSC compartment but a decrease in the number of cells meeting the ‘functional’ HSC definition (i.e., cells with serial pan-lineage hematopoietic repopulation activity following transplantation). Evidence suggests that only HSCs with limited divisional history can fulfill this functional criterion. Repeated cell division may promote changes to the chromatin accessibility profile of HSCs, biasing them via epigenetic drift towards differentiation programs that they have been signaled to promote. Cellular activation also perturbs HSC quiescence and thus may contribute to declining cellular fitness by altering HSC proteostasis or metabolic homeostasis. While the number of HSCs expands with age, the number of HSCs with limited divisional history declines, potentially explaining this paradox. Light gray, functional HSCs; dark gray, nonfunctional HSCs. Trends in Molecular Medicine 2019 25, 494-515DOI: (10.1016/j.molmed.2019.04.006) Copyright © 2019 Terms and Conditions

Figure 3 The Dysregulated Aging Bone Marrow (BM) Niche Microenvironment. In the BM, endosteal regions are rich in arterioles, capillaries, periarteriolar mesenchymal stem cells (MSCs), and their osteoprogenitor derivatives [i.e., osteoblastic lineage cells (OBCs), osteoblasts (Ob)], while medullary regions are enriched in sinusoids and perisinusoidal MSCs. Sympathetic nerves track alongside the vasculature, with predominantly periarteriolar localization. Megakaryocytes (Meg) are located next to BM vessels and adipocytes are found throughout the BM cavity. Various cell types instruct hematopoietic stem cells (HSCs) to stay dormant, cycle, or differentiate through direct interactions and cytokine secretion. Aging leads to remodeling of the BM microenvironment, with increased levels of inflammatory cytokines, loss of endosteal populations, accumulation of adipocytes, and functional deterioration of the central marrow, leading to decreased HSC-supportive activity and promotion of HSC aging features. Trends in Molecular Medicine 2019 25, 494-515DOI: (10.1016/j.molmed.2019.04.006) Copyright © 2019 Terms and Conditions

Figure 4 From Aging to Leukemia. Model for how age-related changes in hematopoietic stem cell (HSC) epigenetic and metabolic state and signals from the dysregulated aging bone marrow (BM) microenvironment lead to clonal expansion and predisposition to leukemic transformation. Gray, functional HSCs; yellow/orange, HSCs that acquired mutations in epigenetic and metabolic genes; red, leukemic stem cells (LSCs). Partially based on [159]. Trends in Molecular Medicine 2019 25, 494-515DOI: (10.1016/j.molmed.2019.04.006) Copyright © 2019 Terms and Conditions