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

E. Tsagkaraki, SM. Nicoloro, T. DeSouza, J. Solivan-Rivera, A. Desai, LM. Lifshitz, Y. Shen, M. Kelly, A. Guilherme, F. Henriques, N. Amrani, R. Ibraheim, TC. Rodriguez, K. Luk, S. Maitland, RH. Friedline, L. Tauer, X. Hu, JK. Kim, SA. Wolfe, EJ....

. 2021 ; 12 (1) : 6931. [pub] 20211126

Language English Country Great Britain

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.

Persistent link   https://www.medvik.cz/link/bmc22011891

Grant support
UH3 TR002668 NCATS NIH HHS - United States
F31 HL147482 NHLBI NIH HHS - United States
R37 DK030898 NIDDK NIH HHS - United States
R01 DK030898 NIDDK NIH HHS - United States
R01 GM115911 NIGMS NIH HHS - United States
UG3 TR002668 NCATS NIH HHS - United States
U2C DK093000 NIDDK NIH HHS - United States

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.

References provided by Crossref.org

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