Abstract
Liver repopulation with bone marrow–derived hepatocytes (BMHs) can cure the genetic liver disease fumarylacetoacetate hydrolase (Fah) deficiency1. BMHs emerge from fusion between donor bone marrow–derived cells and host hepatocytes2. To use such in vivo cell fusion efficiently for therapy requires knowing the nature of the hematopoietic cells that fuse with hepatocytes. Here we show that the transplantation into Fah−/− mice of hematopoietic stem cells (HSCs) from lymphocyte-deficient Rag1−/− mice, lineage-committed granulocyte-macrophage progenitors (GMPs) or bone marrow–derived macrophages (BMMs) results in the robust production of BMHs. These results provide direct evidence that committed myelomonocytic cells such as macrophages can produce functional epithelial cells by in vivo fusion. Because stable bone marrow engraftment or HSCs are not required for this process, macrophages or their highly proliferative progenitors provide potential for targeted and well-tolerated cell therapy aimed at organ regeneration.
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Acknowledgements
We thank C. Baumann, A. Major, G. Faulkner, C. Montgomery, A. Snyder, M. Al-Dhalimy and E. Speel for their work in support of this study, which was funded by US National Institutes of Health grants (RO1-DK067636 to M.G. and RO1-HL69133 to W.H.F.).
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Supplementary information
Supplementary Fig. 1
Hematopoietic repopulation from transplanted GMP. (PDF 155 kb)
Supplementary Fig. 2
Isotype controls for GMP sorting (PDF 152 kb)
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Willenbring, H., Bailey, A., Foster, M. et al. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med 10, 744–748 (2004). https://doi.org/10.1038/nm1062
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DOI: https://doi.org/10.1038/nm1062
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