Lineage Tracing on Transcriptional Landscapes Links State to Fate During Differentiation

Overview

Journal Science

Specialty Science

Date 2020 Jan 25

PMID 31974159

Citations 291

Authors

Caleb Weinreb

Alejo Rodriguez-Fraticelli

Fernando D Camargo

Allon M Klein

Affiliations

Soon will be listed here.

Abstract

A challenge in biology is to associate molecular differences among progenitor cells with their capacity to generate mature cell types. Here, we used expressed DNA barcodes to clonally trace transcriptomes over time and applied this to study fate determination in hematopoiesis. We identified states of primed fate potential and located them on a continuous transcriptional landscape. We identified two routes of monocyte differentiation that leave an imprint on mature cells. Analysis of sister cells also revealed cells to have intrinsic fate biases not detectable by single-cell RNA sequencing. Finally, we benchmarked computational methods of dynamic inference from single-cell snapshots, showing that fate choice occurs earlier than is detected by state-of the-art algorithms and that cells progress steadily through pseudotime with precise and consistent dynamics.

Citing Articles

Consequences of training data composition for deep learning models in single-cell biology.

Nadig A, Thoutam A, Hughes M, Gupta A, Navia A, Fusi N bioRxiv. 2025; .

PMID: 40060416 PMC: 11888162. DOI: 10.1101/2025.02.19.639127.

Single-cell lineage tracing techniques in hematology: unraveling the cellular narrative.

Deng L, Li M, Huang X, Zhao X J Transl Med. 2025; 23(1):270.

PMID: 40038725 PMC: 11877926. DOI: 10.1186/s12967-025-06318-4.

The landscape of cell lineage tracing.

Feng Y, Liu G, Li H, Cheng L Sci China Life Sci. 2025; .

PMID: 40035969 DOI: 10.1007/s11427-024-2751-6.

Decoding heterogeneous single-cell perturbation responses.

Song B, Liu D, Dai W, McMyn N, Wang Q, Yang D Nat Cell Biol. 2025; 27(3):493-504.

PMID: 40011559 PMC: 11906366. DOI: 10.1038/s41556-025-01626-9.

Combining transcriptomic and metabolomic insights to guide the clinical application of adipose- and bone marrow-derived mesenchymal stem cells.

Zhou W, Lin J, Hay D, Yao X, Ouyang H Med Rev (2021). 2025; 5(1):76-82.

PMID: 39974562 PMC: 11834745. DOI: 10.1515/mr-2024-0056.

References

Chan M, Smith Z, Grosswendt S, Kretzmer H, Norman T, Adamson B . Molecular recording of mammalian embryogenesis. Nature. 2019; 570(7759):77-82. PMC: 7229772. DOI: 10.1038/s41586-019-1184-5. View

Sun J, Ramos A, Chapman B, Johnnidis J, Le L, Ho Y . Clonal dynamics of native haematopoiesis. Nature. 2014; 514(7522):322-7. PMC: 4408613. DOI: 10.1038/nature13824. View

Velten L, Haas S, Raffel S, Blaszkiewicz S, Islam S, Hennig B . Human haematopoietic stem cell lineage commitment is a continuous process. Nat Cell Biol. 2017; 19(4):271-281. PMC: 5496982. DOI: 10.1038/ncb3493. View

Mi H, Muruganujan A, Thomas P . PANTHER in 2013: modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees. Nucleic Acids Res. 2012; 41(Database issue):D377-86. PMC: 3531194. DOI: 10.1093/nar/gks1118. View

Herring C, Chen B, McKinley E, Lau K . Single-Cell Computational Strategies for Lineage Reconstruction in Tissue Systems. Cell Mol Gastroenterol Hepatol. 2018; 5(4):539-548. PMC: 5924749. DOI: 10.1016/j.jcmgh.2018.01.023. View

