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    • Aside from phenotypic differences functional differences hav

    2018-10-24

    Aside from phenotypic differences, functional differences have also been described between adult BM and FL LT-HSCs (Higuchi et al. 2003; Bowie et al. 2007). For instance, FL LT-HSCs display significantly faster expansion kinetics when grafted in adult mice, compared with LT-HSCs from BM of 8-week-old mice (Bowie et al. 2007). Furthermore, FL and early postnatal BM LT-HSCs undergo significantly more symmetrical self-renewing cell divisions compared with 8-week-old adult BM LT-HSCs. Although it would be logical to hypothesize that extensively proliferating FL LT-HSCs may require a significantly different metabolic activity to create energy and building blocks for cell renewal, few if any studies have addressed this question. Cell metabolism consists of anabolic and Wnt-C59 that allow cells to survive, function and synthesize new components for cellular division. The generation of cellular energy (ATP), reduction capacity (NADH, NADPH and FADH2) and cellular macromolecules is mainly fueled by the consumption of glucose, glutamine and fatty acids through glycolysis, glutaminolysis and β-oxidation, respectively (Berg et al. 2007; Matés et al. 2009). The function and activity of ATP-generating pathways is known to differ dramatically in stem cells and differentiated progeny. Most stem cells have been shown to use glycolysis for energy production, while more differentiated cells divert glucose to the mitochondria and exhibit a significantly higher rate of OxPhos (Varum et al. 2011; Abu Dawud et al. 2012). This has also been shown for adult BM LT-HSCs. Postnatal BM LT-HSCs depend on glycolysis for energy production, whereas glycolysis decreases upon differentiation and OxPhos increases (Suda et al. 2011; Klimmeck et al. 2012). While TCA cycle-related metabolites such as 2-oxoglutarate, acetyl-CoA, and succinyl-CoA were not detected in LT-HSCs, they were shown to accumulate pyruvate (Takubo et al. 2013). Loss of pyruvate dehydrogenase kinase (Pdk) (Takubo et al. 2013) or lactate dehydrogenase (Ldha) (Wang et al. 2014), which inhibits glycolysis, results in defects in LT-HSC function. As metabolic pathways used can determine fate changes at the stem cell level (Oburoglu et al. 2014), we believe that understanding the metabolism of proliferative FL LT-HSCs will provide insights into how it might be possible to achieve extensive self-renewal of BM LT-HSCs, and hence, create efficient ex vivo LT-HSC expansion systems.
    Materials and methods
    Results and discussion
    Conclusion Our studies thus clearly demonstrate that FL LT-HSCs use OxPhos (aside from glycolysis), which we hypothesize is required to more efficiently generate ATPs and other building blocks essential for the extensive FL-HSC expansion. Unlike adult BM LT-HSCs, wherein OxPhos results in ROS accumulation causing differentiation, DNA damage and aging, LT-HSCs derived from FL that express higher levels of gene-sets related to “cellular response to stress” as well as DNA repair pathways may be able to cope with the increased ROS levels (Fig. 1B; Figs. S1E and S2A). Expression levels of some anti-oxidant genes from these gene-sets were examined in adult BM and E14.5 FL derived LT-HSCs by qRT-PCR (Fig. 2H). We speculate that elevated levels of these genes prevent DNA damage higher baseline ROS and oxygen consumption rate (OCR) in FL LT-HSCs (Nijnik et al. 2007; Rossi et al. 2007).
    Author contributions The following are the supplementary data related to this article.
    Acknowledgements This work was supported by an FWO funding (G085111N), an FWO grant (1.2.665.11.N.00) to S Khurana, an FWO grant (G085111N10), Odysseus funding, CoE-SCIL, PF03, and GOA/11/012 funding from KU Leuven, and the Vanwayenberghe fund to CM Verfaillie. The work of P. Carmeliet is supported by long-term structural funding-Methusalem Funding by the Flemish Government. The authors wish to thank Pier Andree Pentilla and Rob Van Rossom for assistance with FACS sorting and analysis and Sarah Schouteden for technical support.