Slow-cycling/quiescence balance of hematopoietic stem cells is related to physiological gradient of oxygen

Guitart, Amélie V.; Hammoud, Mohammad; Sbarba, Persio Dello; Ivanović, Zoran; Perreten, Vincent

doi:10.1016/j.exphem.2010.06.002

Cited by 75 publications

(45 citation statements)

References 24 publications

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“…These findings suggest that in post mortem muscle stem cells ROS may have an inhibitory effect on NF-κB activation as described thus far only in lung epithelial cells 51 . Interestingly, distinct phenotypic outcomes including quiescence or proliferation, and apoptosis or survival, have been suggested to be modulated by severe or mild hypoxic conditions (0.1-1%) 52 , or the bioenergetic requirement of the cell 53 . Our findings suggest that this might also be the case as the degree of hypoxia/anoxia in dormant muscle stem cells could maintain their viability for unusually long periods in spite of the necrotic microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity

et al. 2012

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“…HSC, as a paradigmatic case, was cultured at low O 2 concentrations that were mainly called ''hypoxia.'' This is a confusing term since 1-7% represent physiological oxygen concentrations of the tissues providing HSC environment (Chow et al, 2001;Shima et al, 2009;Guitart et al, 2010;Winkler et al, 2010). These physiologically low O 2 concentrations protect the primitive hematopoietic cells against oxidative stress in vivo (Jang and Sharkis, 2007;Parmar et al, 2007) and ex vivo (Fan et al, 2007(Fan et al, , 2008.…”

mentioning

confidence: 97%

Combination of low O₂ concentration and mesenchymal stromal cells during culture of cord blood CD34⁺ cells improves the maintenance and proliferative capacity of hematopoietic stem cells

Hammoud

Vlaški

Duchez

et al. 2012

Journal Cellular Physiology

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The physiological approach suggests that an environment associating the mesenchymal stromal cells (MSC) and low O(2) concentration would be most favorable for the maintenance of hematopoietic stem cells (HSCs) in course of ex vivo expansion of hematopoietic grafts. To test this hypothesis, we performed a co-culture of cord blood CD34(+) cells with or without MSC in presence of cytokines for 10 days at 20%, 5%, and 1.5% O(2) and assessed the impact on total cells, CD34(+) cells, committed progenitors (colony-forming cells-CFC) and stem cells activity (pre-CFC and Scid repopulating cells-SRC). Not surprisingly, the expansion of total cells, CD34(+) cells, and CFC was higher in co-culture and at 20% O(2) compared to simple culture and low O(2) concentrations, respectively. However, co-culture at low O(2) concentrations provided CD34(+) cell and CFC amplification similar to classical culture at 20% O(2) . Interestingly, low O(2) concentrations ensured a better pre-CFC and SRC preservation/expansion in co-culture. Indeed, SRC activity in co-culture at 1.5% O(2) was higher than in freshly isolated CD34(+) cells. Interleukin-6 production by MSC at physiologically low O(2) concentrations might be one of the factors mediating this effect. Our data demonstrate that association of co-culture and low O(2) concentration not only induces sufficient expansion of committed progenitors (with respect to the classical culture), but also ensures a better maintenance/expansion of hematopoietic stem cells (HSCs), pointing to the oxygenation as a physiological regulatory factor but also as a cell engineering tool.

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“…First, hypoxia has been implicated in the control of the metabolism and growth of numerous stem cells, and HSC in particular. 19 Second, it has been suggested that HOXB4 induces stem cell expansion through c-myc expression, resulting in enhancement of HSC self-renewal. 20 In agreement, the study by Oshima et al 21 and ours showed that c-myc (and its partner max in our study) was up-regulated in HSC exposed to HOXB4 (or to HOXC4).…”

Section: Hoxb4 and Hoxc4 Regulate Genes Important In Various Cell Gromentioning

confidence: 99%

HOXC4 homeoprotein efficiently expands human hematopoietic stem cells and triggers similar molecular alterations as HOXB4

Auvray¹,

Delahaye²,

Pflumio³

et al. 2012

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundExpansion of hematopoietic stem cells represents an important objective for improving cell and gene therapy protocols. Retroviral transduction of the HoxB4 homeogene in mouse and human hematopoietic stem cells and hematopoietic progenitors is known to promote the cells' expansion. A safer approach consists in transferring homeobox proteins into hematopoietic stem cells taking advantage of the natural ability of homeoproteins to cross cell membranes. Thus, HOXB4 protein transfer is operative for expanding human hematopoietic cells, but such expansion needs to be improved. Design and MethodsTo that aim, we evaluated the effects of HOXC4, a protein encoded by a HOXB4 paralog gene, by co-culturing HOXC4-producing stromal cells with human CD34 + hematopoietic cells. Numbers of progenitors and stem cells were assessed by in vitro cloning assays and injection into immuno-deficient mice, respectively. We also looked for activation or inhibition of target downstream gene expression. ResultsWe show that the HOXC4 homeoprotein expands human hematopoietic immature cells by 3 to 6 times ex vivo and significantly improves the level of in vivo engraftment. Comparative transcriptome analysis of CD34 + cells subjected or not to HOXB4 or HOXC4 demonstrated that both homeoproteins regulate the same set of genes, some of which encode key hematopoietic factors and signaling molecules. Certain molecules identified herein are factors reported to be involved in stem cell fate or expansion in other models, such as MEF2C, EZH2, DBF4, DHX9, YPEL5 and Pumilio. ConclusionsThe present study may help to identify new HOX downstream key factors potentially involved in hematopoietic stem cell expansion or in leukemogenesis.

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Slow-cycling/quiescence balance of hematopoietic stem cells is related to physiological gradient of oxygen

Cited by 75 publications

References 24 publications

Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity

Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity

Combination of low O₂ concentration and mesenchymal stromal cells during culture of cord blood CD34⁺ cells improves the maintenance and proliferative capacity of hematopoietic stem cells

HOXC4 homeoprotein efficiently expands human hematopoietic stem cells and triggers similar molecular alterations as HOXB4

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Slow-cycling/quiescence balance of hematopoietic stem cells is related to physiological gradient of oxygen

Cited by 75 publications

References 24 publications

Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity

Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity

Combination of low O2 concentration and mesenchymal stromal cells during culture of cord blood CD34+ cells improves the maintenance and proliferative capacity of hematopoietic stem cells

HOXC4 homeoprotein efficiently expands human hematopoietic stem cells and triggers similar molecular alterations as HOXB4

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Combination of low O₂ concentration and mesenchymal stromal cells during culture of cord blood CD34⁺ cells improves the maintenance and proliferative capacity of hematopoietic stem cells