Rac1 Deletion Causes Thymic Atrophy

Hunziker, Lukas; Benitah, Salvador Aznar; Braun, Kristin M.; Jensen, Kim B.; McNulty, Katrina; Butler, Colin R.; Potton, Elspeth; Nye, Emma; Boyd, Richard; Laurent, GJ; Glogauer, Michael; Wright, Nicholas; Watt, Fiona M.; Janes, Sam M.

doi:10.1371/journal.pone.0019292

Cited by 8 publications

(10 citation statements)

References 43 publications

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“…Most PLET1 + TECs were found within the medulla, as previously described ( Godfrey et al., 1990 , Depreter et al., 2008 ) ( Figure 1 D). These medullary PLET1 + TECs co-expressed cytokeratin 14 (K14), K5, and Claudin 4 (CLDN4; with PLET1 + mTECs being a subset of CLDN4 + mTECs) and also expressed high levels of RAC1, a skin stem cell-associated marker that has also been implicated in TEC maintenance ( Benitah et al., 2005 , Hunziker et al., 2011 ) ( Figure 1 D). Separate from this PLET1 + mTECs population and consistent with our flow cytometric data, we identified a population of Ly-51 + PLET1 + TECs by immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Bipotent Epithelial Progenitor Population in the Adult Thymus

et al. 2016

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SummaryThymic epithelial cells (TECs) are critically required for T cell development, but the cellular mechanisms that maintain adult TECs are poorly understood. Here, we show that a previously unidentified subpopulation, EpCam+UEA1−Ly-51+PLET1+MHC class IIhi, which comprises <0.5% of adult TECs, contains bipotent TEC progenitors that can efficiently generate both cortical (c) TECs and medullary (m) TECs. No other adult TEC population tested in this study contains this activity. We demonstrate persistence of PLET1+Ly-51+ TEC-derived cells for 9 months in vivo, suggesting the presence of thymic epithelial stem cells. Additionally, we identify cTEC-restricted short-term progenitor activity but fail to detect high efficiency mTEC-restricted progenitors in the adult thymus. Our data provide a phenotypically defined adult thymic epithelial progenitor/stem cell that is able to generate both cTECs and mTECs, opening avenues for improving thymus function in patients.

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Section: Resultsmentioning

confidence: 99%

Identification of a Bipotent Epithelial Progenitor Population in the Adult Thymus

et al. 2016

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“…In this regard, TPA marked suprabasal keratinocytes, which coexpress the terminal marker K10 (data not shown). Likewise, progenitor/stem cells of both lineages share molecular markers such as Plet-1, Rac1, and Smad7 (75)(76)(77). This close relationship between both lineages may even extend to a common progenitor stage, as TEC progenitors can be reprogrammed into multipotent skin stem cells (78).…”

Section: Discussionmentioning

confidence: 99%

Revisiting the Road Map of Medullary Thymic Epithelial Cell Differentiation

Michel

Miller

Küchler

et al. 2017

The Journal of Immunology

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The basic two-step terminal differentiation model of the medullary thymic epithelial cell (mTEC) lineage from immature MHC class II (MHCII) to mature MHCII mTECs has recently been extended to include a third stage, namely the post-Aire MHCII subset as identified by lineage-tracing models. However, a suitable surface marker distinguishing the phenotypically overlapping pre- from the post-Aire MHCII stage has been lacking. In this study, we introduce the lectin agglutinin (TPA) as a novel cell surface marker that allows for such delineation. Based on our data, we derived the following sequence of mTEC differentiation: TPAMHCII → TPAMHCII → TPAMHCII → TPAMHCII Surprisingly, in the steady-state postnatal thymus TPAMHCII pre-Aire rather than terminally differentiated post-Aire TPAMHCII mTECs were marked for apoptosis at an exceptionally high rate of ∼70%. Hence, only the minor cycling fraction of the MHCII subset (<20%) potentially qualified as mTEC precursors. FoxN1 expression inversely correlated with the fraction of slow cycling and apoptotic cells within the four TPA subsets. TPA also further subdivided human mTECs, although with different subset distribution. Our revised road map emphazises close parallels of terminal mTEC development with that of skin, undergoing an alternative route of cell death, namely cornification rather than apoptosis. The high rate of apoptosis in pre-Aire MHCII mTECs points to a "quality control" step during early mTEC differentiation.

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“…The development and the functional integrity of both tissues depend on the transcription factor FoxN1 (2-5), keratinocytes and TECs express similar sets of cytokeratins and late differentiation markers along their maturation (this applies in particular to the medullary TEC [mTEC] lineage) (6-9), and they depend on close interactions with mesenchymal cells and extracellular matrix (ECM) components (10). Moreover, keratinocyte and TEC progenitor/stem cells share molecular markers like Plet-1, Rac1, and Smad7 (11)(12)(13). This relationship has been underscored by the recent demonstration that TEC progenitors can be reprogrammed into multipotent skin stem cells (14).…”

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confidence: 99%

An Organotypic Coculture Model Supporting Proliferation and Differentiation of Medullary Thymic Epithelial Cells and Promiscuous Gene Expression

Pinto

Schmidt

Egle

et al. 2013

The Journal of Immunology

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Understanding intrathymic T cell differentiation has been greatly aided by the development of various reductionist in vitro models that mimic certain steps/microenvironments of this complex process. Most models focused on the faithful in vitro restoration of T cell differentiation and selection. In contrast, suitable in vitro models emulating the developmental pathways of the two major thymic epithelial cell lineages—cortical thymic epithelial cells and medullary thymic epithelial cells (mTECs)—are yet to be developed. In this regard, lack of an in vitro model mimicking the developmental biology of the mTEC lineage has hampered the molecular analysis of the so-called “promiscuous expression” of tissue-restricted genes, a key property of terminally differentiated mTECs. Based on the close biological relationship between the skin and thymus epithelial cell compartments, we adapted a three-dimensional organotypic coculture model, originally developed to provide a bona fide in vitro dermal equivalent, for the culture of isolated mTECs. This three-dimensional model preserves key features of mTECs: proliferation and terminal differentiation of CD80lo, Aire− mTECs into CD80hi, Aire+ mTECs; responsiveness to RANKL; and sustained expression of FoxN1, Aire, and tissue-restricted genes in CD80hi mTECs. This in vitro culture model should facilitate the identification of molecular components and pathways involved in mTEC differentiation in general and in promiscuous gene expression in particular.

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Rac1 Deletion Causes Thymic Atrophy

Cited by 8 publications

References 43 publications

Identification of a Bipotent Epithelial Progenitor Population in the Adult Thymus

Identification of a Bipotent Epithelial Progenitor Population in the Adult Thymus

Revisiting the Road Map of Medullary Thymic Epithelial Cell Differentiation

An Organotypic Coculture Model Supporting Proliferation and Differentiation of Medullary Thymic Epithelial Cells and Promiscuous Gene Expression

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