CellRank for directed single-cell fate mapping

Lange, Marius; Bergen, Volker; Klein, Michal; Setty, Manu; Reuter, Bernhard; Bakhti, Mostafa; Lickert, Heiko; Ansari, Meshal; Schniering, Janine; Schiller, Herbert B.; Pe’er, Dana; Theis, Fabian J.

doi:10.1038/s41592-021-01346-6

Cited by 444 publications

(482 citation statements)

References 100 publications

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“…To do this we calculated the probability of each cell to transit towards one of three terminal states (fate absorption probability) (Figure 3–figure supplement 1C). These probabilities were obtained using CellRank (Lange et al, 2022), which leverages RNA velocity and transcriptomic similarity information to predict transitions between cells. Mapping the fate probabilities of each cell onto UMAP plots of the full dataset (Figure 3C-E, see Figure 3B and Figure 2E-F for reference) shows that cells with low latent time values (i.e., early cells) have low probabilities of becoming neural, neural crest or placodal cells.…”

Section: Resultsmentioning

confidence: 99%

A gradient border model for cell fate decisions at the neural plate border

Thiery

Buzzi

Hamrud

et al. 2022

Preprint

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The vertebrate neural plate border is a transient territory at the edge of the neural plate containing precursors for all ectodermal derivatives: the neural plate, neural crest, placodes, and epidermis. Elegant functional experiments in a range of vertebrate models have provided an in-depth understanding of gene regulatory interactions within the ectoderm. However, these experiments conducted at tissue level have raised seemingly contradictory models for fate allocation of individual cells. Here, we carry out single cell RNA sequencing of chick ectoderm from primitive streak to neurulation stage, to explore cell state diversity and heterogeneity. We identify and characterise the dynamics of gene modules containing key factors known to regulate ectodermal cell fates, allowing us to model the order in which these fates are specified. Furthermore, we find that genes previously classified as neural plate border specifiers typically exhibit dynamic expression patterns and are biased towards either placodal or neural crest fates. Instead, given its transient and heterogenous characteristics, the neural plate border should be defined based on the co-expression of alternative placodal and neural crest gene modules. Finally, we propose a gradient border model for cell fate choice at the neural plate border, with the probability of cell fate allocation closely tied to the spatiotemporal positioning of cells.

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Section: Resultsmentioning

confidence: 99%

A gradient border model for cell fate decisions at the neural plate border

Thiery

Buzzi

Hamrud

et al. 2022

Preprint

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“…In order to determine dynamic changes in gene expression, we extracted splicing information from the *.bam files generated by cell ranger, using the velocyto.py tool 62 . The resulting *.loom files were merged and transformed into h5ad format for further processing by scVelo 63 and CellRank 64 . This analysis pipeline is integrated into the SPATA toolbox 65 .…”

Section: Lðxmentioning

confidence: 99%

T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10

et al. 2022

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Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the anti-tumor immune response. Here we show, by applying an in-silico multidimensional model integrating spatially resolved and single-cell gene expression data of 45,615 immune cells from 12 tumor samples, that a subset of Interleukin-10-releasing HMOX1+ myeloid cells, spatially localizing to mesenchymal-like tumor regions, drive T-cell exhaustion and thus contribute to the immunosuppressive tumor microenvironment. These findings are validated using a human ex-vivo neocortical glioblastoma model inoculated with patient derived peripheral T-cells to simulate the immune compartment. This model recapitulates the dysfunctional transformation of tumor infiltrating T-cells. Inhibition of the JAK/STAT pathway rescues T-cell functionality both in our model and in-vivo, providing further evidence of IL-10 release being an important driving force of tumor immune escape. Our results thus show that integrative modelling of single cell and spatial transcriptomics data is a valuable tool to interrogate the tumor immune microenvironment and might contribute to the development of successful immunotherapies.

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“…This has already been possible with current sequencing pipelines and should be very much improved when paired to techniques aimed at conserving the quiescence signature in vivo ( Dulken et al, 2017 ; Kalamakis et al, 2019 ; Mizrak et al, 2019 ; Borrett et al, 2020 , 2022 ). The use of tools such RNAvelocity ( La Manno et al, 2018 ) and CellRank ( Lange et al, 2022 ) on scRNAseq data will allow us to measure the direction and speed of cells travelling through the matrix and help us identify regions where one direction is favoured (where the probability of going back to the previous state is much lower than that of continuing in the same direction).…”

Section: A Full Dynamic View Of Quiescencementioning

confidence: 99%

Could a Different View of Quiescence Help Us Understand How Neurogenesis Is Regulated?

Urbán

2022

Front. Neurosci.

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The majority of adult neural stem cells (aNSCs) are in a distinct metabolic state of reversible cell cycle exit also known as quiescence. The rate of aNSC activation determines the number of new neurons generated and directly influences the long-term maintenance of neurogenesis. Despite its relevance, it is still unclear how aNSC quiescence is regulated. Many factors contribute to this, like aNSC heterogeneity, the lack of reliable quiescence markers, the complexity of the neurogenic niches or the intricacy of the transcriptional and post-transcriptional mechanisms involved. In this perspective article I discuss possible solutions to these problems. But, first and foremost, I believe we require a model that goes beyond a simple transition toward activation. Instead, we must acknowledge the full complexity of aNSC states, which include not only activation but also differentiation and survival as behavioural outcomes. I propose a model where aNSCs dynamically transition through a cloud of highly interlinked cellular states driven by intrinsic and extrinsic cues. I also show how a new perspective enables us to integrate current results into a coherent framework leading to the formulation of new testable hypothesis. This model, like all others, is still far from perfect and will be reshaped by future findings. I believe that having a more complete view of aNSC transitions and embracing their complexity will bring us closer to understand how aNSC activity and neurogenesis are controlled throughout life.

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CellRank for directed single-cell fate mapping

Cited by 444 publications

References 100 publications

A gradient border model for cell fate decisions at the neural plate border

A gradient border model for cell fate decisions at the neural plate border

T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10

Could a Different View of Quiescence Help Us Understand How Neurogenesis Is Regulated?

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