Investigation into an engraftment defect induced by culturing primitive hematopoietic cells with cytokines

Young, Judy; Lin, Karen; Wu, Spencer; Travis, Marilyn; Hansteen, Gun; Abitorabi, A.; Sirenko, Oksana; Murray, Lesley J.; Hill, Beth

doi:10.1080/146532401317070943

Cited by 11 publications

(17 citation statements)

References 48 publications

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“…13 This rapid and sustained loss of engraftment potential in adult CD34 ϩ cells after cytokine exposure is in accord with findings from another published study. 31 In that study, however, the authors did not follow in parallel the changes in homing behavior. 31 The levels of homing we report here for freshly isolated peripheral blood CD34 ϩ cells are similar to those reported by van Hennik et al, 32 who quantified human CFCs and CAFCs in BM at 22 to 24 hours after injection into irradiated NOD/SCID animals.…”

Section: Discussionmentioning

confidence: 66%

“…31 In that study, however, the authors did not follow in parallel the changes in homing behavior. 31 The levels of homing we report here for freshly isolated peripheral blood CD34 ϩ cells are similar to those reported by van Hennik et al, 32 who quantified human CFCs and CAFCs in BM at 22 to 24 hours after injection into irradiated NOD/SCID animals. The rapid time course of the homing process is also in accord with other reports using cord blood or adult blood CD34 ϩ cells.…”

Section: Discussionmentioning

confidence: 66%

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Impaired bone marrow homing of cytokine-activated CD34+ cells in the NOD/SCID model

Ahmed

Ings

Pizzey

et al. 2004

Blood

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The reduced engraftment potential of hematopoietic stem/progenitor cells (HSPCs) after exposure to cytokines may be related to the impaired homing ability of actively cycling cells. We tested this hypothesis by quantifying the short-term homing of human adult CD34 ؉ cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) animals. We show that the loss of engraftment ability of cytokine-activated CD34 ؉ cells is associated with a reduction in homing of colony-forming cells (CFCs) to bone marrow (BM) at 24 hours after transplantation (from median 2.8% [range, 1.9%-6.1%] to 0.3% [0.0%-0.7%]; n ‫؍‬ 3; P < .01), coincident with an increase in CFC accumulation in the lungs (P < .01). Impaired BM homing of cytokine-activated cells was not restored by using sorted cells in G 0 G 1 or by inducing cell cycle arrest at the G 1 /S border. Blocking Fas ligation in vivo did not increase the BM homing of cultured cells. Finally, we tested cytokine combinations or culture conditions previously reported to restore the engraftment of cultured cells but did not find that any of these was able to reverse the changes in homing behavior of cytokine-exposed cells. We suggest that these changes in homing and, as a consequence, engraftment result from the increased migratory capacity of infused activated cells, leading to the loss of selectivity of the homing process.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 66%

Impaired bone marrow homing of cytokine-activated CD34+ cells in the NOD/SCID model

Ahmed

Ings

Pizzey

et al. 2004

Blood

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“…We believe that inhibition of this pathway may also improve in vivo engraftment of cultured cells. In support of this concept is a study that showed that G-CSF mobilized CD34 cells showed significant loss of NOD/SCID engraftment potential even when cultured with a cytokine combination optimal for preservation of in vitro stem cell capacity (Tpo þ KL þ FL) [Young et al, 2001]. Cultured CD34 þ cells did not show impaired adhesion to VCAM-1 coated plates under both static and flow conditions, and chemotaxis towards SDF-1 was not impaired, suggesting normal function of CXCR4 and VLA4.…”

Section: Fas Receptor Expressionmentioning

confidence: 82%

“…This was associated with altered homing of 3 day cultured cells, with increased numbers lodging or being sequestered in the liver 24 h after transplantation, where they may interact with endogenous Fas ligand and undergo apoptosis. In support of this model, the addition of caspase inhibitors to the CD34 cell cultures improved subsequent NOD/SCID engraftment 2-3 fold [Young et al, 2001].…”

