Pre‐differentiated human committed T‐lymphoid progenitors promote peripheral T‐cell re‐constitution after stem cell transplantation in immunodeficient mice

Eyrich, Matthias; Schreiber, S.; Wollny, Gernot; Ziegler, H; Schlenker, Ramona; Koch-Büttner, Katharina; Wölfl, Matthias; Schlegel, Paul G.; Schilbach, Karin

doi:10.1002/eji.201141561

Cited by 11 publications

(9 citation statements)

References 15 publications

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“…Nevertheless, it appears that this population of CLPs is skewed toward a B lymphocyte fate, whereas cord blood progenitors with a CD34þCD7þCD45RAþ phenotype express T/NK cell lineage-affiliated genes and show enhanced T lineage differentiation potential [44]. Furthermore, recent studies have demonstrated that following ex vivo Notch ligand stimulation of CD34þ progenitors, it is the differentiated CD34þCD7þ CD45RAþ CLP subset that displays augmented in vivo thymus colonization and a more rapid T-cell differentiation than conventional CD34þ progenitors [45][46][47]. Thus, the precursors that settle the human thymus under physiological conditions are likely to share this CD34þCD7þCD45RAþ phenotype.…”

Section: Hematopoietic Precursor Differentiation Within the Thymusmentioning

confidence: 99%

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

2013

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Allogeneic hematopoietic stem cell (HSC) transplantation can cure patients suffering from diverse genetic and acquired diseases as well as cancers. Nevertheless, under conditions where T-cell reconstitution is critical, the entry of donor progenitors into the thymus remains a major bottleneck. It is assumed that following the intravenous injection of HSC, they first home to the BM. More committed progenitors can then be exported to the thymus in response to a myriad of signals regulating thymus seeding. Notably although, the thymus is not continually receptive to the import of hematopoietic progenitors. Furthermore, as stem cells with self-renewing capacity do not take up residence in the thymus under physiological conditions, the periodic colonization of the thymus is essential for the sustained differentiation of T lymphocytes. As such, we and others have invested significant efforts into exploring avenues that might foster a long-term thymus-autonomous differentiation. Here, we review strategic approaches that have resulted in long-term T-cell differentiation in immunodeficient (SCID) mice, even across histocompatibility barriers. These include the forced thymic entry of BM precursors by their direct intrathymic injection as well as the transplantation of neonatal thymi. The capacity of the thymus to support hematopoietic progenitors with renewal potential will hopefully promote the development of new therapeutic strategies aimed at enhancing T-cell differentiation in patients undergoing HSC transplantation.

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Section: Hematopoietic Precursor Differentiation Within the Thymusmentioning

confidence: 99%

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

2013

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“…Nevertheless, it appears that this population of CLPs is skewed toward a B lymphocyte fate, whereas cord blood progenitors with a CD34+CD7+CD45RA+ phenotype express T/NK cell lineage‐affiliated genes and show enhanced T lineage differentiation potential [44]. Furthermore, recent studies have demonstrated that following ex vivo Notch ligand stimulation of CD34+ progenitors, it is the differentiated CD34+CD7+ CD45RA+ CLP subset that displays augmented in vivo thymus colonization and a more rapid T‐cell differentiation than conventional CD34+ progenitors [45–47]. Thus, the precursors that settle the human thymus under physiological conditions are likely to share this CD34+CD7+CD45RA+ phenotype.…”

Section: Hematopoietic Precursor Differentiation Within the Thymusmentioning

confidence: 99%

The Role of Transferrin in Actinide(IV) Uptake: Comparison with Iron(III)

