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Myelomonocytic cells are sufficient for therapeutic cell fusion in liver

Nature Medicine volume 10, pages 744–748 (2004)Cite this article

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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Figure 1: BMHs originate directly from fusion and independently of lymphocytes.
Figure 2: BMHs from transplantation of myelomonocytic progenitors.
Figure 3: BMHs from transplantation of macrophages.

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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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Authors and Affiliations

  1. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, 97239, Oregon, USA

    Holger Willenbring, Mark Foster, Yassmine Akkari, Craig Dorrell, Susan Olson & Markus Grompe

  2. Oregon Stem Cell Center, Oregon Health & Science University, Portland, 97239, Oregon, USA

    Holger Willenbring, Craig Dorrell & Markus Grompe

  3. Division of Hematology & Medical Oncology, Center for Hematologic Malignancies, Oregon Health & Science University, Portland, 97239, Oregon, USA

    Alexis S Bailey & William H Fleming

  4. Department of Pathology, Texas Children's Hospital, Houston, 77030, Texas, USA

    Milton Finegold

  5. Department of Pediatrics, Oregon Health & Science University, Portland, 97239, Oregon, USA

    Markus Grompe

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  1. Holger Willenbring
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Correspondence to Holger Willenbring.

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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)

Supplementary Methods (PDF 6 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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