Hematopoietic stem cells undergo bidirectional fate transitions in vivo.

Fukushima, T.; Kristiansen, T. A.; Wong, L. P.; Keyes, S.; Tanaka, Y.; Mazzola, M.; Zhao, T.; He, L.; Yagi, M.; Hochedlinger, K.; Yamazaki, S.; Sadreyev, R. I.; Scadden, D. T.

doi:10.1101/2025.02.23.639689

bioRxiv · 10.1101/2025.02.23.639689

Hematopoietic stem cells undergo bidirectional fate transitions in vivo.

Fukushima, T.·Kristiansen, T. A.·Wong, L. P.·Keyes, S.·Tanaka, Y.·Mazzola, M.·Zhao, T.·He, L.·Yagi, M.·Hochedlinger, K.·Yamazaki, S.·Sadreyev, R. I.·Scadden, D. T.

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Abstract

Differentiation of haematopoietic stem and progenitor cells (HSPCs) is widely considered unidirectional in vivo. Here, we developed clonal phylogenetic tracing (CP-tracer) by sequential genetic barcoding, which enabled high-resolution analysis of 181,695 subclones derived from 847 individually labelled HSPCs. This approach uncovered bidirectional fate transitions between myeloid-biased (My-) and lineage-balanced haematopoietic stem cells (HSCs). Individual HSC clones, distinguished by temporally unique serial barcodes, exhibited durable lineage bidirectionality, with dynamics favouring progressive accumulation of My-HSCs over time. CRISPR-Cas9 screening identified the homeobox gene Hhex as a suppressor of myeloid differentiation that enables pivoting toward balanced output. Hhex function is age-dependent, with its expression declining in aged HSCs. Together, these findings demonstrate unexpected plasticity in HSC differentiation, modulated in part by Hhex-mediated repression, that shifts over time to drive the myeloid bias characteristic of ageing.

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Fukushima, T., Kristiansen, T. A., Wong, L. P., Keyes, S., Tanaka, Y., Mazzola, M., Zhao, T., He, L., Yagi, M., Hochedlinger, K., Yamazaki, S., Sadreyev, R. I., Scadden, D. T.. 2025-02-23. Hematopoietic stem cells undergo bidirectional fate transitions in vivo.. https://doi.org/10.1101/2025.02.23.639689

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