This is a review (by no means comprehensive) of how the stem cell niche evolved from an abstract concept to a complex system, implemented with a number of experimental data at the cellular and molecular levels, including metabolic cues, on which we focused in particular. The concept was introduced in 1978 to model bone marrow sites suited to host hematopoietic stem cells (HSCs) and favor their self-renewal, while restraining clonal expansion and commitment to differentiation. Studies of the effects of low
oxygen tension on HSC maintenance in vitro led us to hypothesize niches were located within bone marrow areas where
oxygen tension is lower than elsewhere. We named these areas hypoxic stem cell niches, although a low
oxygen tension is to be considered physiological for the environment where HSCs are maintained. HSCs were later shown to have the option of cycling in low
oxygen, which steers this cycling to the maintenance of stem cell potential. Cell subsets capable of withstanding incubation in very low
oxygen were also detected within
leukemia cell populations, including
chronic myeloid leukemia (CML). The oncogenetic Bcr/Abl
protein is completely suppressed in these subsets, whereas Bcr/Abl messenger
ribonucleic acid is not, indicating that CML cells resistant to low
oxygen are independent of Bcr/Abl for persistence in culture but remain genetically leukemic. Accordingly,
leukemia stem cells of CML selected in low
oxygen are refractory to the Bcr/Abl inhibitor
imatinib mesylate. Bcr/Abl
protein suppression turned out to be actually determined when
glucose shortage complicated the effects of low
oxygen, indicating that
ischemia-like conditions are the driving force of
leukemia stem cell refractoriness to
imatinib mesylate. These studies pointed to "ischemic" stem cell niches as a novel scenario for the maintenance of
minimal residual disease of CML. A possible functional relationship of the "ischemic" with the "hypoxic" stem cell niche is discussed.