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

Emmanouela Tsagkaraki, Sarah M. Nicoloro, Tiffany DeSouza, Javier Solivan-Rivera, Anand Desai, Lawrence M. Lifshitz, Yuefei Shen, Mark Kelly, Adilson Guilherme, Felipe Henriques, Nadia Amrani, Raed Ibraheim, Tomas C. Rodriguez, Kevin Luk, Stacy Maitland, Randall H. Friedline, Lauren Tauer, Xiaodi Hu, Jason K. Kim, Scot A. Wolfe, Erik J. Sontheimer, Silvia Corvera () and Michael P. Czech ()
Additional contact information
Emmanouela Tsagkaraki: Program in Molecular Medicine, University of Massachusetts Medical School
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
Scot A. Wolfe: Cell and Cancer Biology, University of Massachusetts Medical School
Erik J. Sontheimer: Program in Molecular Medicine, 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

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-27190-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27190-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-27190-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().