Metabolic regulation of hematopoiesis
Background
All adult stem cells can undergo two types of division: symmetric and asymmetric. When a cell undergoes symmetric division, it can either produce two differentiated cells or two new stem cells. When a cell undergoes asymmetric division, it produces one stem and one differentiated cell. Production of new stem cells is necessary to maintain this population within the body.
Maintenance of quiescence
Glycolysis and Hif signaling
It is well understood that quiescent HSCs have very low levels of metabolic activity. LT-HSCs primarily rely on anaerobic glycolysis to generate energy. Unlike other types of HSCs, little energy is produced from mitochondrial oxidative respiration. The reason from this is likely two-fold: LT-HSCs reside within the hypoxic niche of the bone marrow, and low levels of mitochondrial respiration protect quiescent cells from damage induced ROS.[15][16] When excessive levels of ROS are present, LT-HSCs undergo differentiation or apoptosis, losing their ability to self-renew.[17] This suggests that dependence on glycolysis is not only an environmental adaptation, but also a necessity for LT-HSCs to preserve their stemness.
LT-HSC preference for glycolysis is encoded by the transcription factor
Metabolic reprogramming by HIF1α does not always happen through action on PDKs. HIF1α can also promote expression of the cytosolic protein
Extracellular cytokines and chemokines may also contribute to HIF1α activity, but further work is required to elucidate the exact contribution of these signaling molecules.In addition to HIF1α, MEIS1 induces transcription of HIF2α. Though this enzyme is structurally similar to HIF1α, HIF2α has distinct functions. HIF2α is thought to protect HSCs from mitochondrial ROS production. An accumulation of ROS in HSCs causes stress at the endoplasmic reticulum, eventually inducing the unfolded protein response and apoptosis.[23] HIF2α protects the cell from ROS accumulation by up regulating several genes involved in ROS quenching, including catalase, glutathione peroxidase type I, and superoxide dismutases.[8] Activation of HIF2α is therefore necessary to maintain cellular health during quiescence.
Mitochondrial metabolism
Despite low levels of mitochondrial respiration, emerging evidence shows that LT-HSCs with the highest regenerative potential also have a high number of mitochondria.[25] Despite this, quiescent HSC mitochondria have a low membrane potential and low rates of oxidative phosphorylation. This again highlights the dependence of LT-HSCs on glycolysis to generate energy. Despite their inactivity, possessing many mitochondria may indicate that the quiescent HSCs are prepared for proliferation once an appropriate signal is received[24]
Cell fate decisions
Recently, it has been discovered that fatty acid oxidation (FAO) is a major determinant in whether a stem cell will symmetrically or asymmetrically divide.
Metabolism during proliferation
Hif1 and the switch to mitochondrial metabolism
Though maintenance of quiescence is important to HSCs to preserve their self-renewal capacity, proliferation is necessary to regenerate blood cells and immune cells for the body. During divisions, HSCs leave the hypoxic niche and begin circulating. Under these normoxic conditions, HIF1α is hydroxylated by prolyl hydroxylases PHD1, 2 and 3.
Accompanying the processes driven by HIF1α is an activation of mitochondrial oxidative phosphorylation through inactivation of the protein tyrosine phosphatase mitochondrial 1 (PTPMT1) enzyme.[27] PTPMT-1 is essential for differentiation of HSCs into progenitors, and loss of this enzyme results in failure to produce blood cells in mice.[34] Targets of PTPMT-1 include phosphatidylinositol phosphates (PIPs). When PIPs are acted upon by PTPMT-1, the mitochondrial membrane potential decreases. This decrease inhibits glucose entry into the TCA cycle and subsequent ATP generation through the electron transport chain.[34] Thus, PTPMT-1 activity is crucial for HSCs to differentiate.
MTCH2 signaling
Another important suppressor of mitochondrial metabolism during quiescence is mitochondrial carrier homolog 2 (MTCH2).[16] Loss of MTCH2 increases oxidative phosphorylation and triggers HSC differentiation. As expected, this increase in oxidative phosphorylation increases ROS levels, ATP levels, and mitochondrial size. These phenotypes highlight the importance of MTCH2 in directing HSC fate.
The pentose phosphate pathway
Upregulation of glycolysis in proliferative HSCs may drive the
Other signaling pathways
Several signaling pathways also have roles in mediating the metabolic shift from quiescent to proliferative HSCs. For example, purine metabolism is upregulated and thus promotes entry into the cell cycle through signaling in the p38MAPK pathway. ERK and mTOR, other major signaling pathways, are also activated during cell cycle entry. Among other functions, these pathways promote protein, nucleotide, and lipid synthesis. Active ERK and mTOR pathways also lead to increased nutrient uptake in HSCs. In addition to this biosynthetic role, mTOR can also increase the rate of ATP production in cells.[28]
See also
References
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