An unsupervised method for physical cell interaction profiling of complex tissues

Andrews, Nathanael; Serviss, Jason T.; Geyer, Natalie; Andersson, Agneta; Dzwonkowska, Ewa; Šutevski, Iva; Heijboer, Rosan; Baryawno, Ninib; Gerling, Marco; Enge, Martin

doi:10.1038/s41592-021-01196-2

Cited by 28 publications

(27 citation statements)

References 38 publications

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“…MTG16 has been shown to repress stem, goblet, and enteroendocrine cell genes to drive enterocyte differentiation in the SI (16). However, in accordance with numerous studies demonstrating important differences between SI and colon biology (2, 35, 67–70), Mtg16 -/- colon did not exhibit increased stem cell transcriptional signatures or an overall decrease in secretory genes. Instead, we observed specific upregulation of the enteroendocrine lineage, occurring at least in part due to unrepressed expression of Neurog3 , the class II bHLH transcription factor required for enteroendocrine cell differentiation (42–45).…”

Section: Discussionsupporting

confidence: 90%

MTG16 (CBFA2T3) regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors

Brown

Jacobse

Anant

et al. 2021

Preprint

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Aberrant epithelial differentiation and regeneration pathways contribute to colon pathologies including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). MTG16 (also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 interaction partners include E box-binding basic helix-loop-helix transcription factors (E proteins). MTG16-deficient mice exhibit worse colitis and increased tumor burden in inflammatory carcinogenesis. In this study, we sought to understand the role of MTG16 colonic epithelial homeostasis and the mechanisms by which MTG16 protects the epithelium in colitis and CAC. We demonstrated that MTG16 deficiency enabled enteroendocrine cell differentiation from secretory precursor cells at the expense of goblet cells. Transcriptomic analysis implicated dysregulated E protein function in MTG16-deficient colon crypts. Using a novel mouse model with a point mutation that disrupts MTG16:E protein complex formation (Mtg16P209T), we established that enteroendocrine:goblet cell balance was dependent on MTG16:E protein interactions and that the shift in lineage allocation was associated with enhanced expression of Neurog3, the central driver of enteroendocrine lineage specification. Furthermore, Mtg16 was upregulated in the previously described Ascl2+, de-differentiating cells that replenish the stem cell compartment in response to colon injury. Mtg16 expression was also increased in dextran sulfate sodium (DSS)-treated mouse colon crypts and in IBD patients compared to unaffected controls. We determined that the effects of MTG16 in regeneration are also dependent on its repression of E proteins, as the colonic epithelium failed to regenerate following DSS-induced injury in our novel mutant mouse model. Finally, we revealed that uncoupling MTG16:E protein interactions contributes to the enhanced tumorigenicity in Mtg16-/- colon in the azoxymethane(AOM)/DSS-induced model of CAC. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colonic differentiation and regeneration.

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Section: Discussionsupporting

confidence: 90%

MTG16 (CBFA2T3) regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors

Brown

Jacobse

Anant

et al. 2021

Preprint

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“…Single cell technology and space transcriptome technology, which are widely used because of the development of genomics technology, can solve the above problems step by step. The development and application of multiple sequencing technology can realise the unsupervised analysis of interactions among different cell types in skin wounds on the basis of restoring the spatial characteristics of tissue structure in vivo ( 168 ).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Microenvironment of Skin Wounds

et al. 2022

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Wound healing is a dynamic and highly regulated process that can be separated into three overlapping and interdependent phases: inflammation, proliferation, and remodelling. This review focuses on the inflammation stage, as it is the key stage of wound healing and plays a vital role in the local immune response and determines the progression of wound healing. Inflammatory cells, the main effector cells of the inflammatory response, have been widely studied, but little attention has been paid to the immunomodulatory effects of wound healing in non-inflammatory cells and the extracellular matrix. In this review, we attempt to deepen our understanding of the wound-healing microenvironment in the inflammatory stage by focusing on the interactions between cells and the extracellular matrix, as well as their role in regulating the immune response during the inflammatory stage. We hope our findings will provide new ideas for promoting tissue regeneration through immune regulation.

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“…However, single-cell RNA sequencing methods mostly analyze suspensions of dissociated cells, which completely erase the complexity of the physical organization of cells and provide partial information concerning cell-cell interactions. To overcome such limitations, some investigators have coupled single-cell RNA sequencing on microdissected tissues with staining for multiple targets and imaging mass cytometry ( Zhu et al., 2021 ), or employed bioinformatic tools to profile physically interacting cells in ”multiplets” derived from partially undissociated tissues ( Andrews et al., 2021 ). However, such techniques are not able to produce high-resolution RNA sequencing applied directly on intact tissues through a simple and scalable pipeline.…”

Section: Discussionmentioning

confidence: 99%