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Wang O, Han L, Lin H, Tian M, Zhang S, Duan B, Chung S, Zhang C, Lian X, Wang Y, Lei Y. Fabricating 3-dimensional human brown adipose microtissues for transplantation studies. Bioact Mater 2022; 22:518-534. [PMID: 36330162 PMCID: PMC9619153 DOI: 10.1016/j.bioactmat.2022.10.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 10/06/2022] [Accepted: 10/18/2022] [Indexed: 11/13/2022] Open
Abstract
Transplanting cell cultured brown adipocytes (BAs) represents a promising approach to prevent and treat obesity (OB) and its associated metabolic disorders, including type 2 diabetes mellitus (T2DM). However, transplanted BAs have a very low survival rate in vivo. The enzymatic dissociation during the harvest of fully differentiated BAs also loses significant cells. There is a critical need for novel methods that can avoid cell death during cell preparation, transplantation, and in vivo. Here, we reported that preparing BAs as injectable microtissues could overcome the problem. We found that 3D culture promoted BA differentiation and UCP-1 expression, and the optimal initial cell aggregate size was 100 μm. The microtissues could be produced at large scales via 3D suspension assisted with a PEG hydrogel and could be cryopreserved. Fabricated microtissues could survive in vivo for long term. They alleviated body weight and fat gain and improved glucose tolerance and insulin sensitivity in high-fat diet (HFD)-induced OB and T2DM mice. Transplanted microtissues impacted multiple organs, secreted protein factors, and influenced the secretion of endogenous adipokines. To our best knowledge, this is the first report on fabricating human BA microtissues and showing their safety and efficacy in T2DM mice. The proposal of transplanting fabricated BA microtissues, the microtissue fabrication method, and the demonstration of efficacy in T2DM mice are all new. Our results show that engineered 3D human BA microtissues have considerable advantages in product scalability, storage, purity, safety, dosage, survival, and efficacy.
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Affiliation(s)
- Ou Wang
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln, NE, USA
- Biomedical Engineering Program, University of Nebraska-Lincoln, NE, USA
| | - Li Han
- Department of Biomedical Engineering, Pennsylvania State University, PA, USA
| | - Haishuang Lin
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln, NE, USA
| | - Mingmei Tian
- China Novartis Institutes for BioMedical Research Co., Ltd., Beijing, China
| | - Shuyang Zhang
- Department of Chemistry, University of Nebraska-Lincoln, NE, USA
| | - Bin Duan
- Mary & Dick Holland Regenerative Medicine Program and Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Soonkyu Chung
- Department of Nutrition, University of Massachusetts, Amherst, MA, USA
| | - Chi Zhang
- School of Biological Science, University of Nebraska-Lincoln, NE, USA
| | - Xiaojun Lian
- Department of Biomedical Engineering, Pennsylvania State University, PA, USA
| | - Yong Wang
- Department of Biomedical Engineering, Pennsylvania State University, PA, USA
| | - Yuguo Lei
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln, NE, USA
- Department of Biomedical Engineering, Pennsylvania State University, PA, USA
- Huck Institutes of the Life Sciences, Pennsylvania State University, PA, USA
- Corresponding author. The Pennsylvania State University, PA, USA.
