CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice

Wang, Chih-Hao; Lundh, Morten; Fu, Accalia; Kriszt, Rókus; Huang, Tian Lian; Lynes, Matthew D.; Leiria, Luiz O.; Shamsi, Farnaz; Darcy, Justin; Greenwood, Bennett; Narain, Niven R.; Tolstikov, Vladimir; Smith, Kyle; Emanuelli, Brice; Chang, Young Tae; Hagen, Susan J.; Danial, Nika N.; Kiebish, Michael A.; Tseng, Yu–Hua

doi:10.1126/scitranslmed.aaz8664

Cited by 108 publications

(102 citation statements)

References 69 publications

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“…Overall, this study provides direct evidence that Ang II-induced hypertension is associated with BAT deficiency. The latest study demonstrated that transplantation of engineered human brown-like adipocytes prevents diet-induced obesity, ameliorates metabolic syndrome, and activates endogenous brown fat in mice [27]. This novel study provides a potential strategy to combat metabolic syndrome by using engineered Fig.…”

Section: Discussionmentioning

confidence: 88%

Mitochondrial activity regulates the differentiation of skin-derived mesenchymal stem cells into brown adipocytes to contribute to hypertension

Chen

Sun

et al. 2021

Stem Cell Res Ther

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Background Brown adipocytes (BAs) are major components of brown adipose tissue (BAT), which is involved in blood pressure regulation. BAs are derived from multiple progenitors, including PDGFRα+ adipose-derived stem cells (ASCs). Skin-derived mesenchymal stem cells (S-MSCs) have the capacity to differentiate into adipocytes; however, their ability to differentiate into BAs remains unexplored. We aim to study the ability and regulatory mechanism of the differentiation of S-MSCs into BAs and the direct role of BAT in blood pressure regulation. Methods Protein expression was measured by flow cytometry or Western blotting, and gene mRNA levels were quantified by real-time quantitative PCR (RT-PCR). To induce the differentiation of S-MSCs into BAs, S-MSCs were stimulated with a brown adipogenic cocktail comprising insulin, IBMX, dexamethasone, triiodothyronine (T3), and rosiglitazone for the indicated periods. The oxygen consumption rate (OCR) was measured with an XF24 Extracellular Flux Analyzer. Mitochondrial mass was determined by flow cytometry and fluorescence staining. Hypertension was induced in WT mice by infusion of angiotensin II (Ang II), and systolic blood pressure (SBP) was measured using a tail cuff. Interscapular brown adipose tissue (iBAT)-deficient mice were generated by surgical removal of the iBAT depot, after which the animals were allowed to recover for 6 days. Aortic, iBAT, and heart tissue sections were analyzed by hematoxylin and eosin (HE) staining. Results We found that in vitro, S-MSCs isolated from the mouse dermis expressed the stem cell markers CD90/105 and PDGFRα and readily differentiated into BAs. Mitochondrial biogenesis and oxygen consumption were markedly increased during differentiation of S-MSCs into BAs. In vivo, iBAT was converted to white adipose tissue (WAT) in Ang II-induced hypertensive mice. We assessed the direct role of BAT in blood pressure (BP) regulation by using iBAT-deficient mice (generated by surgical removal of iBAT) and C57BL/6 (wild-type (WT)) mice and found that Ang II-induced BP elevation and vascular damage were markedly aggravated in iBAT-deficient mice compared with WT mice. Conclusions This study demonstrates that PDGFRα+ S-MSCs are able to differentiate into BAs and that this differentiation is regulated by mitochondrial activity. We also show that BAT plays a direct role in ameliorating Ang II-induced hypertension. The therapeutic potential of BAT for the prevention of hypertension-induced organ remodeling thus warrants further investigation. Graphical abstract. Schematic of the in vitro differentiation of PDGFRα+ S-MSCs into BAs via a process regulated by mitochondrial activity. BAT plays a direct role in Ang II-induced hypertension and target organ remodeling

