Lgr5+ telocytes are a signaling hub at the intestinal villus tip

Halpern, Keren Bahar; Massalha, Hassan; Zwick, Rachel K.; Moor, Andreas E.; Castillo-Azofeifa, David; Rozenberg, Milena; Farack, Lydia; Egozi, Adi; Miller, Dan R.; Averbukh, Inna; Harnik, Yotam; Weinberg-Corem, Noa; Sauvage, Frédéric J. de; Amit, Ido; Klein, Ophir D.; Shoshkes-Carmel, Michal; Itzkovitz, Shalev

doi:10.1101/850909

Cited by 17 publications

(30 citation statements)

References 48 publications

(60 reference statements)

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“…Spatially resolved single cell transcriptomics in mice revealed extensive zonation of hepatocyte gene expression along the lobule radial axis (Halpern et al , 2017), and pseudotime analysis of scRNA‐seq data suggested that similar zonation may also be prominent in the human liver (Aizarani et al , 2019). We have recently developed approaches to combine scRNA‐seq with transcriptomics of laser‐capture microdissected (LCM) tissue to infer the zonation patterns of genes in the intestine (Moor et al , 2018; Halpern et al , 2020). We sought to apply this approach to obtain zonation patterns of human hepatocytes.…”

Section: Resultsmentioning

confidence: 99%

A single cell atlas of the human liver tumor microenvironment

Massalha

Halpern

Abu‐Gazala

et al. 2020

Molecular Systems Biology

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115

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Malignant cell growth is fueled by interactions between tumor cells and the stromal cells composing the tumor microenvironment. The human liver is a major site of tumors and metastases, but molecular identities and intercellular interactions of different cell types have not been resolved in these pathologies. Here, we apply single cell RNA‐sequencing and spatial analysis of malignant and adjacent non‐malignant liver tissues from five patients with cholangiocarcinoma or liver metastases. We find that stromal cells exhibit recurring, patient‐independent expression programs, and reconstruct a ligand–receptor map that highlights recurring tumor–stroma interactions. By combining transcriptomics of laser‐capture microdissected regions, we reconstruct a zonation atlas of hepatocytes in the non‐malignant sites and characterize the spatial distribution of each cell type across the tumor microenvironment. Our analysis provides a resource for understanding human liver malignancies and may expose potential points of interventions.

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Section: Resultsmentioning

confidence: 99%

A single cell atlas of the human liver tumor microenvironment

Massalha

Halpern

Abu‐Gazala

et al. 2020

Molecular Systems Biology

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115

114

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“…Concomitantly with robust JNK pathway activation, the crypts underwent a profound mis-differentiation and "villisation". We show ectopic crypt expression of gene programs characteristic of enterocytes at the villus tip 31,37 , where terminally differentiated cells are eliminated by apoptosis. Mounting inflammation and colitis eventually resulted in a lethal loss of intestinal function.…”

Section: Discussionmentioning

confidence: 90%

“…5e). Similar to Creb3l3, the expression of transcription factors Fos and JunB is normally restricted to enterocytes at the villus tip 31,37 . However, in D164A animals 4d pi, Fos and JunB transcripts are ectopically expressed in crypts ( Fig.…”

Section: Jnk Signalling Mediates Major Chromatin Remodelling In D164amentioning

confidence: 99%

Discrete regulation of β-catenin-mediated transcription governs identity of intestinal epithelial stem cells

