Hedgehog Signaling Is Dispensable for Adult Hematopoietic Stem Cell Function

Gao, Jie; Graves, S W; Koch, Ute; Liu, Suqing; Janković, Vladimir; Buonamici, Silvia; Andaloussi, Abdeljabar El; Nimer, Stephen D.; Kee, Barbara L.; Taichman, Russell S.; Radtke, Freddy; Aifantis, Iannis

doi:10.1016/j.stem.2009.03.015

Cited by 167 publications

(158 citation statements)

References 46 publications

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“…with cyclopamine was reported to decrease the MS formation efficacy of human mammary cells (20). These results indicate that the activation of Hh signaling plays an essential role in the maintenance of CSCs (29)(30)(31). With regard to TNBC with characteristics of cancer stem-like cells including more frequent recurrence, chemoresistance and shorter survival than nTNBC, we addressed the hypothesis that there are more active CSCs in TNBC compared to nTNBC, and Hh signaling may contribute to this activation.…”

Section: Cd24mentioning

confidence: 86%

Overexpression of Hedgehog signaling molecules and its involvement in triple-negative breast cancer

et al. 2011

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Abstract. The purpose of this study was to investigate the activation of Hedgehog (Hh) signaling molecules and its involvement in triple-negative breast cancer (TNBC). A total of 123 cases of paraffin blocks, including 83 cases of primary breast carcinoma, 30 cases of mammary hyperplasia and 10 cases of normal breast tissue, were immunohistochemically analyzed for Sonic Hedgehog (SHH), Patched-1 (PTCH1), Smoothened (SMO) and glioma-associated oncogene homoglog 1 (GLI1) expression. The expression of SMO and GLI1 in TNBC was significantly increased in comparison to non-triple-negative breast cancer (nTNBC). GLI1 expression manifested an inverse association with the estrogen receptor. The levels of GLI1 expression were increased in lymph nodepositive cases. The expression of SHH and SMO was increased in high histological grades. Furthermore, the expression of SMO and GLI1 was correlated with superior tumor stage. The expression of SHH, SMO and GLI1 was significantly increased in breast cancer and mammary hyperplasia. PTCH1 expression was significantly decreased in breast cancer compared to mammary hyperplasia and normal breast tissue. For the first time, clinical evidence has been provided in support of significant roles of Hh signaling in TNBC. Hh signaling is involved in breast ductal changes and malignant transformation. Measures to inhibit Hh activity may improve the prognosis of TNBC patients.

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Section: Cd24mentioning

confidence: 86%

Overexpression of Hedgehog signaling molecules and its involvement in triple-negative breast cancer

et al. 2011

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“…This hypothesis is now strengthened by the fact that T cell development is normal in T cell-specific Ptch knockout mice, Ptch-deficient FTOCs, and in thymi with Ptch-deficient stroma, whereas it is compromised in Ptch knockout mice reconstituted with wt BM (T cell-extrinsic Ptch deletion). Recently, the immediate signaling partner of Ptch, Smo, was shown to be dispensable for adult HSC differentiation and specification of the T cell lineage (27). The discrepancy between the role of Smo and its immediate signaling partner Ptch in T cell development can be explained by the fact that Ptch also acts on molecular processes without the involvement of the Smo/Gli axis (28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

T Cell Development Critically Depends on Prethymic Stromal Patched Expression

Uhmann

Brandt

Dittmann

et al. 2011

The Journal of Immunology

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We recently described that T cell specification in mice deficient in the Hedgehog (Hh) receptor Patched (Ptch) is blocked at the level of the common lymphoid progenitor in the bone marrow (BM). Adoptive transfer of wild-type BM in Ptch-deficient mice provides evidence that T cell development strictly depends on Ptch expression in the nonhematopoietic compartment. Transplantation experiments using BM deficient in the glucocorticoid receptor exclude any involvement of the stress hormone corticosterone in our model. Using cell-type–specific knockout mice, we show that T cell development is independent of T cell-intrinsic Ptch expression. Furthermore, Ptch expression by the thymus stroma is dispensable, as revealed by fetal thymus organ culture and thymus transplantation. In contrast, analysis of the earliest thymic progenitors in Ptch-deficient mice indicated that Ptch is required for the development or supply of thymic homing progenitors that give rise to earliest thymic progenitors. Collectively, our findings identified Ptch as an exclusive T cell-extrinsic factor necessary for proper development of T cells at their prethymic stage. This observation may be important for current considerations using Hh inhibitors upstream of Ptch in diseases accompanied by aberrant Hh signaling.

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“…By contrast, CRE-mediated conditional ablation of Smo in both HSCs and their niche from embryonic stages onwards was shown to result in a profound loss of long-term grafting potential of the HSCs in vivo (Zhao et al, 2009). Yet another set of independent studies based on the conditional ablation of Smo in adult hematopoietic tissues concluded that SMO-mediated HH signaling is not required to maintain normal adult HSC function (Gao et al, 2009;Hofmann et al, 2009). In summary, the long list of discrepancies with regard to the requirement for HH in HSC function might result from a differential requirement for HH signaling in the niche versus the HSCs themselves, and/or from a different role for HH at different stages of development.…”

Section: Hematopoiesismentioning

confidence: 99%

Roles for Hedgehog signaling in adult organ homeostasis and repair

2014

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The hedgehog (HH) pathway is well known for its mitogenic and morphogenic functions during development, and HH signaling continues in discrete populations of cells within many adult mammalian tissues. Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.

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Hedgehog Signaling Is Dispensable for Adult Hematopoietic Stem Cell Function

Cited by 167 publications

References 46 publications

Overexpression of Hedgehog signaling molecules and its involvement in triple-negative breast cancer

Overexpression of Hedgehog signaling molecules and its involvement in triple-negative breast cancer

T Cell Development Critically Depends on Prethymic Stromal Patched Expression

Roles for Hedgehog signaling in adult organ homeostasis and repair

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