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Tanaka-Yachi R, Otsu R, Takahashi-Muto C, Kiyose C. Delta-Tocopherol Suppresses the Dysfunction of Thermogenesis due to Inflammatory Stimulation in Brown Adipocytes. J Oleo Sci 2022; 71:1647-1653. [PMID: 36310052 DOI: 10.5650/jos.ess22184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023] Open
Abstract
Brown adipose tissue (BAT) functions as a radiator for thermogenesis and helps maintain body temperature and regulate metabolism. Inflammatory signals have been reported to inhibit PGC-1α activation and UCP1-mediated thermogenesis in brown adipocytes. Inflammation is mainly caused by cell hypertrophy and macrophage invasion due to obesity, and invading macrophages secrete inflammatory cytokines, including TNF-α, IL1β, and IL6, which suppress the thermogenesis in BAT. Tocopherol is a lipid-soluble vitamin with anti-inflammatory effects is expected to contribute to the suppression of inflammation in adipose tissue. In this study, we investigated the protective effect of tocopherols, α-tocopherol (α-toc) and δ-tocopherol (δ-toc), against brown adipocyte inflammation and thermogenesis dysfunction.Inflammatory stimulation by TNF-α, a major inflammatory cytokine, significantly decreased the protein expression levels of UCP1 and PGC-1α in rat primary brown adipocytes. The pre-incubation of α-toc or δ-toc significantly suppressed the decrease in UCP1 and PGC-1α expression and lipid accumulation. Additionally, α-toc and δ-toc suppress the induction of ERK1/2 gene expression, implying that an antiinflammatory effect is involved in this protective effect. We fed mice a high-fat diet for 16 weeks and investigated the effects of α-toc and δ-toc in the diet. Intake of α-toc and δ-toc significantly suppressed weight gain and hypertrophy of brown adipocytes. Our results suggest that α-toc and δ-toc suppress the dysfunction of thermogenesis in brown adipocytes due to inflammation and contribute to the treatment of obesity and obesity-related metabolic diseases.
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Affiliation(s)
- Rieko Tanaka-Yachi
- Department of Applied Biochemistry, Kanagawa Institute of Technology
- Department of Pharmacology, National Research Institute for Child Health and Development
| | - Rena Otsu
- Department of Applied Biochemistry, Kanagawa Institute of Technology
| | - Chie Takahashi-Muto
- Department of Clinical Nutrition, Kitasato Junior College of Health and Hygienic Sciences
| | - Chikako Kiyose
- Department of Nutrition and Life Science, Kanagawa Institute of Technology
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Van Nguyen TT, Vu VV, Pham PV. Transcriptional Factors of Thermogenic Adipocyte Development and Generation of Brown and Beige Adipocytes From Stem Cells. Stem Cell Rev Rep 2021; 16:876-892. [PMID: 32728995 DOI: 10.1007/s12015-020-10013-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Brown and beige adipocytes have been widely known for their potential to dissipate excessive energy into heat form, resulting in an alleviation of obesity and other overweight-related conditions. This review highlights the origins, characteristics, and functions of the various kinds of adipocytes, as well as their anatomic distribution inside the human body. This review mainly focuses on various essential transcriptional factors such as PRDM16, FGF21, PPARα, PPARγ and PGC-1α, which exert their effects on the development and activation of thermogenic adipocytes via important pathways such as JAK-STAT, cAMP-PKA and PI3K-AKT signaling pathways. Additionally, this review will underline promising strategies to generate an unexhausted source of thermogenic adipocytes differentiated from human stem cells. These exogenous thermogenic adipocytes offer therapeutic potential for improvement of metabolic disorders via application as single cell or whole tissue transplantation. Graphical abstract Caption is required. Please provide.
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Affiliation(s)
- Thi-Tuong Van Nguyen
- Stem Cell Institute, University of Science Ho Chi Minh City, Ho Chi Minh City, Viet Nam.,Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Viet Nam
| | - Vuong Van Vu
- Stem Cell Institute, University of Science Ho Chi Minh City, Ho Chi Minh City, Viet Nam.,Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Viet Nam
| | - Phuc Van Pham
- Stem Cell Institute, University of Science Ho Chi Minh City, Ho Chi Minh City, Viet Nam. .,Vietnam National University Ho Chi Minh City, Ho Chi Minh City, Viet Nam. .,Laboratory of Stem Cell Research and Application, University of Science Ho Chi Minh City, Ho Chi Minh City, Viet Nam.
