Gene-level alignment of single cell trajectories

Sumanaweera, Dinithi; Suo, Chenqu; Muraro, Daniele; Dann, Emma; Polański, Krzysztof; Steemers, Alexander; Park, Jong-Eun; Dumitrascu, Bianca; Teichmann, Sarah A.

doi:10.1101/2023.03.08.531713

Cited by 5 publications

(6 citation statements)

References 95 publications

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“…7I). To compare differences between the trajectories we then used genes2genes, which identifies feature-level alignment between two trajectories 40 (Supp. Fig.…”

Section: Resultsmentioning

confidence: 99%

Multiomic analysis reveals developmental dynamics of the human heart in health and disease

Cranley,

Kanemaru,

Bayraktar

et al. 2024

Preprint

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Developmental dynamics encompass both the specification of cell types and their spatial organisation into multicellular niches. Here we harness the power of single-cell and spatial multiomics to unravel embryonic and foetal cardiac tissue niches, which lead to the development of a new tool, TissueTypist. We infer developmental cell trajectories, including evidence for lineage relationships based on shared somatic mutations, within first- and second-trimester human hearts. We reveal that cardiac-resident macrophages likely originate from the yolk sac, forming heterogeneous subsets. CX3CR1+ macrophages with a microglia-like profile localise in the sinoatrial node, which may contribute to axon guidance for the innervating autonomic neurons. Foetal pacemaker cells exhibit distinct characteristics compared to their adult counterparts, including the expression of genes that are known to promote parasympathetic innervation. By comparing somatic mutation profiles of cardiomyocytes, we identify an early branching point where pacemaker cells diverge from working cardiomyocytes. We highlight the enhancer-mediated gene regulatory networks governing atrial and ventricular cardiomyocyte specification. The maturation of atrial cardiomyocytes into distinct left and right phenotypes, driven by transcription factors linked to atrial septal defect genes, underscores the significance of this process for healthy heart development. In the ventricle, cellular and transcriptional gradients along both pseudotime and the transmural axis provide a new molecular understanding of myocardial compaction. Finally, generating data from Trisomy 21 hearts and comparing this with the euploid atlas, we reveal a reduced abundance of specific cell types including compact cardiomyocytes. Overall, this extensive dataset and our precomputed models will form a valuable resource for the field.

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“…7I). To compare differences between the trajectories we then used genes2genes, which identifies feature-level alignment between two trajectories 40 (Supp. Fig.…”

Section: Resultsmentioning

confidence: 99%

Multiomic analysis reveals developmental dynamics of the human heart in health and disease

Cranley,

Kanemaru,

Bayraktar

et al. 2024

Preprint

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“…To understand the agreement and differences between in vitro and in vivo chondrocyte differentiation, we performed a computational alignment between them using dynamic programming (DP). Genes2Genes (G2G) 22 is a Bayesian information-theoretic DP framework that quantifies the similarity between two single-cell transcriptomic pseudotime trajectories by generating their optimal alignment at both gene-level and cell-level. A pseudotime trajectory alignment describes a non-linear mapping between the in vitro and in vivo pseudo timepoints in sequential order.…”

Section: Methodsmentioning

confidence: 99%

Single cell transcriptomics reveals chondrocyte differentiation dynamicsin vivoandin vitro

Lawrence,

Woods,

Roberts

et al. 2023

Preprint

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SummaryThe consistent production ofin vitrochondrocytes that faithfully recapitulatein vivodevelopment would be of great benefit for musculoskeletal disease modelling and regenerative medicine. Current efforts are often limited by off-target differentiation, resulting in a heterogeneous product. Furthermore, the lack of comparison to human embryonic tissue, precludes detailed evaluation ofin vitrocells. Here, we perform single-cell RNA sequencing of embryonic long bones dissected from first trimester hind limbs from a range of gestational ages. We combine this with publicly available data to form a detailed atlas of endochondral ossification, which we then use to evaluate a series of publishedin vitrochondrogenesis protocols, finding substantial variability in cell states produced by each. We apply single-nuclear RNA sequencing to one protocol to enable direct comparison betweenin vitroandin vivo,and perform trajectory alignment between the two to reveal differentiation dynamics at the single-cell level, shedding new light on off-target differentiationin vitro. Using this information, we inhibit the activity of FOXO1, a transcription factor predicted to be active in embryonic bone development and in chondrogenic cellsin vitro, and increase chondrocyte transcriptsin vitro.This study therefore presents a new framework for evaluating tissue engineering protocols, using single-cell data from human development to drive improvement and bring the prospect of true engineered cartilage closer to reality.

