|
| 1 | +Intuitions behind clone2vec |
| 2 | +=========================== |
| 3 | + |
| 4 | +The importance of clonal biology |
| 5 | +-------------------------------- |
| 6 | +A **clone** is a group of cells that all come from a single ancestor cell at some point of development. Stem and progenitor cells |
| 7 | +divide and give rise to different specialized cell types. By studying clones, we can trace how individual cells contribute |
| 8 | +to tissues and organs, helping us understand which cells give rise to which structures and how different cell types emerge |
| 9 | +from the same starting population. |
| 10 | + |
| 11 | +Cells that seem identical at first glance can have very different fates. Even within one |
| 12 | +tissue, different clones generate a mix of different cell types, revealing hidden functional diversity among cell populations. |
| 13 | +By analyzing clones in detail, we can better understand development, disease, and how tissues regenerate. |
| 14 | + |
| 15 | +clone2vec: learning clonal contexts from barcoded scRNAseq data |
| 16 | +--------------------------------------------------------------- |
| 17 | +When analyzing barcoded single-cell transcriptomics data, you notice many clones that have the same combinations of cell types |
| 18 | +or occupy similar transcriptional niches. |
| 19 | + |
| 20 | +.. image:: _static/images/similar_clones.png |
| 21 | + :alt: Clones similar to each other |
| 22 | + :width: 800 |
| 23 | + :align: center |
| 24 | + |
| 25 | +This happens because a cell's lineage history has a big influence on its gene expression state (even within a single cell type). |
| 26 | +These similar-behaving clones are likely to arise from similar (and intuitively, we find, |
| 27 | +spatially nearby) progenitor cells. We were interested in categorizing these clone types in an unbiased way, so we developed **clone2vec**, |
| 28 | +which learns the "clonal context" of cells directly from transcriptional neighborhoods (without using cell type annotations). |
| 29 | + |
| 30 | +Our method is inspired by **word2vec**, a machine learning model used in language processing. In word2vec, each word is represented as |
| 31 | +a point in a multi-dimensional space based on its context. Words that appear together in similar contexts have similar meanings. |
| 32 | +For example, in a language model, "king" and "queen" are close to each other in meaning, just like "apple" and "banana" might be. |
| 33 | + |
| 34 | +Clone2vec works the same way, but instead of words we use clonal identities of cells. Just like word2vec learns relationships between |
| 35 | +words based on the company they keep, clone2vec learns relationships between clones based on the neighborhoods their cells occupy in gene |
| 36 | +expression space. If two clones consistently appear in similar transcriptional neighborhoods, the model will learn to place them close |
| 37 | +together in the clonal embedding space. |
| 38 | + |
| 39 | +.. image:: _static/images/pipeline.png |
| 40 | + :alt: Clone2vec pipeline |
| 41 | + :width: 800 |
| 42 | + :align: center |
| 43 | + |
| 44 | +By mapping clones in this way, we can uncover relationships between cell types, predict how clones are functionally related, and explore |
| 45 | +how different cell lineages contribute to development. Our interactive application **clones2cells** makes this analysis interactive, |
| 46 | +allowing users to explore these complex patterns with simple visualizations. |
| 47 | + |
| 48 | +Advantages of clone2vec for analyzing cell lineages |
| 49 | +--------------------------------------------------- |
| 50 | +Clone2vec embeds clonal data into a vector space, allowing continuous analysis of cellular behaviors. |
| 51 | +Unlike conventional methods, which often rely on binary fate assignments, clone2vec indirectly quantifies and compares the proportions of different |
| 52 | +cell types within clones, thereby capturing subtle variations in cell fate biases. Instead of cell types, the algorithm uses transcriptional |
| 53 | +neighbourhoods, therefore it's becoming more dropout-robust as soon as even within the single cell type clones with similar behaviour usually |
| 54 | +share similar transcriptional signatures. |
| 55 | + |
| 56 | +Clonal embeddings can be applied to address several critical research questions. Researchers can explore how positional signals influence |
| 57 | +cell fate decisions by mapping clone behaviors across spatial contexts (by leveraging known patterning |
| 58 | +systems such as the Hox code). Additionally, integration of multiple time points of injection allows the identification |
| 59 | +of specific developmental periods when cell fate decisions become restricted or flexible. Third, clone2vec also aids in elucidating molecular |
| 60 | +pathways and signaling networks that drive clonal expansion and influence lineage biases, thereby identifying both primary and auxiliary |
| 61 | +regulatory mechanisms that modulate developmental outcomes. |
| 62 | + |
| 63 | +This scalable framework offered by clone2vec can be adapted to other tissue systems in embryonic development, immunology, stem cell |
| 64 | +research, cancer studies, and tissue regeneration. |
| 65 | + |
| 66 | +Exploring the clonal atlas via clonal and transcriptional embeddings with clones2cells |
| 67 | +-------------------------------------------------------------------------------------- |
| 68 | +The **clones2cells** viewer allows users to explore clonal relationships and gene expression patterns in an interactive way. |
| 69 | +The app visualizes how different clones relate to each other and how they map onto transcriptional space. |
| 70 | + |
| 71 | +On the left side (clone2vec UMAP), we show a clonal embedding, in which each dot is a clone. Clonal embeddings display the clones |
| 72 | +positioned relative to each other in a learned space. Clones that appear close together likely share similar fate potentials or arise |
| 73 | +from related progenitors. Users can click on an individual clone or select multiple clones using the lasso tool to visualize cells from |
| 74 | +the clone(s) on the right side (gene expression UMAP). |
| 75 | + |
| 76 | +.. image:: _static/images/clones_selection.png |
| 77 | + :alt: Clones selection |
| 78 | + :width: 800 |
| 79 | + :align: center |
| 80 | + |
| 81 | +An example of clones2cells application can be found for the `Erickson, Isaev, et al. dataset <https://clones2cells.streamlit.app>`. |
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