Metabolic Imaging Reveals a Unique Preference of Symmetric Cell Division and Homing of Leukemia-Initiating Cells in an Endosteal Niche

Abstract

Graphical Abstract Highlights d SoNar serves as a unique tool for in vitro/in vivo studies of stem cell metabolisms d SoNar-high cells prefer glycolysis and are enriched for leukemia-initiating cells d Leukemia-initiating cells home to endosteal niches and prefer symmetric divisions d PDK2 sustains metabolic and leukemogenic activities of leukemia-initiating cells In Brief Hao et al. reveal that a genetically encoded metabolic sensor, SoNar, precisely monitors the metabolic status of leukemia-initiating cells (LICs) both in vitro and in vivo. LICs prefer homing to endosteal niches and symmetric divisions to maintain their leukemogenic activities. PDK2 fine-tunes the glycolysis and cell-fate determinations of LICs. Hao et al., 2019, Cell Metabolism 29, 950-965 April 2, 2019 ª 2018 Elsevier Inc. SUMMARYThe metabolic properties of leukemia-initiating cells (LICs) in distinct bone marrow niches and their relationships to cell-fate determinations remain largely unknown. Using a metabolic imaging system with a highly responsive genetically encoded metabolic sensor, SoNar, we reveal that SoNar-high cells are more glycolytic, enriched for higher LIC frequency, and develop leukemia much faster than SoNar-low counterparts in an MLL-AF9-induced murine acute myeloid leukemia model. SoNar-high cells mainly home to and locate in the hypoxic endosteal niche and maintain their activities through efficient symmetric division. SoNar can indicate the dynamics of metabolic changes of LICs in the endosteal niche. SoNar-high human leukemia cells or primary samples have enhanced clonogenic capacities in vitro or leukemogenesis in vivo. PDK2 fine-tunes glycolysis, homing, and symmetric division of LICs. These findings provide a unique angle for the study of metabolisms in stem cells, and may lead to development of novel strategies for cancer treatment.

MDH1-mediated malate-aspartate NADH shuttle maintains the activity levels of fetal liver hematopoietic stem cells

“…Interestingly, most immunophenotypic Lin 2 Sca-1 1 c-Kit 1 CD150 1 CD48 2 adult HSCs were in the SoNar-mid cell population, as determined by flow cytometric analysis (supplemental Figure 5A-C). Because high SoNar ratios may represent greater glycolysis, as evidenced by a related biochemical analysis ( Figure 3) and our previous study, 41 these results indicate that adult HSCs may have a metabolic profile that differs from that of FL-HSCs. In addition, differentiated BM cells displayed a multilineage pattern that differed from that presented by the FL hematopoietic cells (supplemental Figure 5D).…”

The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

“…Our knowledge of the leukemic bone marrow niche must greatly improve as many LSC vulnerabilities are, in part, niche-directed (reviewed elsewhere 215,216 ). Measuring metabolic alterations in the leukemic niche 77 , and using intravital microscopy 217 to visualise its three-dimensional cellular and histological sub-structures will be critical.…”

A bioenergetic shift is required for spermatogonial differentiation

“…To further determine the changing metabolic preference during spermatogonial differentiation, we established a primary spermatogonial line containing a fluorescent cytosolic SoNar sensor, the intensity of which reflects the cytosolic NAD+ and NADH redox state 41 . In general, glycolysis produces NADH, which may be shuttled to mitochondria and oxidized to NAD+, or be recycled to NAD+ by lactate dehydrogenase (LDH) when generating lactate from pyruvate in the cytosol 42 . Therefore, the cytosolic NAD+/NADH ratio is determined by the net balance of these three pathways 42 .…”

“…In general, glycolysis produces NADH, which may be shuttled to mitochondria and oxidized to NAD+, or be recycled to NAD+ by lactate dehydrogenase (LDH) when generating lactate from pyruvate in the cytosol 42 . Therefore, the cytosolic NAD+/NADH ratio is determined by the net balance of these three pathways 42 . We found that undifferentiated spermatogonia displayed a much higher NAD+/NADH ratio than that of differentiating spermatogonia induced by RA for 24 h (Fig.…”