Two Genetically Separable Steps in the Differentiation of Thymic Epithelium

Nehls, Michael; Kyewski, Bruno; Messerle, Martin; Waldschütz, Ralph; Schüddekopf, Kerstin; Smith, Andrew J.H.; Boehm, Thomas

doi:10.1126/science.272.5263.886

Cited by 416 publications

(421 citation statements)

References 24 publications

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“…Cells were injected subcutaneously into the flank of 4-week old male athymic nude mice. Male athymic nude mice (Foxn1nu/nu), carrying a disruption of the forkhead box n1 gene [Coffer and Burgering, 2004], which leads to thymic atrophy and immunodeficiency [Nehls et al, 1996], were purchased from Harlan, Udine, Italy. Mice were acclimated for 1 week before the start of this study.…”

Section: Cell Lines and Mouse Xenograft Generationmentioning

confidence: 99%

Modeling human osteosarcoma in mice through 3AB‐OS cancer stem cell xenografts

Fiore

Guercio

Puleio

et al. 2012

J of Cellular Biochemistry

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Osteosarcoma is the second leading cause of cancer-related death for children and young adults. In this study, we have subcutaneously injected-with and without matrigel-athymic mice (Fox1nu/nu) with human osteosarcoma 3AB-OS pluripotent cancer stem cells (CSCs), which we previously isolated from human osteosarcoma MG63 cells. Engrafted 3AB-OS cells were highly tumorigenic and matrigel greatly accelerated both tumor engraftment and growth rate. 3AB-OS CSC xenografts lacked crucial regulators of beta-catenin levels (E-cadherin, APC, and GSK-3beta), and crucial factors to restrain proliferation, resulting therefore in a strong proliferation potential. During the first weeks of engraftment 3AB-OS-derived tumors expressed high levels of pAKT, beta1-integrin and pFAK, nuclear beta-catenin, c-Myc, cyclin D2, along with high levels of hyperphosphorylated-inactive pRb and anti-apoptotic proteins such as Bcl-2 and XIAP, and matrigel increased the expression of proliferative markers. Thereafter 3AB-OS tumor xenografts obtained with matrigel co-injection showed decreased proliferative potential and AKT levels, and undetectable hyperphosphorylated pRb, whereas beta1-integrin and pFAK levels still increased. Engrafted tumor cells also showed multilineage commitment with matrigel particularly favoring the mesenchymal lineage. Concomitantly, many blood vessels and muscle fibers appeared in the tumor mass. Our findings suggest that matrigel might regulate 3AB-OS cell behavior providing adequate cues for transducing proliferation and differentiation signals triggered by pAKT, beta1-integrin, and pFAK and addressed by pRb protein. Our results provide for the first time a mouse model that recapitulates in vivo crucial features of human osteosarcoma CSCs that could be used to test and predict the efficacy in vivo of novel therapeutic treatments.

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Section: Cell Lines and Mouse Xenograft Generationmentioning

confidence: 99%

Modeling human osteosarcoma in mice through 3AB‐OS cancer stem cell xenografts

Fiore

Guercio

Puleio

et al. 2012

J of Cellular Biochemistry

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“…Hoxa3, Six1, and Eya1 are required for proper patterning of the pharyngeal pouch endoderm (Manley and Capecchi, 1998;Zou et al, 2006) and the absence of Pax1 (Wallin et al, 1996) or Pax9 (Hetzer-Egger et al, 2002) leads to hypoplastic and/or aberrantly developed thymi. The Foxn1 transcription factor is also critically important for the differentiation or specification of thymic epithelium (Nehls et al, 1996;Dooley et al, 2005b). Recently, p63 activity has been shown to play an important role in maintaining TE progenitor cells (Senoo et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

FGFR2IIIb signaling regulates thymic epithelial differentiation

Dooley

Erickson

LaRochelle

et al. 2007

Developmental Dynamics

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Heterogeneous epithelial populations comprising the thymic environment influence early and late stages of T-cell development. The processes that regulate the differentiation of thymic epithelium and that are responsible for this heterogeneity are not well understood, although mesenchymal/epithelial interactions are clearly involved. Here, we show that targeted expression by thymocytes of an fibroblast growth factor receptor-2IIIb (FGFR2IIIb) ligand, FGF10, profoundly alters the differentiation and function of thymic epithelium (TE). Reconstitution of irradiated lckFGF10 mice with normal bone marrow restores normal thymic organization and function, while wild-type mice reconstituted with lckFGF10 bone marrow recapitulates some of the thymic alterations seen in lckFGF10 mice. We also demonstrate that interference with FGFR2IIIb signaling in the thymus with a soluble FGFR2IIIb dominant-negative fusion protein leads to precocious reductions in thymic size and cellularity that resemble age-related thymic involution. These findings indicate that TE compartments are dynamically maintained and that FGF signals are involved in this process. Developmental Dynamics 236:3459 -3471, 2007.

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“…The few spontaneous (e.g., nu/nu)) (3)(4)(5) and gene-targeted (e.g., IL-7 and MHC class II) (6 -9) mutations of thymic stromal cell genes have provided important insights into the mechanisms by which stromal cells function. In an attempt to identify more such molecules, we have created a PCR-based subtracted cDNA library from stromal cells prepared from fetal thymic organ cultures (FTOC) 4 treated with 2-deoxyguanosine (2-dGuo) (10).…”

Section: A Putative 12 Transmembrane Domain Cotransporter Expressed Imentioning

confidence: 99%

A Putative 12 Transmembrane Domain Cotransporter Expressed in Thymic Cortical Epithelial Cells

Kim

Flomerfelt

Lee

et al. 2000

The Journal of Immunology

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We have isolated a full-length cDNA clone (thymic stromal origin (TSO)-1C12) from a SCID thymus library using a probe from a PCR-based subtractive library enriched for sequences from fetal thymic stromal cells. TSO-1C12 mRNA is expressed mainly in the thymic cortex and is highly enriched in SCID thymus. Expression per cell is highest during fetal thymus development and decreases after day 16. Antipeptide Abs immunoprecipitated a hydrophobic, plasma membrane glycoprotein (thymic stromal cotransporter, TSCOT) whose translated sequence has weak homology to bacterial antiporters and mammalian cation cotransporters with 12 transmembrane domains. TSCOT represents a new member of this superfamily that is highly expressed in thymic cortical epithelial cells.

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Two Genetically Separable Steps in the Differentiation of Thymic Epithelium

Cited by 416 publications

References 24 publications

Modeling human osteosarcoma in mice through 3AB‐OS cancer stem cell xenografts

Modeling human osteosarcoma in mice through 3AB‐OS cancer stem cell xenografts

FGFR2IIIb signaling regulates thymic epithelial differentiation

A Putative 12 Transmembrane Domain Cotransporter Expressed in Thymic Cortical Epithelial Cells

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