Page 59 - JCTR-11-5

Journal of Clinical and
Translational Research Metabolism of healthy and leukemic stem cells

primarily by osteoblasts and enhances HSC quiescence by both quiescence and repression of lineage commitment
stabilizing stem cell interactions through the Tie2 and in HSCs. Of interest, mice deficient in Gli1 exhibit
57
phosphatidylinositol 3-kinase/protein kinase B pathways. decreased HSC proliferation and enhanced short- and
33
The niche factor CXCL12 is produced by BM stromal and long-term HSC engraftment, supporting the role of HH
endothelial cells and binds the C-X-C motif chemokine signaling in HSC maintenance and quiescence. 59
receptor type 4 on HSCs to reinforce dormancy. 34,35 Collectively, these findings demonstrate the tight
Secreted by osteoblasts and adipocytes, SCF supports regulation of HSC quiescence and how the niche-derived
HSC quiescence by regulating metabolic homeostasis and factors, cell cycle regulatory components, and developmental
promoting survival. 36-38 Alternatively, TPO limits cell cycle
entry by stimulating the expression of Tie2 on HSCs and pathways work independently or cooperatively to ensure
42
preserves stemness. 39,42 OPN, secreted by osteoblasts and long-term hematopoietic homeostasis and regenerative
stromal cells, interacts with integrin receptors to suppress capacity.
cell cycle progression and enhance HSC anchoring in the 2.2. Glycolysis versus OXPHOS in quiescent and
BM niche. 40,41 active HSCs
Moreover, cell cycle regulatory components are equally Sustained quiescence in HSCs depends on maintaining
essential for governing HSC dormancy and quiescence by low metabolic rates and minimal mitochondrial
tightly controlling cell cycle entry and progression. 1,19,20 OXPHOS. 1,5,14 However, the transition out of dormancy
These include members of the retinoblastoma (Rb) involves rapid changes in cellular metabolism. This
5,14
family 43-45 and the Forkhead box class O proteins, 46,47 as well transition from highly glycolytic metabolism to OXPHOS
as the interaction between cyclin D and cyclin-dependent supports the heightened energetic demands required
kinase (CDK) 4/6, 48,49 and the CDK interacting protein/ for rapid proliferation and differentiation. Glycolysis
5,14
kinase inhibitory protein family (e.g., p21, p27, p57, and is a central metabolic pathway through which cells can
p53). 50-52 In HSCs, the Rb family restricts the transition derive critical metabolites and metabolic precursors from
from G /G into S phase by suppressing DNA replication a single glucose molecule. In the quiescent state, HSCs
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0
1
and cell proliferation through regulation of TPO- rely on glycolysis independent of the presence of oxygen.
mediated signaling, thus reinforcing a quiescent state. 43-45 This is important, since a primary characteristic of the
The Forkhead box class O transcription factor proteins BM niche is a highly hypoxic microenvironment. 1,6,21 In
suppress HSC cell cycle progression and are involved in
ROS resistance, further promoting HSC quiescence. 46,47 fact, in vivo measurements in the hypoxic BM niche
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Alternatively, cyclin D and CDK4/6 form a complex as showed a local oxygen tension (pO ) of <32 mm Hg
2
62
a fundamental step controlling progression of the cell compared with an average atrial pO of 90 mmHg. Such
2
cycle out of quiescence by inhibiting Rb and promoting a hypoxic microenvironment creates ideal conditions to
transition from G into S phase. 48,49 The CDK-interacting stabilize a key transcription factor and mediator of cellular
1
21,63
protein/kinase inhibitory protein family functions to hypoxia, hypoxia-inducible factor (HIF)-1α. HSCs
21
suppress the activity of the cyclin D–CDK4/6 complex, are known to express HIF-1α at high levels. Previous
thereby preserving HSC dormancy and quiescence. 50-52 studies have shown that HIF-1α–deficient mice exhibit a
loss of HSC quiescence and decreased HSC abundance,
In addition, evolutionarily conserved pathways, highlighting the importance of HIF-1α stabilization in
including the Wnt, 53,54 Notch, 53,55,56 and Hedgehog (HH) HSCs. Alternatively, overexpression of HIF-1α maintains
57
64
developmental pathways, play supportive roles in the quiescence but decreases transplantation capacity,
maintenance of HSC quiescence, self-renewal, and suggesting an intricate and tightly regulated balance of
inhibition of differentiation. 1,20,37 Wnt signaling promotes HIF-1α expression in the maintenance of HSC quiescence.
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HSC self-renewal through downstream activation of Nevertheless, the stabilization of HIF-1α reinforces the
β-catenin and transcriptional genes governing the cell prioritization of glycolytic metabolism, thereby providing
cycle, while also suppressing lineage-specific transcription long-term protection of HSCs from oxidative damage by
factors. 53,54 Interestingly, overexpression of β-catenin in OXPHOS-derived ROS. 1,5,6,21
HSCs increases HSC expansion and inhibits differentiation
both in vitro and in vivo. Alternatively, Notch signaling Upon activation, HSCs increase glycolytic influx to
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reinforces HSC quiescence and self-renewal in an meet the rising metabolic and biosynthetic demands
undifferentiated state by upregulating transcriptional required for proliferation and differentiation. 5,14,19 This
repressors that inhibit differentiation and enhance cell compels HSCs to increase expression of glycolytic
cycle repression. 53,55,56 Through the activation of the Gli transporters (e.g., glucose transporter 1 [GLUT1])
transcription factor, HH signaling similarly supports downstream of TGF-β1 stimulation, thereby enhancing

Volume 11 Issue 5 (2025) 53 doi: 10.36922/JCTR025320053