Page 57 - JCTR-11-5

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

1. Introduction guide the transition between quiescent and active HSCs
and initiate oncogenic transformation into LSCs. 15-17 In
Hematopoiesis is a tightly regulated process that produces this review, we summarize the key metabolic features
differentiated blood cells to meet the physiological that guide HSC activation and distinguish healthy HSCs
demands of the human body. Located within the human from LSCs. Furthermore, we highlight how advances
1,2
bone marrow (BM) niche, hematopoietic stem cells in metabolomic technologies can decode the metabolic
(HSCs) play pivotal roles in sustaining these demands framework and uncover novel biochemical pathways and
by intricately balancing self-renewal and regenerative therapeutic strategies for regulating and targeting HSC and
proliferation with differentiation and lineage commitment LSC metabolism, respectively.
at an average rate of 1 × 10 cells/s. At homeostasis, HSCs
6
1-4
in the BM are maintained in a highly quiescent state, the 2. Metabolic landscape of healthy HSCs
G phase of the cell cycle, and only enter proliferation or
0
differentiation upon stimulation. 1,4,5 When stimulated by 2.1. Metabolic profile of HSCs within the BM
extrinsic and intrinsic factors (e.g., colony-stimulating microenvironment
factors, growth factors, and cytokines), HSCs either Under normal homeostatic conditions, HSCs are
6,7
transition into a state of self-renewal or differentiate preserved in extended periods of quiescence through a
heterogeneously through a hierarchy of multipotent tightly regulated balance between glycolysis and OXPHOS
progenitors into fully differentiated myeloid and lymphoid dependence 1,4,5,9,10,14 (Figure 1). Quiescent HSCs primarily
cells to adapt to changing physiological needs. 1,4,5 The exit rely on glycolysis for the minimal energetic demands of
of HSCs from quiescence is an energy-intensive process stem cell maintenance, as previously stated, and allow
that coincides with a rapid and critical metabolic shift for the minimization of reactive oxygen species (ROS)
from glycolysis to mitochondrial metabolism, including production commonly associated with fatty acid oxidation
increased mitochondrial biogenesis to support oxidative (FAO), such that quiescent HSCs can preserve their
phosphorylation (OXPHOS). 1,5,8-10 This metabolic shift is a genomic integrity and protect themselves against metabolic
cornerstone of the unique self-renewal and differentiation stress and functional decline. 1,4,5,9,10,14 This level of sustained
capabilities of HSCs. 5,8-10 quiescence is largely due to the hypoxic microenvironment

However, dysfunction in the metabolic processes that of the BM niche and provides protection against genomic
guide HSC exit from quiescence often leads to metabolic instability, metabolic stress, and functional decline induced
hijacking and ultimately the transformation of HSCs by ROS production. 1,8,14
into leukemia stem cells (LSCs). 1,3,11-14 LSCs are found in The BM niche provides HSCs with a stabilized and
the BM niche and are characterized by stemness features, specialized microenvironment comprised of support
including drug resistance, self-renewal, and lack of cells and extracellular components. These components
differentiation, as well as highly heterogeneous phenotypes, include a heterogenous array of osteoblasts, endothelial
genetic mutations, and metabolic alterations. 3,12,13 While cells, mesenchymal stem cells, adipocytes, fibroblasts,
HSCs and LSCs share fundamental self-renewal and macrophages, and extracellular matrix proteins that
drug resistance capabilities (i.e., high expression of ATP- support the hypoxic microenvironment and provide
binding cassette [ABC] transporters for genotoxin efflux), favorable conditions to maintain HSC quiescence. 1,8,18
1
their metabolic programs differ significantly to support Furthermore, the BM niche provides HSCs with
the altered biosynthetic and energetic demands associated several critical niche factors, modulators of cell cycle
with malignant transformation. 3,5,12-14 Understanding the progression, and developmental signaling pathways that
metabolic divergence between HSCs and LSCs can provide work independently and often redundantly to maintain
insight into stem cell homeostasis, leukemogenesis, drug quiescence and stemness (Table 1). 1,19,20
resistance, and therapeutic targeting. 11,13,14 Niche factors, including transforming growth factor
Advances in metabolic profiling have enabled beta 1 (TGF-β1), 29-32 angiopoietin-1 (Ang-1), stromal cell-
33
researchers to dissect these metabolic states and provide derived factor-1α (CXCL12), 34,35 stem cell factor (SCF), 36-38
insight into what drives the pathological shift from HSCs thrombopoietin (TPO), and osteopontin (OPN), 40,41
39
to LSCs. 15,16 Through metabolic profiling, recent studies work to enforce HSC quiescence by influencing the
have confirmed that profound alterations in cellular regulators of the cell cycle or acting as negative regulators
metabolism are a key determinant of ultimate stem cell of proliferation and differentiation. The TGF-β1 niche
behavior. Meanwhile, several studies have developed factor promotes HSC dormancy through the activation
emerging metabolic tools to shed light on the biochemical of the Smad signaling pathway, which ultimately inhibits
pathways and dynamic metabolic characteristics that HSC proliferation and differentiation. 29-32 Ang-1 is secreted

Volume 11 Issue 5 (2025) 51 doi: 10.36922/JCTR025320053