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Section: Discussionmentioning

confidence: 88%

Mitochondrial activity regulates the differentiation of skin-derived mesenchymal stem cells into brown adipocytes to contribute to hypertension

Chen

Sun

et al. 2021

Stem Cell Res Ther

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“…3D adipospheres and human adipose tissue were fixed and stained for lipid droplets (red) and proteins of the extra cellular matrix indicated engineering hiPSCs-derived adipocytes to maintain UCP1 expression. Very interestingly, Yu-Hua Tseng's group has recently reported the possibility to activate endogenous UCP1 expression in immortalized white preadipocytes (HUMBLE cells) through clustered regularly interspaced short palindromic repeat-associated Cas9 (CRISPR/Cas9) technology [51]. In contrast to primary adipose progenitors, CRISPR-mediated genome editing of hiPSCs is practicable [52].…”

Section: Future Perspectives For Bat and Ipsc-derived Adipocyte Transmentioning

confidence: 99%

Transplantation of fat tissues and iPSC-derived energy expenditure adipocytes to counteract obesity-driven metabolic disorders: Current strategies and future perspectives

Dani

Yao

Dani

2021

Rev Endocr Metab Disord

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Several therapeutic options have been developed to address the obesity epidemic and treat associated metabolic diseases. Despite the beneficial effects of surgery and drugs, effective therapeutic solutions have been held back by the poor long-term efficiency and detrimental side effects. The development of alternative approaches is thus urgently required. Fat transplantation is common practice in many surgical procedures, including aesthetic and reconstructive surgery, and is a budding future direction for treating obesity-related metabolic defects. This review focuses on adipose tissue transplantation and the recent development of cell-based therapies to boost the mass of energy-expenditure cells. Brown adipocyte transplantation is a promising novel therapy to manage obesity and associated metabolic disorders, but the need to have an abundant and relevant source of brown fat tissue or brown adipocytes for transplantation is a major hurdle to overcome. Current studies have focused on the rodent model to obtain a proof of concept of a tissue-transplantation strategy able to achieve effective long-term effects to reverse metabolic defects in obese patients. Future perspectives and opportunities to develop innovative human fat tissue models and 3D engineered hiPSC-adipocytes are discussed.

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“…The recruitment of brown adipocytes has been suggested as a therapy to restore the metabolic balance of WAT and ameliorate insulin resistance [ 81 ]. Indeed, the transplantation of CRISPR-engineered UCP-1 expressing adipocytes in obese mice restores both the glucose tolerance and the insulin sensitivity, thus reverting the obesity-associated phenotype [ 82 ]. Other strategies have been proposed to increase the browning of WAT, such as the deacetylation of PPAR-γ [ 83 ] or the ablation of the macrophage IRE1α pathway [ 84 ].…”

Section: Molecular Alterations In Obesity and Bcmentioning

confidence: 99%

Cellular and Molecular Players in the Interplay between Adipose Tissue and Breast Cancer

Reggiani

Falvo

2021

IJMS

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The incidence and severity of obesity are rising in most of the world. In addition to metabolic disorders, obesity is associated with an increase in the incidence and severity of a variety of types of cancer, including breast cancer (BC). The bidirectional interaction between BC and adipose cells has been deeply investigated, although the molecular and cellular players involved in these mechanisms are far from being fully elucidated. Here, we review the current knowledge on these interactions and describe how preclinical research might be used to clarify the effects of obesity over BC progression and morbidity, with particular attention paid to promising therapeutic interventions.

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CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice

Cited by 108 publications

References 69 publications

Mitochondrial activity regulates the differentiation of skin-derived mesenchymal stem cells into brown adipocytes to contribute to hypertension

Mitochondrial activity regulates the differentiation of skin-derived mesenchymal stem cells into brown adipocytes to contribute to hypertension

Transplantation of fat tissues and iPSC-derived energy expenditure adipocytes to counteract obesity-driven metabolic disorders: Current strategies and future perspectives

Cellular and Molecular Players in the Interplay between Adipose Tissue and Breast Cancer

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