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Publication
CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease.
Authors Tsagkaraki E, Nicoloro SM, DeSouza T, Solivan-Rivera J, Desai A, Lifshitz LM,
Shen Y, Kelly M, Guilherme A, Henriques F, Amrani N, Ibraheim R, Rodriguez TC,
Luk K, Maitland S, Friedline RH, Tauer L, Hu X, Kim JK, Wolfe SA, Sontheimer EJ,
Corvera S, Czech MP
Submitted By Submitted Externally on 1/10/2022
Status Published
Journal Nature communications
Year 2021
Date Published 11/1/2021
Volume : Pages 12 : 6931
PubMed Reference 34836963
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.




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