Abstract
Quiescent and self-renewing hematopoietic stem cells (HSCs) rely on glycolysis rather than on mitochondrial oxidative phosphorylation (OxPHOS) for energy production. HSC reliance on glycolysis is considered an adaptation to the hypoxic environment of the bone marrow (BM) and reflects the low energetic demands of HSCs. Metabolic rewiring from glycolysis to mitochondrial-based energy generation accompanies HSC differentiation and lineage commitment. Recent evidence, however, highlights that alterations in mitochondrial metabolism and activity are not simply passive consequences but active drivers of HSC fate decisions. Modulation of mitochondrial activity and metabolism is therefore critical for maintaining the self-renewal potential of primitive HSCs and might be beneficial for ex vivo expansion of transplantable HSCs. In this review, we emphasize recent advances in the emerging role of mitochondria in hematopoiesis, cellular reprograming, and HSC fate decisions.
Highlights
Hematopoiesis is a complex process that allows sustained production of each of the blood cell lineages throughout the lifespan of an individual
This defense mechanism acts in concert with a remodeled primitive mitochondrial network, which exhibits reduced oxidative phosphorylation (OxPHOS) activity [36]. Consistent with this decrease is the suppression of p38 activity as well as the upregulation of MEIS1 [36]. These events underscore the array of coordinated mechanisms that control reactive oxygen species (ROS) levels and limit mitochondrial functions required for cellular reprograming of human functional hematopoietic stem cells (HSCs) and their ex vivo expansion
HSC reliance on glycolysis has been perceived as an adaptation to the hypoxic niche of the bone marrow (BM) until now
Summary
Hematopoiesis is a complex process that allows sustained production of each of the blood cell lineages throughout the lifespan of an individual. HSCs are predominantly quiescent, and their metabolic wiring and reliance on glycolysis are distinct from those of committed progenitors and the other cells in the BM that encompass primarily lineage-differentiated cells [4, 5, 27] Unlike their progeny, HSCs accumulate high levels of 1,6-bisphosphate and other products of the final ATP-producing step of glycolysis. Whereas RISP-null fetal HSCs have defects in their differentiation capacity, the RISP-null adult HSCs are characterized by loss of quiescence and entry into the cell cycle that is associated with lethality [32] These studies suggest that the self-renewing HSCs rely heavily, but not solely, on glycolysis, emphasizing the importance of limited mitochondrial activity and metabolism in hematopoiesis and HSC fate decisions. It might be the result of a series of events that occur before the onset of the well-known “metabolic switch.” Importantly, these events might engage mechanisms that impact and act in concert with this “metabolic switch” to coordinate and control the balance between HSC self-renewal and differentiation
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