Efficient generation of human T cells from a tissue-engineered thymic organoid

Poznansky, Mark C.; Evans, Richard H.; Foxall, Russell B.; Olszak, Ivona T.; Piascik, Anita H.; Hartman, Kelly E.; Berthou, Christian; Meyer, Thomas; Pykett, Mark; Chabner, Karissa T.; Kalams, Spyros A.; Rosenzweig, Michael; Scadden, David T.

doi:10.1038/77288

Cited by 145 publications

(93 citation statements)

References 23 publications

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“…Current culture systems that support the development of human T cells from bone marrow precursor cells use animal or unrelated human tissues, making them less desirable for the production of T cells for use in humans (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Human skin cells support thymus-independent T cell development

Clark

Yamanaka²,

Bai³

et al. 2005

Journal of Clinical Investigation

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Thymic tissue has previously been considered a requirement for the generation of a functional and diverse population of human T cells. We report that fibroblasts and keratinocytes from human skin arrayed on a synthetic 3-dimensional matrix support the development of functional human T cells from hematopoietic precursor cells in the absence of thymic tissue. Newly generated T cells contained T cell receptor excision circles, possessed a diverse T cell repertoire, and were functionally mature and tolerant to self MHC, indicating successful completion of positive and negative selection. Skin cell cultures expressed the AIRE, Foxn1, and Hoxa3 transcription factors and a panel of autoantigens. Skin and bone marrow biopsies can thus be used to generate de novo functional and diverse T cell populations for potential therapeutic use in immunosuppressed patients.

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Section: Introductionmentioning

confidence: 99%

Human skin cells support thymus-independent T cell development

Clark

Yamanaka²,

Bai³

et al. 2005

Journal of Clinical Investigation

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“…This system has been reported to yield functional, singlepositive T cells from huCD34 1 HSCs after 14 days [13,14]. After 3 wk of co-culture, there was a significantly increased number of mononuclear cells in thymic but not in skin co-cultures ( Fig.…”

Section: Hla-b7mentioning

confidence: 89%

“…CellFoam cell-culture dishes 10 mm in diameter Â 1 mm in depth with an average pore density of 80 pores per inch (Cytomatrix) were pre-cultured with fragmented thymic or skin tissue as described previously [13]. After 22-35 days purified huCD34…”

Section: -D Cell-culture Matrixmentioning

confidence: 99%

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

et al. 2011

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T‐cell re‐constitution after allogeneic stem cell transplantation (alloSCT) is often dampened by the slow differentiation of human peripheral blood CD34+ (huCD34+) hematopoietic stem cells (HSCs) into mature T cells. This process may be accelerated by the co‐transfer of in vitro‐pre‐differentiated committed T/NK‐lymphoid progenitors (CTLPs). Here, we analysed the developmental potential of huCD34+ HSCs compared with CTLPs from a third‐party donor in a murine NOD‐scid IL2Rγnull model of humanised chimeric haematopoiesis. CTLPs (CD34+lin−CD45RA+CD7+) could be generated in vitro within 10 days upon co‐culture of huCD34+ or cord blood CD34+ (CB‐CD34) HSCs on murine OP9/N‐DLL‐1 stroma cells but not in a novel 3‐D cell‐culture matrix with DLL‐1low human stroma cells. In both in vitro systems, huCD34+ and CB‐CD34+ HSCs did not give rise to mature T cells. Upon transfer into 6‐wk‐old immune‐deficient mice, CTLPs alone did not engraft. However, transplantation of CTLPs together with huCD34+ HSCs resulted in rapid T‐cell engraftment in spleen, bone marrow and thymus at day 28. Strikingly, at this early time point mature T cells originated exclusively from CTLPs, whereas descendants of huCD34+ HSCs still expressed a T‐cell‐precursor phenotype (CD7+CD5+CD1a+/−). This strategy to enhance early T‐cell re‐constitution with ex vivo‐pre‐differentiated T‐lymphoid progenitors could bridge the gap until full T‐cell recovery in severely immunocompromised patients after allogeneic stem cell transplantation.

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“…The experimental study of human T-cell lymphopoiesis has been largely limited to the use of the OP9 expressing the Notch ligand Delta-like 1 (OP9--DL1) SCID-hu mouse model (Galy et al 1993), murine and human thymic organ cultures (Rosenzweig et al 1994;Yeoman et al 1993), and human thymic monolayers (Poznansky et al 2000). Zuniga-Pflucker demonstrated that retrovirally transduced DL1 Notch ligand to the OP9 bone marrow stromal cell line inhibited the development of B cells but favored the development of T cells from fetal liver-derived HSCs and CB-derived HSCs (La Motte-Mohs et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Detection of a CD4+CD8−CD3− cell subpopulation during the differentiation of cord blood CD34+ cells into T cells in vitro

Jin¹,

Bai²,

Yao³

et al. 2009

Arch. Immunol. Ther. Exp.

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Introduction: Umbilical cord blood contains relatively abundant primitive CD34 + hematopoietic progenitor cells which can differentiate into T lymphocytes ex vivo. Materials and Methods: In this study, thymic stromal cells (TSCs) were isolated from aborted fetuses and a monolayer culture system was established. Highly-purified CD34 + cells from umbilical cord blood were cultured on the TSCs after limiting-dilution. The cells were then harvested and evaluated for CD4, CD8, and CD3 expression at different time points. CD4 + CD8 -CD3 -lymphoid progenitor cells that could differentiate into mature T lymphocytes were observed after 15 days when a cocktail of cytokines, including Flt-3 ligand, stem cell factor, interleukin (IL)-12, and IL-2, was added. Results: These results thus show that CD4 + CD8 -CD3 -cells can be derived from CD34 + cells in vitro when cultured on TSCs. Conclusions: We showed that CD4 + CD8 -CD3 -cells can be derived from highly purified CD34 + cells on TSCs during T-cell lymphopoiesis in vitro.

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Efficient generation of human T cells from a tissue-engineered thymic organoid

Cited by 145 publications

References 23 publications

Human skin cells support thymus-independent T cell development

Human skin cells support thymus-independent T cell development

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

Detection of a CD4+CD8−CD3− cell subpopulation during the differentiation of cord blood CD34+ cells into T cells in vitro

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