Section: Fas Receptor Expressionmentioning

confidence: 93%

Cytokine and chemokine networks influencing stem cell proliferation, differentiation, and marrow homing

Moore

2002

J. Cell. Biochem.

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The hematopoietic stem cell (HSC) is an attractive target for gene therapy of genetic diseases of the immune and hematopoietic system, and for drug-resistance strategies in which genes conferring resistance to a variety of chemotherapeutic agents can be transduced. Stem cells are relatively easy to obtain; e.g., by marrow aspiration or G-CSF mobilization into the peripheral blood, and can be enriched e.g., by the use of anti-CD34 þ monoclonal antibody. For conventional retroviral transduction, normally quiescent HSC must be activated into the cell cycle by priming with appropriate cytokines, and it has been critical to identify cytokine combinations that preserve the self-renewal capacity of long-term repopulating HSC. It has become apparent that strategies designed to optimize HSC cycling and proviral integration can compromise the capacity of transduced HSC to compete in vivo against endogenous HSC or HSC that have not been activated into cell cycle. Lentiviral vectors can integrate genes into non-cycling cells but there is an increased efficiency of transduction if Go HSC are activated into G1-phase of the cell cycle. This reduced efficiency of long-term engraftment of ex vivo cultured HSC may be due to impaired self-renewal capacity or reduced marrow homing efficiency. The latter may be attributed to down modulation of chemokine receptors necessary for chemotactic homing to the marrow. Alternatively, or in addition, there may be down modulation of (1) HSC adhesion molecules necessary for endothelial adhesion and egress from the circulation: (2) metalloproteinases secreted by HSC that facilitate their migration through extracellular matrix and promote release of critical soluble regulatory factors in the marrow microenvironment. A more controversial view is that cell death pathways, for example those involving FasR (CD95) may be activated in cycling HSC, resulting in their selective destruction upon transplantation and localization to sites rich in Fas ligand such as the liver.

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“…It has been shown that extended in vitro culture leads to the up-regulation of CD95 expression on hematopoietic stem cells, and that this expression negatively impacts stem cell engraftment in the mouse. 26,27 We have detected strong CD95 expression on the majority of cells from the long-term cultures (data not shown), which may explain the low level of human cells present in the mouse after 6 weeks. Nonetheless, several in vitro assays routinely used to monitor stem cell activity (CAFC and LTC-IC) demonstrate that these long-term cultures retain significant stem cell activity.…”

Section: Discussionmentioning

confidence: 94%

Maintaining the self-renewal and differentiation potential of human CD34+ hematopoietic cells using a single genetic element

Mulloy

Cammenga

Berguido

et al. 2003

Blood

110

126

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Hematopoiesis is a complex process involving hematopoietic stem cell (HSC) self-renewal and lineage commitment decisions that must continue throughout life. Establishing a reproducible technique that allows for the long-term ex vivo expansion of human HSCs and maintains self-renewal and multipotential differentiation will allow us to better understand these processes, and we report the ability of the leukemia-associated AML1-ETO fusion protein to establish such a system. AML1-ETO-transduced human CD34 ؉ hematopoietic cells routinely proliferate in liquid culture for more than 7 months, remain cytokine dependent for survival and proliferation, and demonstrate self-renewal of immature cells that retain both lymphoid and myeloid potential in vitro. These cells continue to express the CD34 cell surface marker and have ongoing telomerase activity with maintenance of telomere ends, however they do not cause leukemia in nonobese

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Investigation into an engraftment defect induced by culturing primitive hematopoietic cells with cytokines

Cited by 11 publications

References 48 publications

Impaired bone marrow homing of cytokine-activated CD34+ cells in the NOD/SCID model

Impaired bone marrow homing of cytokine-activated CD34+ cells in the NOD/SCID model

Cytokine and chemokine networks influencing stem cell proliferation, differentiation, and marrow homing

Maintaining the self-renewal and differentiation potential of human CD34+ hematopoietic cells using a single genetic element

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