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4
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New Role for Growth/Differentiation Factor 15 in the Survival of Transplanted Brown Adipose Tissues in Cooperation with Interleukin-6. Cells 2020; 9:cells9061365. [PMID: 32492819 PMCID: PMC7349565 DOI: 10.3390/cells9061365] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/18/2020] [Accepted: 05/27/2020] [Indexed: 12/15/2022] Open
Abstract
To identify factors involved in the earliest phase of the differentiation of human embryonic stem cells (hESCs) into brown adipocytes (BAs), we performed multi-time point microarray analyses. We found that growth/differentiation factor 15 (GDF15) expressions were specifically upregulated within three days of differentiation, when expressions of immature hESC markers were sustained. Although GDF15 expressions continued to increase in the subsequent differentiation phases, GDF15-deficient hESCs differentiated into mature BAs (Day 10) without apparent abnormalities. In addition, GDF15-deficient mice had normal brown adipose tissue (BAT) and were metabolically healthy. Unexpectedly, we found that interleukin-6 (IL6) expression was significantly lowered in the BAT of GDF15-/- mice. In addition, GDF15-/- hESCs showed abortive IL6 expressions in the later phase (>Day 6) of the differentiation. Interestingly, GDF15 expression was markedly repressed throughout the whole course of the differentiation of IL6-/- hESCs into BAs, indicating IL6 is essential for the induction of GDF15 in the differentiation of hESCs. Finally, intraperitoneally transplanted BAT grafts of GDF15-/- donor mice, but not those of wild-type (WT) mice, failed in the long-term survival (12 weeks) in GDF15-/- recipient mice. Collectively, GDF15 is required for long-term survival of BAT grafts by creating a mutual gene induction loop with IL6.
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Oka M, Kobayashi N, Matsumura K, Nishio M, Saeki K. Exogenous Cytokine-Free Differentiation of Human Pluripotent Stem Cells into Classical Brown Adipocytes. Cells 2019; 8:cells8040373. [PMID: 31022954 PMCID: PMC6523334 DOI: 10.3390/cells8040373] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/20/2019] [Accepted: 04/22/2019] [Indexed: 01/17/2023] Open
Abstract
We previously established a method for a directed differentiation of human pluripotent stem cells into classical brown adipocytes (BA) by forming aggregates via massive floating culture in the presence of a specific cytokine cocktail. However, use of recombinant cytokines requires significant cost. Moreover, an enforced differentiation by exogenously added cytokines may amend skewed differentiation propensity of patient’s pluripotent stem cells, providing unsatisfactory disease models. Therefore, an exogenous cytokine-free method, where cytokines required for differentiation are provided in an auto/paracrine manner mimicking natural developmental process, is beneficial. Here we show that, if human pluripotent stem cells are cultured as size-controlled spheroids (100–120 µm radius, 2000–2500 cells/spheroid) in a mutually segregated manner with half-change of the medium every other day, they differentiate into classical BA via an authentic MYF5-positive myoblast route in the absence of exogenous cytokines. Differentiated BA exerted thermogenic activity in transplanted mice in response to beta-adrenergic receptor agonist stimuli. The cytokine-free differentiation method has further advantages in exploring BATokines, BA-derived physiologically active substances. Indeed, we have found that BA produces an unknown small (<1000 Da), highly hydrophilic molecule that augments insulin secretion from pancreatic beta cells. Our upgraded technique will contribute to an advancement of stem cell study for diverse purposes.
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Affiliation(s)
- Masako Oka
- Department of Disease Control, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
| | - Norihiko Kobayashi
- Department of Disease Control, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
| | - Kazunori Matsumura
- Department of Disease Control, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
| | - Miwako Nishio
- Department of Disease Control, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
| | - Kumiko Saeki
- Department of Disease Control, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
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6
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Dong M, Lin J, Lim W, Jin W, Lee HJ. Role of brown adipose tissue in metabolic syndrome, aging, and cancer cachexia. Front Med 2017; 12:130-138. [PMID: 29119382 DOI: 10.1007/s11684-017-0555-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 04/29/2017] [Indexed: 02/07/2023]
Abstract
Brown adipose tissue (BAT) plays a fundamental role in maintaining body temperature by producing heat. BAT that had been know to exist only in mammals and the human neonate has received great attention for the treatment of obesity and diabetes due to its important function in energy metabolism, ever since it is recently reported that human adults have functional BAT. In addition, beige adipocytes, brown adipocytes in white adipose tissue (WAT), have also been shown to take part in whole body metabolism. Multiple lines of evidence demonstrated that transplantation or activation of BAT or/and beige adipocytes reversed obesity and improved insulin sensitivity. Furthermore, many genes involved in BATactivation and/or the recruitment of beige cells have been found, thereby providing new promising strategies for future clinical application of BAT activation to treat obesity and metabolic diseases. This review focuses on recent advances of BAT function in the metabolic aspect and the relationship between BAT and cancer cachexia, a pathological process accompanied with decreased body weight and increased energy expenditure in cancer patients. The underlying possible mechanisms to reduce BAT mass and its activity in the elderly are also discussed.
