The role of hypoxia in the maintenance of hematopoietic stem cells

Abstract

Bone marrow cell liquid cultures were incubated at various oxygen concentrations ranging from 0% to 18% (air). The total number of cells in culture (CT) at the end of a 6-day incubation was found to be directly proportional to the oxygen concentration. As compared with air- incubated controls, cells recovered from severely hypoxic (1% oxygen) day-5 liquid cultures showed (1) the same day-7 colony-formation efficiency in semisolid culture (neutrophilic/monocytic colonies) or in spleen; (2) a higher day-14 spleen colony-formation efficiency; (3) an enhanced radio-protection ability; and (4) an increased marrow repopulation ability, as measured by determining either total cell number in recipient marrow MRAcell, or the capacity of the latter of generating day-7 neutrophilic/monocytic colonies in secondary in vitro assays (MRACFU-NM). Taking into account CT, the absolute numbers of progenitors in culture were also computed. The results showed that, with respect to time 0, incubation in air produced an increase in the number of day-7 CFUs and a decrease in the number of the other progenitors, whereas in hypoxic cultures all types of progenitors decreased. However, as compared with air-incubated controls, all progenitors, except cells sustaining MRACFU-NM, were reduced in hypoxic cultures. The degree of reduction paralleled the position of the progenitor in the hematopoietic hierarchy, being maximum for day-7 CFUs and null for cells sustaining MRACFU-NM, which, in fact, were better preserved in hypoxic cultures.

Reduced oxygen tension attenuates differentiation capacity of human mesenchymal stem cells and prolongs their lifespan

“…To a large extent, O 2 can only be supplied by the circulation, which further supports differentiation by distributing nutrients and growth factors. This model agrees with what is known for HSC: these cells remain quiescent under low O 2 conditions, while proliferating and differentiating optimally at elevated pO 2 (Cipolleschi et al ., 1993). Whether O 2 is a decisive signal for the differentiation of mesenchymal progenitor cells in vivo has to be tested in future experiments.…”

Hypoxia or in situ normoxia: The stem cell paradigm

“…With respect to the stem cell fate, the concept presented above could be applied to two hypotheses: (1) the stem cells exhibit the same metabolic type as other cells, but, residing in highly hypoxic niches (Chow et al, 2000; Nilsson et al, 2001; Wilson and Trumpp, 2006; Arai and Suda, 2007; Parmar et al, 2007) they are quiescent (as proposed by Cipolleschi et al, 1993) or allowed to proliferate slowly without differentiation. This hypothesis is compatible with the concept of slow self‐renewing divisions of somatic stem cells (Bradford et al, 1997); (2) stem cells exhibit a particular, peculiar metabolic type, permitting their proliferation without differentiation in highly hypoxic conditions, a property lost in course of differentiation.…”

“…Basically the same phenomenon was evidenced for VEGF (Brunet de la Grange et al, 2003). The real nature of stem cells, that is, their maintenance in G0 phase, self‐renewal, commitment, etc., which are, of course, regulated by certain cytokines and growth factors, should be evaluated only at appropriately low O 2 concentrations characterizing the stem cell niche (Cipolleschi et al, 1993, 2000; Ivanovic et al, 2000a). Thus, here again, the response of stem cells to the cytokine stimulation is completely different at 0.1, 1, 3–5, or at 20–21% O 2 , implying a physiological regulatory role of oxygen concentration in early hematopoiesis (Ivanovic et al, 2000a, 2002, 2004; Hermitte et al, 2006).…”

Concise Review: Current Concepts in Bone Marrow Microenvironmental Regulation of Hematopoietic Stem and Progenitor Cells

“…VEGF is strongly induced by hypoxia and moreover, the direct role of hypoxia on HSPC regulation has also been explored. It has been established that the most quiescent HSPCs reside in the least perfused niches and are better preserved ex vivo in hypoxia [90–93]. Although their niches tend to be hypoxic, HSPCs are also capable of maintaining intracellular hypoxia and stabilizing HIF1α protein [94].…”