Borrelli

Valenta

Handler

et al. 2020

Preprint

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The homeostasis of the gut epithelium relies upon continuous renewal and proliferation of crypt-resident intestinal epithelial stem cells (IESCs). Wnt/β-catenin signaling is required for IESC maintenance, however, it remains unclear how this pathway selectively governs the identity and proliferative decisions of IESCs. Here, we demonstrate that C-terminally-recruited transcriptional co-factors of β-catenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with β-catenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune β-catenin's transcriptional output to ensure proper self-renewal and proliferative behaviour of IESCs. Impairment of N-terminal interactions triggers transient hyperproliferation of IESCs, eventually resulting in exhaustion of the self-renewing stem cell pool. IESC mis-differentiation, accompanied by intrinsic and extrinsic stress signalling results in a process resembling aberrant "villisation" of intestinal crypts. Our data suggest that IESC-specific Wnt/β-catenin output requires discrete regulation of transcription by transcriptional co-factors. Results Attenuation of N-vs. C-terminal β-catenin transcriptional outputs has contrasting effects on intestinal homeostasisWe previously generated transgenic β-catenin (Ctnnb1) alleles harboring mutations that prevent interactions with N-or C-terminal transcriptional co-factors (NTFs and CTFs, respectively) 7 . The D164A mutation abrogates interaction with NTFs, the ∆C truncation abrogates the interaction with the CTFs (Fig. 1a). To overcome embryonic lethality of these alleles, we used compound heterozygous mice carrying one mutant and one conditional βcatenin allele (Extended Data Fig. 1a). Similarly to constitutively hemizygous Ctnnb1 KO/wt mice, Ctnnb1 D164A/flox and Ctnnb1 ∆C/flox animals show no overt abnormalities, indicating haplosufficiency of β-catenin for the maintenance of intestinal homeostasis. Combination with the villin-CreER T2 driver 16 enables the inducible deletion of the conditional β-catenin allele (Ctnnb1 flox ) specifically in the intestinal epithelium, thus leaving the Wnt-transcriptional outputs solely under the control of mutant β-catenin (D164A or ∆C). While villin-CreER T2 ;Ctnnb1 wt/flox (control) mice are perfectly viable and indistinguishable from homozygous wild type animals, the presence of only mutant β-catenin is lethal: villin-CreER T2 ;Ctnnb1 ∆C/flox (∆C) animals exhibit atrophic crypts at 4d post Cre induction (pi) (Extended Data Fig. 1b). This is in accordance with our previous results in villin-CreER T2 ;Ctnnb1 dm/flox animals, which express double mutant (dm) β-catenin harboring both N-and C-terminal mutations 17 . Unlike dm and ∆C animals, villin-CreER T2 ;Ctnnb1 D164A/flox (D164A) animals only reach humane endpoint at 7d pi, as they suffer from severe colitis (Extended Data Fig. 1c). The different intestinal phenotypes that arise upon blocking C-or N-terminal transcriptional outputs of β-catenin are consist...

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“…Indeed, several studies have described specific cell subsets that act as regulators of the stem cell niche [6,7,13,[15][16][17][18]. Accordingly, although less studied, telocytes and specific fibroblast subsets identified by sc-RNA sequencing analyses have been shown to express BMPs and regulators of epithelial differentiation [6,7,14,19,29].…”

Section: Discussionmentioning

confidence: 99%

“…Examples include CD34, Foxl1, PDGFRα and Gli1 positive IMCs, which act as critical regulators of the intestinal stem cell niche through their production of Wnts, R-spondins and Gremlin 1, although they are not strictly restricted to single cell types [6,7,12,13,17,18]. Lgr5 + villous tip telocytes were also recently shown to regulate epithelial villus tip gene expression programs [19].…”

Section: Introductionmentioning

confidence: 99%

Col6a1⁺/CD201⁺ mesenchymal cells regulate intestinal morphogenesis and homeostasis

Melissari

Henriques

Tzaferis

et al. 2021

Preprint

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Intestinal mesenchymal cells encompass multiple subsets, whose origins, functions, and pathophysiological importance are still not clear. Here, we used the Col6a1Cre mouse, which targets telocytes and perivascular cells that can be further distinguished by the combination of the CD201, PDGFRα and αSMA markers. Lineage tracing revealed that telocytes originate from mesenchymal aggregates and are crucial for intestinal morphogenesis and patterning. Cell depletion experiments showed that Col6a1+/CD201+ telocytes regulate homeostatic enteroendocrine cell differentiation and epithelial proliferation. During acute colitis, they expressed an inflammatory and extracellular matrix remodeling gene signature, but they also retained their properties and topology. Notably, both in homeostasis and tissue regeneration, they were dispensable for normal organ architecture, as they were replaced by CD34+ mesenchymal cells, providing thus evidence for the plasticity potential of distinct mesenchymal populations in the intestine. Therefore, our results provide a comprehensive analysis of the identities, origin, and functional significance of colonic Col6a1Cre+ telocytes.

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Lgr5+ telocytes are a signaling hub at the intestinal villus tip

Cited by 17 publications

References 48 publications

A single cell atlas of the human liver tumor microenvironment

A single cell atlas of the human liver tumor microenvironment

Discrete regulation of β-catenin-mediated transcription governs identity of intestinal epithelial stem cells

Col6a1⁺/CD201⁺ mesenchymal cells regulate intestinal morphogenesis and homeostasis

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Lgr5+ telocytes are a signaling hub at the intestinal villus tip

Cited by 17 publications

References 48 publications

A single cell atlas of the human liver tumor microenvironment

A single cell atlas of the human liver tumor microenvironment

Discrete regulation of β-catenin-mediated transcription governs identity of intestinal epithelial stem cells

Col6a1+/CD201+ mesenchymal cells regulate intestinal morphogenesis and homeostasis

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Col6a1⁺/CD201⁺ mesenchymal cells regulate intestinal morphogenesis and homeostasis