Abstract
Leukemia poses a serious challenge to current therapeutic strategies. This has been attributed to leukemia stem cells (LSCs), which occupy endosteal and sinusoidal niches in the bone marrow similar to those of hematopoietic stem cells (HSCs). The signals from these niches provide a viable setting for the maintenance, survival, and fate specifications of these stem cells. Advancements in genetic engineering and microscopy have enabled us to critically deconstruct and analyze the anatomic and functional characteristics of these niches to reveal a wealth of new knowledge in HSC biology, which is quite ahead of LSC biology. In this paper, we examine the present understanding of the regulatory mechanisms governing HSC niches, with the goals of providing a framework for understanding the mechanisms of LSC regulation and suggesting future strategies for their elimination.
Highlights
A dysfunctional stem cell microenvironment, or niche, contributes signi cantly to disease pathology, in cancer [1]
Testing of the prevailing theory, proposed by Scho eld, regarding the underlying indispensable role of the bone marrow structure in engineering hematopoiesis [5] became possible only with the advent and introduction of new in vivo technological tools such as intravital multiphoton microscopy (IVM), which is powerful in optical sectioning of deep tissues and providing real-time visualization of cellular interactions [5, 6]. is has led to a radical revolution in the way stem cells are studied in the bone marrow
Hypoxia is necessary for the long-term maintenance of hematopoietic stem cells (HSCs) and is regulated by hypoxia-inducible factor (HIF)1αα [42]. e metabolic activity of these long-term HSCs is dependent on glycolysis, which is driven by Meis1 via transcriptional activation of HIF-1αα [43]. e same HIF-1αα stabilizes endosteal HSCs and maintains them in a state of quiescence, enabling them to withstand stressful conditions. is maintenance and survival of HSCs occurs via HIF regulation of vascular endothelial growth factor alpha (VEGFαα), Cripto/GRP78 signaling, and upregulation of CXCR4 [44, 45]
Summary
A dysfunctional stem cell microenvironment, or niche, contributes signi cantly to disease pathology, in cancer [1]. Ese niches are complex, encompassing a broad range of bone marrow cells that includes bone lining cells (osteoblasts and osteoclasts), mesenchymal stem cells (MSCs), sinusoidal endothelium and perivascular stromal cells, immune cells, and several others that play different roles in HSC regulation [14]. Ncertainty about which speci c sinusoidal or endosteal niche cell is functionally important in producing any of these molecules and sufficient to maintain HSCs led Ding et al to conduct the study already mentioned in which crelox conditional knockout mice were used to delete SCF in vivo from osteoblasts, sinusoidal endothelium, perivascular stromal cells, and nestin-positive MSCs [9]. Eir results showed that sinusoidal endothelium and lepr-expressing perivascular stromal cells, but not osteoblasts or nestin-creor nestin-creER-expressing cells, are directly responsible for the expression of SCF and functionally regulate HSCs in the sinusoidal niche; their deletion resulted in decreased hematopoiesis in the liver, spleen, and bone marrow. SCF deletion by genetic knockout in embryos led to lethality due to hematopoietic de ciencies. is pivotal study paved the way for studying the functional speci city of cells that make up HSC niches
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