Bnip3lb-driven mitophagy sustains expansion of the embryonic hematopoietic stem cell pool

Meader, E.; Walcheck, M. T.; Leder, M. R.; Jing, R.; Wrighton, P. J.; Sugden, W. W.; Najia, M. A.; Oderberg, I. M.; Taylor, V. M.; LeBlanc, Z. C.; Quenzer, E. D.; Lim, S.-E.; Daley, G. Q.; Goessling, W.; North, T. E.

doi:10.1101/2024.09.23.614531

bioRxiv · 10.1101/2024.09.23.614531

Bnip3lb-driven mitophagy sustains expansion of the embryonic hematopoietic stem cell pool

Meader, E.·Walcheck, M. T.·Leder, M. R.·Jing, R.·Wrighton, P. J.·Sugden, W. W.·Najia, M. A.·Oderberg, I. M.·Taylor, V. M.·LeBlanc, Z. C.·Quenzer, E. D.·Lim, S.-E.·Daley, G. Q.·Goessling, W.·North, T. E.

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Abstract

Embryonic hematopoietic stem and progenitor cells (HSPCs) have the unique ability to undergo rapid proliferation while maintaining multipotency, a clinically-valuable quality which currently cannot be replicated in vitro. Here, we show that embryonic HSPCs achieve this state by precise spatio-temporal regulation of reactive oxygen species (ROS) via Bnip3lb-associated developmentally-programmed mitophagy, a distinct autophagic regulatory mechanism from that of adult HSPCs. While ROS drives HSPC specification in the dorsal aorta, scRNAseq and live-imaging of Tg(ubi:mitoQC) zebrafish indicate that mitophagy initiates as HSPCs undergo endothelial-to-hematopoietic transition and colonize the caudal hematopoietic tissue (CHT). Knockdown of bnip3lb reduced mitophagy and HSPC numbers in the CHT by promoting myeloid-biased differentiation and apoptosis, which was rescued by anti-oxidant exposure. Conversely, induction of mitophagy enhanced both embryonic HSPC and lymphoid progenitor numbers. Significantly, mitophagy activation improved ex vivo functional capacity of hematopoietic progenitors derived from human-induced pluripotent stem cells (hiPSCs), enhancing serial-replating hematopoietic colony forming potential. HIGHLIGHTSO_LIROS promotes HSPC formation in the dorsal aorta but negatively affects maintenance thereafter. C_LIO_LIHSPCs colonizing secondary niches control ROS levels via Bnip3lb-directed mitophagy. C_LIO_LIMitophagy protects nascent HSPCs from ROS-associated apoptosis and maintains multipotency. C_LIO_LIInduction of mitophagy enhances long-term hematopoietic potential of iPSC-derived HSPCs. C_LI

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Meader, E., Walcheck, M. T., Leder, M. R., Jing, R., Wrighton, P. J., Sugden, W. W., Najia, M. A., Oderberg, I. M., Taylor, V. M., LeBlanc, Z. C., Quenzer, E. D., Lim, S.-E., Daley, G. Q., Goessling, W., North, T. E.. 2024-09-23. Bnip3lb-driven mitophagy sustains expansion of the embryonic hematopoietic stem cell pool. https://doi.org/10.1101/2024.09.23.614531

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