Hypoxia mediates low cell-cycle activity and increases the proportion of long-term–reconstituting hematopoietic stem cells during in vitro culture

Eliasson, Pernilla; Rehn, Matilda; Hammar, Petter; Larsson, Peter; Sirenko, Oksana; Flippin, Lee A.; Cammenga, Jörg; Jönsson, Jan‐Ingvar

doi:10.1016/j.exphem.2010.01.005

Cited by 145 publications

(127 citation statements)

References 36 publications

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“…However, despite multiple positive preclinical and clinical studies using cell-based therapies for myocardial infarction, an understanding of the mechanisms underlying these beneficial effects is still lacking. Previous studies have reported that the hypoxic environment induced an increase in the percentage of hematopoietic stem cells with long-term engraftment potential, through mechanisms mediated in part by HIF-1a [20]. These findings were in accordance with the hypothesis that stem cells with long-term engraftment capabilities were predominantly located at the lowest end of an oxygen gradient in the bone marrow, in hypoxic regions containing sinusoids rather than capillary structures [21].…”

Section: Discussionsupporting

confidence: 81%

Factors Secreted by Mesenchymal Stem Cells and Endothelial Progenitor Cells Have Complementary Effects on Angiogenesis In Vitro

Burlacu

Grigorescu

Rosca

et al. 2013

Stem Cells and Development

145

120

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Stem cell-based therapy for myocardial regeneration has reported several functional improvements that are attributed mostly to the paracrine effects stimulating angiogenesis and cell survival. This study was conducted to comparatively evaluate the potential of factors secreted by mesenchymal stem cells (MSCs) in normoxic and hypoxic conditions to promote tissue repair by sustaining endothelial cell (EC) adhesion and proliferation and conferring protection against apoptosis. To this aim, a conditioned medium (CM) was generated from MSCs after 24-h incubation in a serum-free normal or hypoxic environment. MSCs exhibited resistance to hypoxia, which induced increased secretion of vascular endothelial growth factor (VEGF) and decreased levels of other cytokines, including stromal-derived factor-1 (SDF). The CM derived from normal (nMSC-CM) and hypoxic cells (hypMSC-CM) induced similar protective effects on H9c2 cells in hypoxia. Minor differences were noticed in the potential of normal versus hypoxic CM to promote angiogenesis, which were likely connected to SDFa and VEGF levels: the nMSC-CM was more effective in stimulating EC migration, whereas the hypMSC-CM had an enhanced effect on EC adhesion. However, the factors secreted by MSCs in normoxic or hypoxic conditions supported adhesion, but not proliferation, of ECs in vitro, as revealed by impedance-based dynamic assessments. Surprisingly, factors secreted by other stem/progenitor cells, such as endothelial progenitor cells (EPCs), had complementary effects to the MSC-CM. Thus, the EPC-CM, in either a normal or hypoxic environment, supported EC proliferation, but did not sustain EC adhesion. Combined use of the MSC-CM and EPC-CM promoted both EC adhesion and proliferation, suggesting that the local angiogenesis at the site of ischemic injury might be better stimulated by simultaneous releasing of factors secreted by multiple stem/progenitor cell populations.

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Section: Discussionsupporting

confidence: 81%

Factors Secreted by Mesenchymal Stem Cells and Endothelial Progenitor Cells Have Complementary Effects on Angiogenesis In Vitro

Burlacu

Grigorescu

Rosca

et al. 2013

Stem Cells and Development

145

120

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“…Given the common characteristics of stem cells, it was speculated that androgens may promote HSC proliferation rather than maintain the self-renewal of HSCs. Hypoxia (1%) is conducive to maintaining the undifferentiated HSC state but does not promote amplification (16). The results of the present study demonstrated that a combination of hypoxia and testosterone in vitro may increase CD34 + cell differentiation and prolong the HPC stage.…”

Section: Discussionsupporting

confidence: 48%

“…Throughout the bone marrow, physiological oxygen concentrations are <4% and almost 0% in certain areas (13). It has been hypothesized that the hypoxic environment maintains the characteristics of HSCs and numerous in vitro studies investigating the cultivation of HSCs under hypoxic conditions have been performed (14)(15)(16)(17). Thus, the present study included hypoxia as a condition in the study design, in order to determine the effects of the three small molecules on CD34 + cell amplification under hypoxic conditions.…”

Section: Introductionmentioning

confidence: 99%

Effect of testosterone and hypoxia on the expansion of umbilical cord blood CD34+ cells in vitro

et al. 2017

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Abstract. Successfully expanding hematopoietic stem cells (HSCs) is advantageous for clinical HSC transplantation. The present study investigated the influence of testosterone on the proliferation, antigen phenotype and expression of hematopoiesis-related genes in umbilical cord blood-derived cluster of differentiation (CD)34 + cells under normoxic or hypoxia conditions. Cord blood (CB) CD34 + cells were separated using magnetic activated cell sorting. A cytokine cocktail and feeder cells were used to stimulate the expansion of CD34 + cells under normoxic (20% O 2 ) and hypoxic (1% O 2 ) conditions for 7 days and testosterone was added accordingly. Cells were identified using flow cytometry and reconstruction capacity was determined using a colony-forming unit (CFU) assay. The effects of oxygen concentration and testosterone on the expression of hematopoietic-related genes, including homeobox (HOX)A9, HOXB2, HOXB4, HOXC4 and BMI-1, were measured using reverse transcription-quantitative polymerase chain reaction. The results indicated that the number of CFUs and total cells in the testosterone group increased under normoxic and hypoxic conditions compared with the corresponding control groups. Furthermore, the presence of testosterone increased the number of CFU-erythroid colonies. In liquid culture, the growth of CD34 + cells was rapid under normoxic conditions compared with under hypoxic conditions, however CD34 + cells were maintained in an undifferentiated state under hypoxic conditions. The addition of testosterone under hypoxia promoted the differentiation of CD34 + cells into CD34 + CD38 + CD71 + erythroid progenitor cells. Furthermore, it was determined that the expression of hematopoietic-related genes was significantly increased (P<0.05) in the hypoxia testosterone group compared with the other groups.Therefore, the results of the current study indicate that a combination of hypoxia and testosterone may be a promising cultivation condition for HSC/hemopoietic progenitor cell expansion ex vivo.

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“…They were irradiated in a cage with two opposed fields, using a linear accelerator (Varian Clinac 600C) with a 6 MV photon spectra to a total absorbed dose in water of 9 Gy, single fraction. The irradiation procedure followed the same experimental set-up as described earlier (Eliasson et al, 2010). Mice were injected intravenously within 6-18 hours post-irradiation with 2 x 10 6 freshly prepared GFP + CD45 + bone marrow cells from either IL-6 KO or WT mice, in a total volume of 0.2 ml.…”

Section: Irradiation and Bone Marrow Transplantationmentioning

confidence: 99%

Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response

Hamzic

Tang

Eskilsson

et al. 2013

Brain, Behavior, and Immunity

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KO background, but with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on a WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of non-hematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.Hamzic et al., page 3

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Hypoxia mediates low cell-cycle activity and increases the proportion of long-term–reconstituting hematopoietic stem cells during in vitro culture

Cited by 145 publications

References 36 publications

Factors Secreted by Mesenchymal Stem Cells and Endothelial Progenitor Cells Have Complementary Effects on Angiogenesis In Vitro

Factors Secreted by Mesenchymal Stem Cells and Endothelial Progenitor Cells Have Complementary Effects on Angiogenesis In Vitro

Effect of testosterone and hypoxia on the expansion of umbilical cord blood CD34+ cells in vitro

Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response

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