In Vitro Models of Human T Cell Development: Dishing Out Progenitor T Cells

Motte-Mohs, Ross N. La; Awong, Génève; Zúñiga‐Pflücker, Juan Carlos

doi:10.2174/157339507779802205

Cited by 3 publications

(1 citation statement)

References 261 publications

(336 reference statements)

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“…Various methodologies, including the use of thymic stroma, have been described toward this end (Hare et al , 1999; Plum et al , 2000; LA MOTTE-MOHS et al , 2007). Clustering of human CD34 + CB cells with murine fetal thymic epithelial cells in reaggregated thymic organ cultures (RTOC) implanted into NOD/SCID mice gave rise to CD4 + CD8 + immature double positive (DP) as well as some functionally mature CD4 + and CD8 + single positive (SP) T-cells (Saito et al , 2002).…”

Section: The Utility Of Hesc-derived Hemangioblasts For Generating Thmentioning

confidence: 99%

Challenges and strategies for generating therapeutic patient-specific hemangioblasts and hematopoietic stem cells from human pluripotent stem cells

Peters¹,

Burridge²,

Pryzhkova³

et al. 2010

Int. J. Dev. Biol.

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Recent characterization of hemangioblasts differentiated from human embryonic stem cells (hESC) has further confirmed evidence from murine, zebrafish and avian experimental systems that hematopoietic and endothelial lineages arise from a common progenitor. Such progenitors may provide a valuable resource for delineating the initial developmental steps of human hemato-endotheliogenesis, which is a process normally difficult to study due to the very limited accessibility of early human embryonic/fetal tissues. Moreover, efficient hemangioblast and hematopoietic stem cell (HSC) generation from patient-specific pluripotent stem cells has enormous potential for regenerative medicine, since it could lead to strategies for treating a multitude of hematologic and vascular disorders. However, significant scientific challenges remain in achieving these goals, and the generation of transplantable hemangioblasts and HSC derived from hESC currently remains elusive. Our previous work has suggested that the failure to derive engraftable HSC from hESC is due to the fact that current methodologies for differentiating hESC produce hematopoietic progenitors developmentally similar to those found in the human yolk sac, and are therefore too immature to provide adult-type hematopoietic reconstitution. Herein, we outline the nature of this challenge and propose targeted strategies for generating engraftable human pluripotent stem cell-derived HSC from primitive hemangioblasts using a developmental approach. We also focus on methods by which reprogrammed somatic cells could be used to derive autologous pluripotent stem cells, which in turn could provide unlimited sources of patient-specific hemangioblasts and HSC.

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Section: The Utility Of Hesc-derived Hemangioblasts For Generating Thmentioning

confidence: 99%

Challenges and strategies for generating therapeutic patient-specific hemangioblasts and hematopoietic stem cells from human pluripotent stem cells

Peters¹,

Burridge²,

Pryzhkova³

et al. 2010

Int. J. Dev. Biol.

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Generation of pro-T cells in vitro: potential for immune reconstitution

Awong

Motte-Mohs

Zúñiga‐Pflücker

2007

Seminars in Immunology

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Characterization in vitro and engraftment potential in vivo of human progenitor T cells generated from hematopoietic stem cells

Awong

Herer

Surh

et al. 2009

Blood

125

129

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T-cell development follows a defined set of stage-specific differentiation steps. However, molecular and cellular events occurring at early stages of human T-cell development remain to be fully elucidated. To address this, human umbilical cord blood (UCB) hematopoietic stem cells (HSCs) were induced to differentiate to the T lineage in OP9-DL1 cocultures. A developmental program involving a sequential and temporally discrete expression of key differentiation markers was revealed. Quantitative clonal analyses demonstrated that CD34 ؉ CD38 ؊ and CD34 ؉ CD38 lo subsets of UCB contain a similarly high Tlineage progenitor frequency, whereas the frequency in CD34 ؉ CD38 ؉/hi cells was 5-fold lower. Delta-like/Notch-induced signals increased the T-cell progenitor frequency of CD34 ؉ CD38 ؊/lo cells differentiated on OP9-DL1, and 2 distinct progenitor subsets, CD34 ؉ CD45RA ؉ CD7 ؉؉ CD5 ؊ CD1a ؊ (proT1) and CD34 ؉ CD45RA ؉ CD7 ؉؉ CD5 ؉ CD1a ؊ (proT2), were identified and their thymus engrafting capacity was examined, with proT2 cells showing a 3-fold enhanced reconstituting capacity compared with the proT1 subset. Furthermore, in vitrogenerated CD34 ؉ CD7 ؉؉ progenitors effectively engrafted the thymus of immunodeficient mice, which was enhanced by the addition of an IL-7/IL-7 antibody complex. Taken IntroductionT cells develop within the thymus from bone marrow-derived hematopoietic progenitors, and follow a series of stage-specific differentiation events, which are broadly characterized by the developmentally coordinated expression of CD4 and CD8. 1 The initial stages of human T-cell development include precursors that express the stem cell marker CD34, 2,3 which is also present on hematopoietic stem cells (HSCs) and on multipotent or lineage-specified progenitor cells. Within the known hierarchy of T-cell development, the earliest precursor subset is further defined by the lack of CD3, CD4, CD8, and CD1a expression. 4 Although immature stages of T-cell development are typically delineated as CD34 ϩ CD1a Ϫ and CD34 ϩ CD1a ϩ cells, these populations remain heterogeneous. Of note, CD7 expression is considered to be one of the earliest cell surface markers known to appear during T lymphopoiesis. 2,5 Importantly, the transition from CD34 ϩ CD7 ϩ CD1a Ϫ to CD34 ϩ CD7 ϩ CD1a ϩ by early thymocytes is associated with T-cell commitment, as a small percentage (ϳ 10%) of these cells show rearrangement at the T-cell receptor ␤-chain (TCR␤) locus. 6 In addition, CD34 ϩ CD7 ϩ CD1a ϩ cells appear to be T-lineage restricted, as these cells show low precursor activity toward non-T-cell lineages. 7 Current understanding of the aforementioned early stages has been obtained from analyses of human fetal or adult thymocyte subsets, and by analyzing T-cell development in vitro using xenogeneic engraftment of mouse fetal thymus organ cultures (FTOCs). 8,9 Although these systems have provided important insight into T-cell development, the capacity to evaluate specific progenitor populations has remained difficult to assess given the requirem...

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In Vitro Models of Human T Cell Development: Dishing Out Progenitor T Cells

Cited by 3 publications

References 261 publications

Challenges and strategies for generating therapeutic patient-specific hemangioblasts and hematopoietic stem cells from human pluripotent stem cells

Challenges and strategies for generating therapeutic patient-specific hemangioblasts and hematopoietic stem cells from human pluripotent stem cells

Generation of pro-T cells in vitro: potential for immune reconstitution

Characterization in vitro and engraftment potential in vivo of human progenitor T cells generated from hematopoietic stem cells

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