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Programming human pluripotent stem cells into white and brown adipocytes

Nature Cell Biology volume 14, pages 209–219 (2012)Cite this article

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Abstract

The utility of human pluripotent stem cells is dependent on efficient differentiation protocols that convert these cells into relevant adult cell types. Here we report the robust and efficient differentiation of human pluripotent stem cells into white or brown adipocytes. We found that inducible expression of PPARG2 alone or combined with CEBPB and/or PRDM16 in mesenchymal progenitor cells derived from pluripotent stem cells programmed their development towards a white or brown adipocyte cell fate with efficiencies of 85%–90%. These adipocytes retained their identity independent of transgene expression, could be maintained in culture for several weeks, expressed mature markers and had mature functional properties such as lipid catabolism and insulin-responsiveness. When transplanted into mice, the programmed cells gave rise to ectopic fat pads with the morphological and functional characteristics of white or brown adipose tissue. These results indicate that the cells could be used to faithfully model human disease.

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Figure 1: Experimental scheme and characterization of hPSC-derived MPCs.
Figure 2: Programming hPSC-derived MPCs with PPARG2, PPARG2–CEBPB or PPARG2–CEBPB–PRDM16 generates white and brown adipocytes.
Figure 3: Programmed adipocytes exhibit a mature white or brown adipocyte gene expression profile.
Figure 4: Global transcriptional analysis confirms the identity of programmed hPSC-derived white and brown adipocytes.
Figure 5: Programmed hPSC-derived white adipocytes exhibit mature functional properties.
Figure 6: Programmed hPSC-derived brown adipocytes demonstrate mature functional properties.
Figure 7: Generation of functional hPSC-derived brown and white adipose tissue in vivo.

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Acknowledgements

The authors would like to thank T. Holm, A. Foudi and E. Hanson for critical reading, insight and suggestions; M. Henderson, J. Hom, K. Hom, I. Pomerantseva, A. Tseng and K. Kulig for their technical help; L. Prickett-Rice and K. Folz-Donahue of the HSCI-CRM Flow Cytometry Core Facility; D. Lieber and V. Mootha for assistance with cellular bioenergetic measurements; and J. Truelove and R. Weissleder for assistance with PET–CT imaging. T. Ahfeldt was supported by the Roberto and Allison Mignone Fund for Stem Cell Research. This work was financially sponsored in part by the Harvard Stem Cell Institute, Hoffman-La Roche and the Stowers Medical Institute.

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  1. Tim Ahfeldt, Robert T. Schinzel and Youn-Kyoung Lee: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    Tim Ahfeldt, Robert T. Schinzel, Youn-Kyoung Lee, David Hendrickson, Adam Kaplan, Raymond Camahort, Fang Xia, Jennifer Shay, Tony Shen, Alicia Cowley, Heba Al-Siddiqi, Kiran Musunuru, John L. Rinn & Chad A. Cowan

  2. Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    Tim Ahfeldt, Robert T. Schinzel, Youn-Kyoung Lee, Adam Kaplan, Raymond Camahort, Fang Xia, Jennifer Shay, Tony Shen, Frank H. Lau, Alicia Cowley, Greg Mowrer, Heba Al-Siddiqi & Chad A. Cowan

  3. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    Tim Ahfeldt, Robert T. Schinzel, Youn-Kyoung Lee, Adam Kaplan, Raymond Camahort, Fang Xia, Jennifer Shay, Eugene P. Rhee, Frank H. Lau, Greg Mowrer, Heba Al-Siddiqi, Robert E. Gerszten & Chad A. Cowan

  4. Institut für Biologie–Mikrobiologie, Fachbereich Biologie, Chemie, Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 12-16, 14195 Berlin, Germany

    Robert T. Schinzel

  5. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA

    David Hendrickson, Eugene P. Rhee, Clary B. Clish, Kiran Musunuru, Robert E. Gerszten, John L. Rinn & Chad A. Cowan

  6. Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA

    David H. Lum

  7. Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84112, USA

    David H. Lum

  8. Cardiovascular Research Institute, University of California San Francisco, San Francisco, California 94143, USA

    Rahul C. Deo

  9. Department of Medicine, University of California San Francisco, San Francisco, California 94143, USA

    Rahul C. Deo

  10. Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA

    Rahul C. Deo

  11. Research Division, Qatar Foundation, Doha, Qatar

    Heba Al-Siddiqi

  12. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge St., Boston, Massachusetts 02114, USA

    Matthias Nahrendorf

  13. Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

    Kiran Musunuru

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Correspondence to Chad A. Cowan.

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Ahfeldt, T., Schinzel, R., Lee, YK. et al. Programming human pluripotent stem cells into white and brown adipocytes. Nat Cell Biol 14, 209–219 (2012). https://doi.org/10.1038/ncb2411

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