The molecular basis for the cytokine-induced defect in homing and engraftment of hematopoietic stem cells

Berrios, Virla M.; Dooner, Gerri; Nowakowski, G. S.; Frimberger, Angela E.; Valinski, Helen; Quesenberry, Peter J.; Becker, Pamela S.

doi:10.1016/s0301-472x(01)00734-2

Cited by 68 publications

(49 citation statements)

References 39 publications

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“…These categories included transcription factors (22), protein synthesis regulators (11), surface proteins (11), mitochondrial sequences (10), RNA metabolism proteins (10), signaling pathway factors (9), and cytokines (8). In separate studies, we have also shown that Lin Ϫ Rho dull Ho dull marrow cells express adhesion proteins 48,49 and cytokine receptors 50 on the cell surface. These data indicate a different picture of the primitive marrow stem cell than is usually envisioned-a functional cell in which a large number of stem cell-specific, as opposed to differentiated, functions are manifest (Figure 2).…”

Section: Stem Cell Genes and Functionsmentioning

confidence: 86%

“…73,74 Studies of adhesion protein cell-surface expression on Lin Ϫ Rho dull Ho dull and Lin Ϫ Sca-1 ϩ hematopoietic stem cells with cell cycle transit showed fluctuations of ␣-4, ␣-5, ␣-6, ␤-1, L-selectin, and platelet-endothelial cell adhesion molecule-1 (PECAM-1) at different points in the cell cycle. 48,49 A probable causal role for these fluctuations in the engraftment fluctuations was shown by homing studies in which it was found that CFDA-SE (5-(and -6)-carboxyfluorescein diacetate succinimidyl ester)-labeled Lin Ϫ Sca ϩ stem cells cultured in IL-3, IL-6, IL-11, and steel factor showed a marked depression in homing at a time when engraftment and ␣-4 were also markedly depressed (48 hours of culture). 75 A schematic summarizing the results with marrow cells cultured in IL-3, IL-6, IL-11, and steel factor is shown in Figure 4.…”

Section: Changing Engraftable Multipotent Stem Cell Phenotype With Cementioning

confidence: 99%

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The chiaroscuro stem cell: a unified stem cell theory

Quesenberry

Colvin

Lambert

2002

Blood

120

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Hematopoiesis has been considered hierarchical in nature, but recent data suggest that the system is not hierarchical and is, in fact, quite functionally plastic. Existing data indicate that engraftment and progenitor phenotypes vary inversely with cell cycle transit and that gene expression also varies widely. These observations suggest that there is no progenitor/stem cell hierarchy, but rather a reversible continuum. This may, in turn, be dependent on shifting chromatin and gene expression with cell cycle transit. If the phenotype of these primitive marrow cells changes from engraftable stem cell to progenitor and back to engraftable stem cell with cycle transit, then this suggests that the identity of the engraftable stem cell may be partially masked in nonsynchronized marrow cell popula- IntroductionWe present here a different view of early hematopoiesis. This is not the standard dogma of many investigators in the field, but is built upon solid work by many laboratories over many years. This is a perspective, and thus naturally reflects the biases of the authors. These, in turn, have a basis in many published studies from our laboratory and other laboratories and also from extensive unpublished, but abstracted, data from our laboratory. It is appropriate to consider this contribution as speculative in nature.The term chiaroscuro refers to the treatment of light and shade in painting. Our current view of the changing phenotype of the marrow stem cell suggests a chiaroscuro nature to this picture.In general, models of stem cell regulation have been hierarchical. 1,2 A primitive stem cell, with great potential, gives rise to a proliferating progenitor pool, which in turn gives rise to recognizable differentiated cells. During this process, proliferative potential is lost, while specific differentiated features are acquired. Presumptively, but without definite proof, there is also self-renewal at the most primitive stem cell level, and this is also lost with differentiation. Many data exist to support such a hierarchical model. Marrow cells have been separated with short-and long-term repopulation potential 3,4 and progenitors have been characterized as exclusively committed to the production of restricted progeny. 5,6 In addition, the clear expansion of different progenitor types in cytokinestimulated in vitro culture with a loss of long-term engraftment capacity speaks to the existence of a progenitor hierarchy, at least at the more differentiated progenitor levels. 7,8 A model encompassing these features is shown in Figure 1.This model does not fit with all published data. For instance, the "daughter cell" or paired-progenitor experiments of Suda and colleagues 9 indicate that a primitive progenitor cell can make totally different lineage choices during one cell cycle transit, such that, for example, one daughter cell forms an erythroid colony while the other daughter (or sister) cell forms a neutrophilmacrophage colony. Out of a total of 387 pairs evaluated, 68 pairs of colonies consisted of dissimilar com...