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Affiliation(s)
- Meng Dong
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,The University of the Chinese Academy of Sciences, Beijing, 100049, China
| | - Jun Lin
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,The University of the Chinese Academy of Sciences, Beijing, 100049, China
| | - Wonchung Lim
- Department of Sports Medicine, College of Health Science, Cheongju University, Cheongju, 363-764, Republic of Korea
| | - Wanzhu Jin
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Hyuek Jong Lee
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Center for Vascular Research, Institute for Basic Science (IBS), Daejeon, 34141, Republic of Korea.
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8
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Lin H, Li Q, Lei Y. Three-dimensional tissues using human pluripotent stem cell spheroids as biofabrication building blocks. Biofabrication 2017; 9:025007. [PMID: 28287080 DOI: 10.1088/1758-5090/aa663b] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
A recently emerged approach for tissue engineering is to biofabricate tissues using cellular spheroids as building blocks. Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), can be cultured to generate large numbers of cells and can presumably be differentiated into all the cell types of the human body in vitro, thus are an ideal cell source for biofabrication. We previously developed a hydrogel-based cell culture system that can economically produce large numbers of hPSC spheroids. With hPSCs and this culture system, there are two potential methods to biofabricate a desired tissue. In Method 1, hPSC spheroids are first utilized to biofabricate an hPSC tissue that is subsequently differentiated into the desired tissue. In Method 2, hPSC spheroids are first converted into tissue spheroids in the hydrogel-based culture system and the tissue spheroids are then utilized to biofabricate the desired tissue. In this paper, we systematically measured the fusion rates of hPSC spheroids without and with differentiation toward cortical and midbrain dopaminergic neurons and found spheroids' fusion rates dropped sharply as differentiation progressed. We found Method 1 was appropriate for biofabricating neural tissues.
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Affiliation(s)
- Haishuang Lin
- Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, Nebraska, United States of America
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9
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Lin H, Li Q, Lei Y. An Integrated Miniature Bioprocessing for Personalized Human Induced Pluripotent Stem Cell Expansion and Differentiation into Neural Stem Cells. Sci Rep 2017; 7:40191. [PMID: 28057917 PMCID: PMC5216399 DOI: 10.1038/srep40191] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 12/01/2016] [Indexed: 01/01/2023] Open
Abstract
Human induced pluripotent stem cells (iPSCs) are ideal cell sources for personalized cell therapies since they can be expanded to generate large numbers of cells and differentiated into presumably all the cell types of the human body in vitro. In addition, patient specific iPSC-derived cells induce minimal or no immune response in vivo. However, with current cell culture technologies and bioprocessing, the cost for biomanufacturing clinical-grade patient specific iPSCs and their derivatives are very high and not affordable for majority of patients. In this paper, we explored the use of closed and miniature cell culture device for biomanufacturing patient specific neural stem cells (NSCs) from iPSCs. We demonstrated that, with the assist of a thermoreversible hydrogel scaffold, the bioprocessing including iPSC expansion, iPSC differentiation into NSCs, the subsequent depletion of undifferentiated iPSCs from the NSCs, and concentrating and transporting the purified NSCs to the surgery room, could be integrated and completed within two closed 15 ml conical tubes.
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Affiliation(s)
- Haishuang Lin
- