Time-resolved single-cell state tracing exposes bidirectional state dynamics during differentiation
- 1Erasmus MC
Abstract
Differentiation dynamics have been challenging to study across time as measuring cell state, transcriptionally or epigenetically, typically requires its destruction. Here, we developed single-cell state tracing using the DCM-Time machine to enable the characterization of two transcriptomes, separated in time in single cells during epithelial cell differentiation in the intestine of living animals, and during neuronal differentiation in culture. We show that retrospective transcriptional histories and current states are consistent with bidirectional movements along differentiation trajectories both in vivo and in vitro that become rarer as cells mature. Furthermore, we observe rare transcriptome conversions, across canonical lineage boundaries. Our data support a model in which differentiating cells occasionally fail to stabilize lineage-associated programs, enabling reversals and subsequent resolution toward alternative lineage states.
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BibTeX
@misc{sanchez2026timeresolved,
title = {{Time-resolved single-cell state tracing exposes bidirectional state dynamics during differentiation}},
author = {E. Gonzalez Sanchez and F. Fabro and J. Klavert and G. Vroeg in de Wei and J. Boers and B. Tan and M. van Leeuwen and A. Sacchetti and E. Bindels and R. Boers and J. Gribnau and M. Creyghton},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.18.752672},
url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752672v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Time-resolved single-cell state tracing exposes bidirectional state dynamics during differentiation
AU - E. Gonzalez Sanchez
AU - F. Fabro
AU - J. Klavert
AU - G. Vroeg in de Wei
AU - J. Boers
AU - B. Tan
AU - M. van Leeuwen
AU - A. Sacchetti
AU - E. Bindels
AU - R. Boers
AU - J. Gribnau
AU - M. Creyghton
PY - 2026
DA - 2026/09/18
PB - bioRxiv
DO - 10.64898/2026.09.18.752672
UR - https://www.biorxiv.org/content/10.64898/2026.09.18.752672v1
AB - Differentiation dynamics have been challenging to study across time as measuring cell state, transcriptionally or epigenetically, typically requires its destruction. Here, we developed single-cell state tracing using the DCM-Time machine to enable the characterization of two transcriptomes, separated in time in single cells during epithelial cell differentiation in the intestine of living animals, and during neuronal differentiation in culture. We show that retrospective transcriptional histories and current states are consistent with bidirectional movements along differentiation trajectories both in vivo and in vitro that become rarer as cells mature. Furthermore, we observe rare transcriptome conversions, across canonical lineage boundaries. Our data support a model in which differentiating cells occasionally fail to stabilize lineage-associated programs, enabling reversals and subsequent resolution toward alternative lineage states.
ER -