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“…Genes2Genes (G2G) 63 is a Bayesian Information-theoretic DP framework that consistently captures matches and mismatches between two trajectories at both gene-level and cell-level.…”

Section: In Vivo-in Vitro Trajectory Alignment Analysismentioning

confidence: 99%

“…4g, Supplementary Table 7), providing orthogonal validation of our findings and reinforcing the utility of the skin organoid as an accurate model of prenatal skin development. We further evaluated the differentiation trajectory alignment between prenatal skin and skin organoid using the Genes2Genes analysis framework 63 to compare the expression of transcription factors (TFs) along the 'hair fibroblast' trajectory (HOXC5 + early fibroblast to dermal papilla). Alignment was computed at both TF level and cell level (aggregated TF-level alignments) (see methods).…”

Section: Hair Follicle -Dermal Condensate and Dermal Papilla Differen...mentioning

confidence: 99%

“…In vivo-in vitro trajectory alignment analysis We used Dynamic Programming (DP) based alignment to evaluate agreement between the single-cell trajectories of prenatal skin and skin organoid fibroblasts which describe the in vivo and in vitro differentiation lineages from HOXC5 + early fibroblasts to dermal papilla. Genes2Genes (G2G) 63 is a Bayesian Information-theoretic DP framework that consistently captures matches and mismatches between two trajectories at both gene-level and cell-level.…”

Section: Trajectory Analysismentioning

confidence: 99%

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A human prenatal skin cell atlas reveals immune cell regulation of skin morphogenesis

Gopee,

Huang,

Olabi

et al. 2023

Preprint

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Human prenatal skin is populated by innate immune cells including macrophages, and whether they act solely in immunity or have additional functions in morphogenesis is unclear. We assembled the first comprehensive multi-omic reference atlas of prenatal human skin (7-16 post-conception weeks), combining single cell and spatial transcriptomic data, to characterise the skin's microenvironmental cellular organisation. This revealed that crosstalk between non-immune and immune cells underpins formation of hair follicles, has implications for scarless wound healing, and is critical for skin angiogenesis. We benchmarked a skin organoid model, derived from human embryonic stem (ES) and induced pluripotent stem (iPS) cells, against prenatal and adult skin, demonstrating close recapitulation of the epidermal and dermal skin components during hair follicle development. Notably, the skin organoid lacked immune cells and had markedly diminished endothelial cell heterogeneity and quantity. From our in vivo skin cell atlas data, we found that macrophages and macrophage-derived growth factors play a key role in driving endothelial development prenatally. Indeed, vascular network formation was enhanced following transfer of autologous iPS-derived macrophages into both endothelial cell angiogenesis assays and skin organoid cultures. In summary, innate immune cells moonlight as key players in skin morphogenesis beyond their conventional immune roles, a function they achieve via extensive crosstalk with non-immune cells. Finally, we leveraged our human prenatal skin cell atlas to further our understanding of the pathogenesis of genetic hair and skin disorders.

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Gene-level alignment of single cell trajectories

Cited by 5 publications

References 95 publications

Multiomic analysis reveals developmental dynamics of the human heart in health and disease

Multiomic analysis reveals developmental dynamics of the human heart in health and disease

Single cell transcriptomics reveals chondrocyte differentiation dynamicsin vivoandin vitro

A human prenatal skin cell atlas reveals immune cell regulation of skin morphogenesis

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