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

Adipocytes, Brown / metabolism Adipocytes, White / metabolism Adult Stem Cells / physiology Animals CRISPR-Cas Systems / genetics Cell Culture Techniques / methods Cell Differentiation Diet, High-Fat / adverse effects Disease Models, Animal Fatty Liver / etiology Gene Editing / methods Glucose Intolerance / etiology Humans Lipid Metabolism / genetics Male Mice Nuclear Receptor Interacting Protein 1 / genetics Obesity / complications RNA, Guide, Kinetoplastida / genetics Subcutaneous Fat / cytology Thermogenesis / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
26 11 2021
Historique:
received: 28 10 2020
accepted: 08 11 2021
entrez: 27 11 2021
pubmed: 28 11 2021
medline: 8 1 2022
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-021-27190-y PMID: 34836963 PMC: PMC8626495
pubmed: 34836963
doi: 10.1038/s41467-021-27190-y
pii: 10.1038/s41467-021-27190-y
pmc: PMC8626495
doi:

Substances chimiques

NRIP1 protein, human 0
Nuclear Receptor Interacting Protein 1 0
RNA, Guide 0

Types de publication

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.

Langues

eng

Sous-ensembles de citation

IM

Pagination

6931

Subventions

Organisme : NCATS NIH HHS
ID : UH3 TR002668
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK089101
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM115911
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK123028
Pays : United States
Organisme : NHLBI NIH HHS
ID : F31 HL147482
Pays : United States
Organisme : NIDDK NIH HHS
ID : R37 DK030898
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK030898
Pays : United States
Organisme : NCATS NIH HHS
ID : UG3 TR002668
Pays : United States
Organisme : NIDDK NIH HHS
ID : U2C DK093000
Pays : United States

Informations de copyright

© 2021. The Author(s).

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Auteurs

Emmanouela Tsagkaraki (E)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
University of Crete School of Medicine, Crete, 71003, Greece.
ORCID: 0000-0001-7754-8945

Sarah M Nicoloro (SM)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
ORCID: 0000-0002-8638-4556

Tiffany DeSouza (T)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Javier Solivan-Rivera (J)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Anand Desai (A)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Lawrence M Lifshitz (LM)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Yuefei Shen (Y)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Mark Kelly (M)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
ORCID: 0000-0001-9018-594X

Adilson Guilherme (A)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
ORCID: 0000-0003-0535-5911

Felipe Henriques (F)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
ORCID: 0000-0002-9245-7141

Nadia Amrani (N)

University of Crete School of Medicine, Crete, 71003, Greece.

Raed Ibraheim (R)

RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
ORCID: 0000-0002-0961-7299

Tomas C Rodriguez (TC)

RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
ORCID: 0000-0002-8724-5427

Kevin Luk (K)

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Stacy Maitland (S)

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Randall H Friedline (RH)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
ORCID: 0000-0003-0894-448X

Lauren Tauer (L)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
ORCID: 0000-0002-2315-1050

Xiaodi Hu (X)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Jason K Kim (JK)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
ORCID: 0000-0002-7185-042X

Scot A Wolfe (SA)

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
ORCID: 0000-0002-7042-201X

Erik J Sontheimer (EJ)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
ORCID: 0000-0002-0881-0310

Silvia Corvera (S)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA. Silvia.Corvera@umassmed.edu.
ORCID: 0000-0002-0009-4129

Michael P Czech (MP)

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA. Michael.Czech@umassmed.edu.
ORCID: 0000-0003-4075-7350

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules du tissu conjonctif › Adipocytes › Adipocytes bruns › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Cellules › Cellules du tissu conjonctif › Adipocytes › Adipocytes blancs › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches adultes › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Eucaryotes › Animaux › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Extinction de l'expression des gènes › Systèmes CRISPR-Cas › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Techniques d'investigation › Techniques in vitro › Techniques de culture › Techniques de culture cellulaire › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Phénomènes physiologiques › Alimentation et nutrition › Phénomènes physiologiques nutritionnels › Régime alimentaire › Alimentation riche en graisse › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Stéatose hépatique › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Génie génétique › Édition de gène › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles du métabolisme du glucose › Hyperglycémie › Intolérance au glucose › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Métabolisme › Métabolisme lipidique › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Protéine-1 interagissant avec le récepteur nucléaire › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Obésité › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › ARN guide › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Tissus › Tissu conjonctif › Tissu adipeux › Tissu adipeux blanc › Graisse sous-cutanée › CRISPR-enhanced human adipocyte browning as...
questionsmedicales.fr › Phénomènes biologiques › Adaptation biologique › Adaptation physiologique › Régulation de la température corporelle › Thermogenèse › CRISPR-enhanced human adipocyte browning as...