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Section: Stem Cell Genes and Functionsmentioning

confidence: 86%

Section: Changing Engraftable Multipotent Stem Cell Phenotype With Cementioning

confidence: 99%

The chiaroscuro stem cell: a unified stem cell theory

Quesenberry

Colvin

Lambert

2002

Blood

120

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“…In this study, using ␤ 7 Ϫ/Ϫ donor T cells in murine allogeneic HSCT models, we built on previous findings to assess the role of ␣ 4 ␤ 7 43,44 in GVHD by permanent inhibition of the ␤ 7 integrin in alloreactive T cells. This represents a significant departure from our previous study, 32 in which we used ␣ 4 ␤ 7 Ϫ selection as a method of adoptive cell transfer by preventing re-expression of ␣ 4 ␤ 7 and from previous studies using a-GVHR models, because using lethally Lethally irradiated (1300 cGy) B10.BR recipients underwent transplantation with 5 ϫ 10 6 WT TCD-BM and either 1 ϫ 10 6 WT or ␤7 Ϫ/Ϫ splenic T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the promising early results of strategies targeting the ␣ 4 integrin subunit in patients with IBD, the ␣ 4 subunit plays a role in stem cell homing to the marrow compartment and in trafficking of prothymocytes to thymus, 43,44 making it a less attractive target in the context of HSCT, where blockade could interfere with engraftment. Experiments with ␣ 4 Ϫ/Ϫ mice have demonstrated defective migration of prothymocytes from bone marrow to thymus.…”

Section: Discussionmentioning

confidence: 99%

Absence of β7 integrin results in less graft-versus-host disease because of decreased homing of alloreactive T cells to intestine

Waldman

Hubbard

et al. 2006

Blood

105

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The ␣4␤7 integrin plays a central role in the homing of T cells to the gut. We hypothesized that absence of the ␤7 subunit would result in a reduction of intestinal graft-versus-host disease (GVHD) and an improvement in overall GVHD morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT). Analysis of alloreactive ␤7 ؊/؊ T cells showed intact activation, proliferation, cytokine production, and cytotoxicity. However, recipients of ␤7 ؊/؊ donor T cells in murine HSCT models experienced less GVHD morbidity and mortality than recipients of wild-type (WT) T cells, associated with a decrease in donor T-cell infiltration of the liver and intestine and with an overall significant decrease in hepatic and intestinal GVHD. In graft-versustumor (GVT) experiments, we demonstrated intact or even enhanced GVT activity of ␤7 ؊/؊ donor T cells. In conclusion,

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“…19 Further studies showed marked modulation of adhesion protein and cytokine receptor expression with cell cycle transit. 20,21 VLA4 was downmodulated at the time of poor engraftment and poor marrow homing. The latter was shown by a direct homing assay using cytokine-incubated CFDA-SE labeled Lin(À1) Sca-1(+) cells and assessing marrow fluorescent events 3 hours after cell infusion.…”

Section: Cell Cycle Relation To Stem Cell Phenotypementioning

confidence: 99%

The marrow stem cell: the continuum

Quesenberry

Colvin

Abedi

et al. 2003

Bone Marrow Transplant

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Summary:The marrow hematopoietic stem cell is currently being redefined as to all aspects of its phenotype and its total differentiation capacity. This redefinition now includes its plasticity as to production of nonhematopoietic and hematopoietic cell types, the determinants of its in vivo engraftment potential and its expression of stem cell functional characteristics. Bone Marrow Transplantation (2003) 32, S19-S22. doi:10.1038/sj.bmt.1703938 Keywords: stem cell; progenition cell cycle Engraftment phenotypeThe marrow pluripotent stem cell has been defined by its ability to engraft and restore in vivo hematopoiesis in lethally irradiated mice. Dogma has held that space must be cleared for engraftment to occur. This view has strongly influenced many investigators' approaches to the study of stem cell biology. This view is, however, simply wrong. In a series of definitive manuscripts, we have shown that essentially all stem cells engraft in a nontreated host mouse model and that the final donor host chimerism is simply determined by the ratio of donor-to-host stem cells. 1,2 If host stem cell are reduced by cytotoxic therapy, then there will be a higher percentage of donor stem cells and their progeny. 3 We were not the first to report engraftment in nonmyeloablated mice. Although interpretations of results may have differed, Micklem et al 4 reported similar data in the 1960s and Brecher et al, 5 subsequently, using higher cell levels, showed that significant engraftment could be obtained. We modeled our studies on those of Brecher et al. 5 We subsequently showed that therapy that would selectively reduce host stem cells without impacting significantly on marrow cellularity would markedly increase donor chimerism and allow for a reduction in the number of donor marrow cells necessary for engraftment. Exposure of mice to 100 cGy proved to be an ideal nonmyeloablative/stem cell ablative regimen. 3 Thus, high levels of chimerism could be obtained without toxicity in a syngeneic setting. This approach could be extended to allogeneic transplantation with the addition of a tolerizing treatment, initially the use of antigen pre-exposure and administration of anti-CD40 ligand antibody in the peritransplant period. 6 More recent studies have allowed for the omission of irradiation and the reduction of CD40 ligand antibody in an H2-mismatched murine transplant when the administration of marrow cells was scheduled over time. 7 These concepts are presented schematically in Figure 1.These approaches formed a base for the current wave of nonmyeloablative treatments, probably first published by Kolb et al 8 and effectively followed up by others. [9][10][11] We have used our murine engraftment studies as a base for treating resistant cancers using 100 cGy whole body irradiation and infusion of mixtures of CD3 T cells and CD34+ peripheral blood cells in both HLA-matched and haplo-identical transplants. 12,13 Encouraging results with complete remissions have been obtained in patients with refractory marrow malignancies. Cell cycle...

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The molecular basis for the cytokine-induced defect in homing and engraftment of hematopoietic stem cells

Cited by 68 publications

References 39 publications

The chiaroscuro stem cell: a unified stem cell theory

The chiaroscuro stem cell: a unified stem cell theory

Absence of β7 integrin results in less graft-versus-host disease because of decreased homing of alloreactive T cells to intestine

The marrow stem cell: the continuum

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