Energy Producing Metabolic Pathways in Functional Regulation of the Hematopoietic Stem Cells

Abstract

The hematopoietic system has a very well-studied hierarchy with the long-term (LT) hematopoietic stem cells (HSCs) taking the top position. The pool of quiescent adult LT-HSCs generated during the fetal and early postnatal life acts as a reservoir to supply all the blood cells. Therefore, the maintenance of this stem cell pool is pivotal to maintaining homeostasis in hematopoietic system. It has long been known that external cues, along with the internal genetic factors influence the status of HSCs in the bone marrow (BM). Hypoxia is one such factor that regulates the vascular as well as hematopoietic ontogeny from a very early time point in development. The metabolic outcomes of a hypoxic microenvironment play important roles in functional regulation of HSCs, especially in case of adult BM HSCs. Anaerobic metabolic pathways therefore perform prominent role in meeting energy demands. Increased oxidative pathways on the other hand result in loss of stemness. Recent studies have attributed the functional differences in HSCs across different life stages to their metabolic phenotypes regulated by respective niches. Indicating thus, that various energy production pathways could play distinct role in regulating HSC function at different developmental/physiological states. Here, we review the current status of our understanding over the role that energy production pathways play in regulating HSC stemness. © 2018 IUBMB Life, 70(7):612-624, 2018.

3D culture technologies of cancer stem cells: promising ex vivo tumor models

“…22 This hypothesis was supported by studies that demonstrated that primitive hematopoietic stem cells inhabit areas with low oxygen pressure, given that they are likely to occupy regions that are far from the vessels. 101,102 Emerging evidence also suggests that under a hypoxic environment, the stemness of breast cancer cells can be enhanced to increase malignancy and therapeutic resistance. 100 The hypoxic tumor microenvironment could also activate CSC-related signaling pathways.…”

Insight into Hypoxia Stemness Control

“…In a low O 2 culture, MSCs improve the maintenance of their undifferentiated state through the suppression of mitochondrial activity and promote genetic stability [202]. Even more, adult HSCs, residing in low O 2 niches, have a metabolism that is mainly based on glycolysis for the energy demand, and an increase in mitochondrial activity is linked to a decline in stemness [203].…”

“…The loss of Meis1 in HSCs results in disruption of stem cells quiescence through increased ROS production, increased apoptosis and down-regulation of both HIF-1α and HIF-2α [208]. Thus, HIF-1α and ROS closely work together, along with O 2 homeostasis and energy metabolism, to maintain HSCs function [203].…”

Metabolism of Stem and Progenitor Cells: Proper Methods to Answer Specific Questions

“…In particular, a proper quality control of mitochondrial function has been recently highlighted as a key factor in SC maintenance and commitment (Shyh-Chang et al, 2013). In order to demonstrate hematopoietic SC (HSC) repopulating capacity, HSCs are kept in a quiescent state, where they exhibited higher glycolysis rate and lower mitochondrial respiration than committed progenitor cells (Chandel et al, 2016; Roy et al, 2018). The disruption of this metabolic checkpoint leads to the loss of quiescence and to a reduced regenerative capacity, and directs HSCs towards lineage commitment where the displacement to mitochondrial metabolism (mitochondrial oxidative phosphorylation) is essential, in order to rapidly respond to the increased demand of energy (Vannini et al, 2016).…”

“…Mitochondria also act as the leading site for the production of Reactive Oxygen Species (ROS), and ROS accumulation finally contributes to the defective functioning of HSCs and their loss of stemness. Accordingly, ROS clearance exhibits a positive effect on HSC recovery of stemness (Chandel et al, 2016; Roy et al, 2018). In this scenario, autophagy, or rather mitophagy, a self-degradative process involved in the energy balance (Mizushima and Komatsu, 2011), plays an essential role in the reversion of metabolically active HSCs to quiescence by clearing healthy but active mitochondria, thus preventing the induction of (epi) genetic programs that lead to HSC commitment, and thereby supporting the maintenance of healthy hemeatopoiesis (Riffelmacher and Simon, 2017; Jin et al, 2018).…”