Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.31.230649v1?rss=1 Authors: Jiang, Y., Fan, X., Lu, P., Cui, X., Wu, P., Lin, W., Zhang, D., Yuan, S., Liu, B., Chen, F., You, H., Wei, H., He, F., Jia, J. Abstract: Kupffer cells (KCs) originate from yolk sac progenitors before birth. Throughout adulthood, they self-maintain independently from the input of circulating monocytes (MOs) at steady state, and are replenished within 2 weeks after having been depleted, but the origin of repopulating KCs in adult remains unclear. The current paradigm dictates that repopulating KCs originate from preexisting KCs or monocytes, but there remains a lack of fate-mapping evidence. In current study, we firstly traced the fate of preexisting KCs and that of monocytic cells with tissue-resident macrophage-specific and monocytic cell-specific fate mapping mouse models, respectively, and found no evidences that repopulating KCs originate from preexisting KCs or MOs. Secondly, we performed genetic lineage tracing to determine the type of progenitor cells involved in response to KC depletion in mice, and found that in response to KC depletion, hematopoietic stem cells (HSCs) proliferated in the bone marrow, mobilized into the blood, adoptively transferred into the liver and differentiated into KCs. Finally, we traced the fate of HSCs in a HSC-specific fate-mapping mouse model, in context of chronic liver inflammation induced by repeated carbon tetrachloride treatment, and confirmed that repopulating KCs originated directly from HSCs. Taken together, these findings provided strong in vivo fate-mapping evidences that repopulating KCs originate directly from Hematopoietic stem cells not from preexisting KCs or from MOs. Copy rights belong to original authors. Visit the link for more info