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CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease

Author

Listed:
  • Emmanouela Tsagkaraki

    (Program in Molecular Medicine, University of Massachusetts Medical School
    University of Crete School of Medicine)

  • Sarah M. Nicoloro

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Tiffany DeSouza

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Javier Solivan-Rivera

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Anand Desai

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Lawrence M. Lifshitz

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Yuefei Shen

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Mark Kelly

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Adilson Guilherme

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Felipe Henriques

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Nadia Amrani

    (University of Crete School of Medicine)

  • Raed Ibraheim

    (RNA Therapeutics Institute, University of Massachusetts Medical School)

  • Tomas C. Rodriguez

    (RNA Therapeutics Institute, University of Massachusetts Medical School)

  • Kevin Luk

    (Cell and Cancer Biology, University of Massachusetts Medical School)

  • Stacy Maitland

    (Cell and Cancer Biology, University of Massachusetts Medical School)

  • Randall H. Friedline

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Lauren Tauer

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Xiaodi Hu

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Jason K. Kim

    (Program in Molecular Medicine, University of Massachusetts Medical School
    University of Massachusetts Medical School)

  • Scot A. Wolfe

    (Cell and Cancer Biology, University of Massachusetts Medical School
    Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School)

  • Erik J. Sontheimer

    (Program in Molecular Medicine, University of Massachusetts Medical School
    RNA Therapeutics Institute, University of Massachusetts Medical School
    Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School)

  • Silvia Corvera

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Michael P. Czech

    (Program in Molecular Medicine, University of Massachusetts Medical School)

Abstract

Obesity and type 2 diabetes are associated with disturbances in insulin-regulated glucose and lipid fluxes and severe comorbidities including cardiovascular disease and steatohepatitis. Whole body metabolism is regulated by lipid-storing white adipocytes as well as “brown” and “brite/beige” adipocytes that express thermogenic uncoupling protein 1 (UCP1) and secrete factors favorable to metabolic health. Implantation of brown fat into obese mice improves glucose tolerance, but translation to humans has been stymied by low abundance of primary human beige adipocytes. Here we apply methods to greatly expand human adipocyte progenitors from small samples of human subcutaneous adipose tissue and then disrupt the thermogenic suppressor gene NRIP1 by CRISPR. Ribonucleoprotein consisting of Cas9 and sgRNA delivered ex vivo are fully degraded by the human cells following high efficiency NRIP1 depletion without detectable off-target editing. Implantation of such CRISPR-enhanced human or mouse brown-like adipocytes into high fat diet fed mice decreases adiposity and liver triglycerides while enhancing glucose tolerance compared to implantation with unmodified adipocytes. These findings advance a therapeutic strategy to improve metabolic homeostasis through CRISPR-based genetic enhancement of human adipocytes without exposing the recipient to immunogenic Cas9 or delivery vectors.

Suggested Citation

  • Emmanouela Tsagkaraki & Sarah M. Nicoloro & Tiffany DeSouza & Javier Solivan-Rivera & Anand Desai & Lawrence M. Lifshitz & Yuefei Shen & Mark Kelly & Adilson Guilherme & Felipe Henriques & Nadia Amran, 2021. "CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27190-y
    DOI: 10.1038/s41467-021-27190-y
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    References listed on IDEAS

    as
    1. Michael Roden & Gerald I. Shulman, 2019. "The integrative biology of type 2 diabetes," Nature, Nature, vol. 576(7785), pages 51-60, December.
    2. Amanda Finck & Saar I. Gill & Carl H. June, 2020. "Cancer immunotherapy comes of age and looks for maturity," Nature Communications, Nature, vol. 11(1), pages 1-4, December.
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    Cited by:

    1. M. Kyle Cromer & Valentin V. Barsan & Erich Jaeger & Mengchi Wang & Jessica P. Hampton & Feng Chen & Drew Kennedy & Jenny Xiao & Irina Khrebtukova & Ana Granat & Tiffany Truong & Matthew H. Porteus, 2022. "Ultra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Antoine Gagelin & Corentin Largeau & Sandrine Masscheleyn & Mathilde S. Piel & Daniel Calderón-Mora & Frédéric Bouillaud & Jérôme Hénin & Bruno Miroux, 2023. "Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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