Plasschaert L, Zilionis R, Choo-Wing R, Savova V, Knehr J, Roma G . A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature. 2018; 560(7718):377-381. PMC: 6108322. DOI: 10.1038/s41586-018-0394-6. View

Woodworth M, Girskis K, Walsh C . Building a lineage from single cells: genetic techniques for cell lineage tracking. Nat Rev Genet. 2017; 18(4):230-244. PMC: 5459401. DOI: 10.1038/nrg.2016.159. View

Kester L, van Oudenaarden A . Single-Cell Transcriptomics Meets Lineage Tracing. Cell Stem Cell. 2018; 23(2):166-179. DOI: 10.1016/j.stem.2018.04.014. View

Jensen P, Dymecki S . Essentials of recombinase-based genetic fate mapping in mice. Methods Mol Biol. 2013; 1092:437-54. PMC: 4035813. DOI: 10.1007/978-1-60327-292-6_26. View

10.

Kinney J, Atwal G . Equitability, mutual information, and the maximal information coefficient. Proc Natl Acad Sci U S A. 2014; 111(9):3354-9. PMC: 3948249. DOI: 10.1073/pnas.1309933111. View

11.

Weinreb C, Wolock S, Tusi B, Socolovsky M, Klein A . Fundamental limits on dynamic inference from single-cell snapshots. Proc Natl Acad Sci U S A. 2018; 115(10):E2467-E2476. PMC: 5878004. DOI: 10.1073/pnas.1714723115. View

12.

Gerrits A, Dykstra B, Kalmykowa O, Klauke K, Verovskaya E, Broekhuis M . Cellular barcoding tool for clonal analysis in the hematopoietic system. Blood. 2010; 115(13):2610-8. DOI: 10.1182/blood-2009-06-229757. View

13.

Herman J, Sagar , Grun D . FateID infers cell fate bias in multipotent progenitors from single-cell RNA-seq data. Nat Methods. 2018; 15(5):379-386. DOI: 10.1038/nmeth.4662. View

14.

Schiebinger G, Shu J, Tabaka M, Cleary B, Subramanian V, Solomon A . Optimal-Transport Analysis of Single-Cell Gene Expression Identifies Developmental Trajectories in Reprogramming. Cell. 2019; 176(6):1517. PMC: 6615720. DOI: 10.1016/j.cell.2019.02.026. View

15.

La Manno G, Soldatov R, Zeisel A, Braun E, Hochgerner H, Petukhov V . RNA velocity of single cells. Nature. 2018; 560(7719):494-498. PMC: 6130801. DOI: 10.1038/s41586-018-0414-6. View

16.

Gupta D, Shah H, Malu K, Berliner N, Gaines P . Differentiation and characterization of myeloid cells. Curr Protoc Immunol. 2014; 104:22F.5.1-22F.5.28. PMC: 4539021. DOI: 10.1002/0471142735.im22f05s104. View

17.

Weinreb C, Wolock S, Klein A . SPRING: a kinetic interface for visualizing high dimensional single-cell expression data. Bioinformatics. 2017; 34(7):1246-1248. PMC: 6030950. DOI: 10.1093/bioinformatics/btx792. View

18.

Naik S, Schumacher T, Perie L . Cellular barcoding: a technical appraisal. Exp Hematol. 2014; 42(8):598-608. DOI: 10.1016/j.exphem.2014.05.003. View

19.

Lu R, Neff N, Quake S, Weissman I . Tracking single hematopoietic stem cells in vivo using high-throughput sequencing in conjunction with viral genetic barcoding. Nat Biotechnol. 2011; 29(10):928-33. PMC: 3196379. DOI: 10.1038/nbt.1977. View

20.

Kanamori M, Konno H, Osato N, Kawai J, Hayashizaki Y, Suzuki H . A genome-wide and nonredundant mouse transcription factor database. Biochem Biophys Res Commun. 2004; 322(3):787-93. DOI: 10.1016/j.bbrc.2004.07.179. View