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This study demonstrates that human embryonic stem cells possess heritable "clonal memory" that influences their differentiation outcomes independently of external signals. Using lineage tracing combined with single-cell analysis, researchers found that clonally related cells show predictable fate biases during endoderm differentiation, with these biases encoded in pre-existing chromatin accessibility patterns at lineage-specific regulatory regions rather than in gene expression differences. Clones with distinct chromatin landscapes at the pluripotent stage predictably generate either successful endoderm cells or off-target mesoderm cells, explaining a major source of heterogeneity in stem cell differentiation protocols.
Why it matters
This work reveals why stem cell differentiation protocols often produce unwanted cell types alongside target cells, identifying pre-existing chromatin states as the culprit. Understanding and potentially controlling these intrinsic biases could improve the consistency and purity of stem cell-derived tissues for regenerative medicine and disease modeling applications.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Cell fate decisions during development are shaped not only by extrinsic signals but also by heritable intrinsic states passed on across cell division. The extent to which this phenomenon, termed clonal memory, can explain the persistent heterogeneity observed from directed differentiation of human embryonic stem cells is unclear. Here, we combine lineage tracing with single-cell transcriptomics and chromatin accessibility profiling to track clonal behaviour across human embryonic stem cell differentiation towards definitive endoderm. Using a lentiviral barcoding system coupled with a split-well sampling strategy, we find that clonally related cells exhibit reproducible, probabilistic fate outcomes that cannot be explained by signalling environment alone. Fate-biased clones are transcriptionally indistinguishable at the pluripotent stage yet display distinct chromatin accessibility landscapes at lineage-specific cis-regulatory elements. Pre-existing accessibility at these lineage-specific regulatory regions distinguish clones that undergo successful endoderm differentiation from those that generate off-target mesoderm derivatives. Together, these findings provide an explanation for how off-target populations arise during directed differentiation, identifying heritable chromatin states within pluripotent cultures as a source of variability relevant to stem cell-derived in vitro models and cell therapies.
Source: Clonal memory in human embryonic stem cells biases fate potential during endoderm differentiation