Regulation of thymic epithelium by keratinocyte growth factor

Erickson, Matthew; Morkowski, Stanislaw; Lehar, Sophie M.; Gillard, Geoffrey O.; Beers, Courtney; Dooley, James; Rubin, Jeffrey S.; Rudensky, Alexander Y.; Farr, Andrew G.

doi:10.1182/blood-2002-04-1036

Cited by 139 publications

(130 citation statements)

References 62 publications

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“…Wnt signaling has been implicated in the regulation of Foxn1 expression (Balciunaite et al, 2002), while signaling pathways that regulate NFkB activity are known to play an important role in the development of a functional medullary TE compartment (Burkly et al, 1995;Boehm et al, 2003;Rossi et al, 2007c). Signaling mediated by bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) has also been implicated in proper TE differentiation (Erickson et al, 2002;Jenkinson et al, 2003;Bleul and Boehm, 2005;Rossi et al, 2007c).…”

Section: Introductionmentioning

confidence: 99%

“…Persistence of the FGFR2IIIb, FGF7, and FGF10 in the postnatal thymus (Erickson et al, 2002;Gray et al, 2007;Rossi et al, 2007b) provides circumstantial evidence that this signaling pathway continues to play a role in the maintenance of the adult thymic environment. Exogenous FGF7 can ameliorate the deleterious effects of pretransplantation conditioning regimens on thymic function, increasing thymic cellularity and restoration of the peripheral T-cell pool (Panoskaltsis-Mortari et al, 1998;Min et al, 2002;Alpdogan et al, 2006) and can also partially reverse the agerelated declines of thymic cellularity and function in aged mice (Alpdogan et al, 2006;Min et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FGFR2IIIb signaling regulates thymic epithelial differentiation

Dooley

Erickson

LaRochelle

et al. 2007

Developmental Dynamics

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“…Therefore, unravelling the mechanisms mediating thymic stroma development is required for the development of therapies aimed at maintaining thymus function 6 . In this context, KGF administration was reported to enhance thymic recovery after irradiation and dexamethasone treatment 8 and to expand mTEC in Rag2 À / À mice 37 . Also, IL-22 administration accelerates the recovery of epithelial microenvironment after total body irradiation 9 , and miR-29a protects thymic epithelium from inappropriate infection-associated involution 38 .…”

Section: Discussionmentioning

confidence: 99%

Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output

et al. 2013

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Thymic epithelial cells (TEC) are heterogeneous stromal cells that generate microenvironments required for the formation of T cells within the thymus. Defects in TEC lead to immunodeficiency or autoimmunity. Here we identify TEC as the major source of cysteinerich protein 61 (CYR61), a matricellular protein implicated in cell proliferation and migration. Binding of CYR61 to LFA-1, ICAM-1 and integrin a6 supports the adhesion of TEC and thymocytes as well as their interaction. Treatment of thymic lobes with recombinant CYR61 expands the stromal compartment by inducing the proliferation of TEC and activates Akt signalling. Engraftment of CYR61-overexpressing thymic lobes into athymic nude mice drastically boosts the yield of thymic output via expansion of TEC. This increases the space for the recruitment of circulating hematopoietic progenitors and the development of T cells. Our discovery paves the way for therapeutic interventions designed to restore thymus stroma and T-cell generation.

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“…Exogenous keratinocyte growth factor (KGF) potently augments thymopoiesis 7 and protects from thymic damage 8 by signaling via FGFR2IIIb expressed by thymic epithelium cells (TECs), but the exact mechanism by which KGF augments thymopoiesis remains unclear. Because KGF can expand TECs 9 and has been reported to increase IL-7 production in treated mice 7,8 and TSLP production in fetal thymic organ cultures (FTOC), 10 we hypothesized that TSLP and/or IL-7 might mediate the thymopoietic effects of KGF. To investigate whether IL-7R␣ signaling by thymocytes mediated KGF thymopoietic effects, we administered KGF to WT and Tslpr Ϫ/Ϫ mice in the presence or absence of anti-IL-7R␣ mAb.…”

Section: To the Editormentioning

confidence: 99%