Plcl1 Regulates Hematopoietic Stem Cell Function During Aging and Stress by Modulating Calcium Dynamics

Yabushita, T.; Tanaka, Y.; Fukushima, T.; Wakahashi, K.; Umemoto, T.; Takizawa, H.; Goyama, S.; Kitamura, T.; Nishiyama, A.; Tamura, T.; Yamazaki, S.; Suda, T.

doi:10.1101/2025.09.15.674672

bioRxiv · 10.1101/2025.09.15.674672

Plcl1 Regulates Hematopoietic Stem Cell Function During Aging and Stress by Modulating Calcium Dynamics

Yabushita, T.·Tanaka, Y.·Fukushima, T.·Wakahashi, K.·Umemoto, T.·Takizawa, H.·Goyama, S.·Kitamura, T.·Nishiyama, A.·Tamura, T.·Yamazaki, S.·Suda, T.

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Abstract

Long-term hematopoietic stem cells (HSCs) can generate all blood lineages but typically remain quiescent, becoming activated only in response to acute stress. We previously demonstrated that quiescent HSCs exhibit heterogeneity in intracellular calcium levels. However, the mechanisms underlying this heterogeneity and its physiological relevance remain unclear. Herein, we identify phospholipase C-like 1 (Plcl1), a noncatalytic protein that binds inositol 1,4,5-trisphosphate (IP3), as being selectively enriched in the most quiescent HSC subset. Loss-of-function studies revealed that Plcl1 deficiency at steady state reduced basal intracellular calcium levels and skewed the HSC compartment toward CD41 subsets while preserving overall HSC numbers and long-term reconstitution capacity. Under acute hematopoietic stress, Plcl1 loss accelerated and amplified platelet rebound and the expansion of non-canonical megakaryocyte progenitors (ncMkPs), indicating activation of the thrombopoietic bypass pathway. In aged HSCs, Plcl1 deficiency exacerbated aging-related features, including expansion of the HSC pool, accumulation of CD41 HSCs and ncMkPs, and myeloid-skewed differentiation with impaired competitive reconstitution. These changes were accompanied by diminished induction of calcium-responsive immediate-early genes. Collectively, we identified Plcl1 as an intrinsic regulator that stabilizes calcium dynamics in HSCs, thereby restraining stress- and aging-associated megakaryocytic priming and preserving stem cell function.

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Yabushita, T., Tanaka, Y., Fukushima, T., Wakahashi, K., Umemoto, T., Takizawa, H., Goyama, S., Kitamura, T., Nishiyama, A., Tamura, T., Yamazaki, S., Suda, T.. 2025-09-16. Plcl1 Regulates Hematopoietic Stem Cell Function During Aging and Stress by Modulating Calcium Dynamics. https://doi.org/10.1101/2025.09.15.674672

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