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bioRxiv · 10.1101/2025.07.28.667115

The hidden predictors of human haematopoietic clonal fate

Tomei, S.·Zhang, S.·Lin, M.·Audiger, C.·Weber, T. S.·Naik, S.
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Abstract

Human haematopoietic stem and progenitor cells (HSPCs) exhibit heterogeneous lineage output, but the molecular programs underlying clonal fate remain poorly defined. To address this, we developed a human haematopoietic organoid supporting differentiation into 15 lineages and used it to track barcoded HSPC clones over time. By integrating single-cell transcriptomes, surface phenotypes, and clonal fate, we applied machine learning to identify clonal fate modules - gene and marker signatures predictive of lineage commitment. This approach uncovered hidden transcriptional and surface correlates of multipotency, including CD200, which marked a subset of HSCs with broad output capacity, which we leveraged to increase manufactured type 1 dendritic cell purity for immunotherapy applications. Our study provides a framework for decoding clonal fate decisions in human HSPCs and identifies molecular features that distinguish truly multipotent clones, advancing strategies for stem cell purification and therapeutic engineering.

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Tomei, S., Zhang, S., Lin, M., Audiger, C., Weber, T. S., Naik, S.. 2025-08-01. The hidden predictors of human haematopoietic clonal fate. https://doi.org/10.1101/2025.07.28.667115

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