Lgr proteins in epithelial stem cell biology

Barker, Nick; Tan, Shawna; Clevers, Hans

doi:10.1242/dev.083113

Cited by 137 publications

(135 citation statements)

References 90 publications

(114 reference statements)

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“…Because canonical Wnt signaling is well-established as a key pathway supporting adult stem cells in a variety of contexts, one possibility was that the Wnt signaling we observed in the nail matrix might include activity in nail stem cells. Extensive work has shown that Lgr5 is a faithful marker of several epithelial adult stem cell populations (16) and has pinpointed Lgr5 as a key modulator of Wnt signaling in adult stem cell biology (23). We therefore set out to determine whether Lgr5 was expressed in the mouse digit tip, specifically in the nail epithelium.…”

Section: Lgr5 Expression Marks Mesenchymal Progenitors Local To Specimentioning

confidence: 99%

“…Although Lgr4 is more broadly expressed in a wide range of tissues (14,15), Lgr5 and Lgr6 are tightly regulated and mark several adult stem cell populations throughout the body (16), including Lgr5 in the intestinal epithelium and hair follicle (17,18), as well as Lgr6 in the sweat glands and interfollicular epidermis (19). Canonical Wnt signaling has been shown to be necessary for appendage regeneration in many vertebrate epimorphic regenerative systems, including zebrafish fin, axolotl limb, and Xenopus tail (20)(21)(22).…”

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confidence: 99%

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Lgr6 marks nail stem cells and is required for digit tip regeneration

Lehoczky

Tabin

2015

Proc. Natl. Acad. Sci. U.S.A.

109

128

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The tips of the digits of some mammals, including human infants and mice, are capable of complete regeneration after injury. This process is reliant on the presence of the overlaying nail organ and is mediated by a proliferative blastema. Epithelial Wnt/β-catenin signaling has been shown to be necessary for mouse digit tip regeneration. Here, we report on Lgr5 and Lgr6 (leucine-rich repeat-containing G protein-coupled receptor 5 and 6), two important agonists of the Wnt pathway that are known to be markers of several epithelial stem cell populations. We find that Lgr5 is expressed in a dermal population of cells adjacent to the specialized epithelia surrounding the keratinized nail plate. Moreover, Lgr5-expressing cells contribute to this dermis, but not the blastema, during digit tip regeneration. In contrast, we find that Lgr6 is expressed within cells of the nail matrix portion of the nail epithelium, as well as in a subset of cells in the bone and eccrine sweat glands. Genetic lineage analysis reveals that Lgr6-expressing cells give rise to the nail during homeostatic growth, demonstrating that Lgr6 is a marker of nail stem cells. Moreover, Lgr6-expressing cells contribute to the blastema, suggesting a potential direct role for Lgr6-expressing cells during digit tip regeneration. This role is confirmed by analysis of Lgr6-deficient mice, which have both a nail and bone regeneration defect.

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Section: Lgr5 Expression Marks Mesenchymal Progenitors Local To Specimentioning

confidence: 99%

mentioning

confidence: 99%

Lgr6 marks nail stem cells and is required for digit tip regeneration

Lehoczky

Tabin

2015

Proc. Natl. Acad. Sci. U.S.A.

109

128

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“…Lgr5 is also known to mark actively cycling stem cells in small intestine, colon, stomach, and hair follicle, as well as quiescent stem cells in liver, pancreas, and cochlea (8). Isolated Lgr5 + adult stem cells from multiple tissues are able to generate so-called organoid structures ex vivo (9)(10)(11).…”

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confidence: 99%

Single Lgr5- or Lgr6-expressing taste stem/progenitor cells generate taste bud cells ex vivo

Ren

Lewandowski

Watson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

182

189

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Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) and its homologs (e.g., Lgr6) mark adult stem cells in multiple tissues. Recently, we and others have shown that Lgr5 marks adult taste stem/progenitor cells in posterior tongue. However, the regenerative potential of Lgr5-expressing (Lgr5 + ) cells and the identity of adult taste stem/progenitor cells that regenerate taste tissue in anterior tongue remain elusive. In the present work, we describe a culture system in which single isolated Lgr5 + or Lgr6 + cells from taste tissue can generate continuously expanding 3D structures ("organoids"). Many cells within these taste organoids were cycling and positive for proliferative cell markers, cytokeratin K5 and Sox2, and incorporated 5-bromo-2'-deoxyuridine. Importantly, mature taste receptor cells that express gustducin, carbonic anhydrase 4, taste receptor type 1 member 3, nucleoside triphosphate diphosphohydrolase-2, or cytokeratin K8 were present in the taste organoids. Using calcium imaging assays, we found that cells grown out from taste organoids derived from isolated Lgr5 + cells were functional and responded to tastants in a dose-dependent manner. Genetic lineage tracing showed that Lgr6 + cells gave rise to taste bud cells in taste papillae in both anterior and posterior tongue. RT-PCR data demonstrated that Lgr5 and Lgr6 may mark the same subset of taste stem/progenitor cells both anteriorly and posteriorly. Together, our data demonstrate that functional taste cells can be generated ex vivo from single Lgr5 + or Lgr6 + cells, validating the use of this model for the study of taste cell generation. Lgr5 (leucine-rich repeat-containing G protein-coupled receptor 5), encoded by a Wnt (wingless-type MMTV integration site family) target gene, marks adult stem/progenitor cells in taste tissue in posterior tongue that in vivo give rise to all major types of taste bud cells, as well as perigemmal cells (6, 7). Lgr5 is also known to mark actively cycling stem cells in small intestine, colon, stomach, and hair follicle, as well as quiescent stem cells in liver, pancreas, and cochlea (8). Isolated Lgr5 + adult stem cells from multiple tissues are able to generate so-called organoid structures ex vivo (9-11). For instance, Sato and colleagues (10) developed a 3D culture system to grow crypt-villus organoids from single intestinal stem cells; all differentiated cell types were found in these structures, indicating the multipotent nature of these cells. We hypothesized that Lgr5 + taste stem/progenitor cells in a 3D culture system would be capable of expanding and giving rise to taste receptor cells ex vivo. In the present study, we isolated Lgr5 + stem/progenitor cells from taste tissue and cultured them in a 3D culture system. Single Lgr5 + cells grew into organoid structures ex vivo in defined culture conditions, with the presence of both proliferating cells and differentiated mature taste cells in which taste signaling components are functionally expressed. When organoids were replated onto a 2D sur...

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“…The requirement of CBL and CBL-B for the maintenance of MaSCs was independently confirmed by selectively inducing Cbl/ Cbl-b DKO in Lgr5 + MECs, which have recently been established as bi-potent MaSCs with MG-regenerating ability (Barker et al, 2007(Barker et al, , 2013. Tamoxifen-induced, MaSC-specific Cbl/Cbl-b DKO led to a rapid depletion of Lgr5 + cells (Fig.…”

Section: Discussionmentioning

confidence: 77%

“…Wnt ligands help propagate MaSCs in vitro (Kessenbrock et al, 2013;Wang et al, 2013;Zeng and Nusse, 2010) and partly mediate the hormonal regulation of MaSCs (Cai et al, 2014). The Wnt pathway target gene Lgr5, which marks epithelial stem cells in the intestine, skin and other tissues (Barker et al, 2007(Barker et al, , 2013, was recently shown to mark MaSCs (Plaks et al, 2013;Rios et al, 2014). Lgr5 + MaSCs can regenerate a MG upon transplantation (Plaks et al, 2013).…”

Section: Introductionmentioning

confidence: 99%