Jeanson¹,

Ferrand²,

Funke³

et al. 2010

Chemistry A European J

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The impact of actinides on living organisms has been the subject of numerous studies since the 1950s. From a general point of view, these studies show that actinides are chemical poisons as well as radiological hazards. Actinides in plasma are assumed to be mainly complexed to transferrin, the iron carrier protein. This paper casts light on the uptake of actinides(IV) (thorium, neptunium, plutonium) by transferrin, focusing on the pH dependence of the interaction and on a molecular description of the cation binding site in the protein. Their behavior is compared with that of iron(III), the endogenous transferrin cation, from a structural point of view. Complementary spectroscopic techniques (UV/Vis spectrophotometry, microfiltration coupled with gamma spectrometry, and X-ray absorption fine structure) have been combined in order to propose a structural model for the actinide-binding site in transferrin. Comparison of our results with data available on holotransferrin suggests some similarities between the behavior of Fe(III) and Np(IV)/Pu(IV)/ Np(IV) is not complexed at pH <7, whereas at pH approximately 7.4 complexation can be regarded as quantitative. This pH effect is consistent with the in vivo transferrin "cycle". Pu(IV) also appears to be quantitatively bound by apotransferrin at around pH approximately 7.5, whereas Th(IV) was never complexed under our experimental conditions. EXAFS data at the actinide edge have allowed a structural model of the actinide binding site to be elaborated: at least one tyrosine residue could participate in the actinide coordination sphere (two for iron), forming a mixed hydroxo-transferrin complex in which actinides are bound with transferrin both through An-tyrosine and through An--OH bonds. A description of interatomic distances is provided.

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“…Notch‐1 signaling plays a major role for priming human stem cells (HSCs) toward the T‐cell lineage and thus for early thymopoiesis [9–11]. Notch‐based culture systems, such as delta‐like‐1 (DL‐1)‐expressing BM stromal cells (OP9/DL‐1 cells), allow in vitro generation of large numbers of human T‐cell progenitors that have been demonstrated to promote de novo thymopoiesis in humanized mice [12–14]. This working hypothesis was further supported by observations in conventional mouse models: when transferred into allogeneic recipients, murine T‐cell progenitors generated in OP9/DL‐1 coculture accelerated de novo thymopoiesis and emergence of host‐tolerant, functional T cells that afforded protection against infectious agents and residual tumor cells when transferred into an allogeneic HSCT model [15, 16].…”

Section: Introductionmentioning

confidence: 99%

Human T‐Lymphoid Progenitors Generated in a Feeder‐Cell‐Free Delta‐Like‐4 Culture System Promote T‐Cell Reconstitution in NOD/SCID/γc ^−/− Mice

et al. 2012

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Slow T-cell reconstitution is a major clinical concern after transplantation of cord blood (CB)-derived hematopoietic stem cells. Adoptive transfer of in vitro-generated T-cell progenitors has emerged as a promising strategy for promoting de novo thymopoiesis and thus accelerating T-cell reconstitution. Here, we describe the development of a new culture system based on the immobilized Notch ligand Delta-like-4 (DL-4). Culture of human CD34+ CB cells in this new DL-4 system enabled the in vitro generation of large amounts of T-cell progenitor cells that (a) displayed the phenotypic and molecular signatures of early thymic progenitors and (b) had high T lymphopoietic potential. When transferred into NOD/SCID/γc−/− (NSG) mice, DL-4 primed T-cell progenitors migrated to the thymus and developed into functional, mature, polyclonal αβ T cells that subsequently left the thymus and accelerated T-cell reconstitution. T-cell reconstitution was even faster and more robust when ex vivo-manipulated and nonmanipulated CB samples were simultaneously injected into NSG mice (i.e., a situation reminiscent of the double CB transplant setting). This work provides further evidence of the ability of in vitro-generated human T-cell progenitors to accelerate T-cell reconstitution and also introduces a feeder-cell-free culture technique with the potential for rapid, safe transfer to a clinical setting.

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Pre‐differentiated human committed T‐lymphoid progenitors promote peripheral T‐cell re‐constitution after stem cell transplantation in immunodeficient mice

Cited by 11 publications

References 15 publications

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

The Role of Transferrin in Actinide(IV) Uptake: Comparison with Iron(III)

Human T‐Lymphoid Progenitors Generated in a Feeder‐Cell‐Free Delta‐Like‐4 Culture System Promote T‐Cell Reconstitution in NOD/SCID/γc ^−/− Mice

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Pre‐differentiated human committed T‐lymphoid progenitors promote peripheral T‐cell re‐constitution after stem cell transplantation in immunodeficient mice

Cited by 11 publications

References 15 publications

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

The Role of Transferrin in Actinide(IV) Uptake: Comparison with Iron(III)

Human T‐Lymphoid Progenitors Generated in a Feeder‐Cell‐Free Delta‐Like‐4 Culture System Promote T‐Cell Reconstitution in NOD/SCID/γc −/− Mice

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Human T‐Lymphoid Progenitors Generated in a Feeder‐Cell‐Free Delta‐Like‐4 Culture System Promote T‐Cell Reconstitution in NOD/SCID/γc ^−/− Mice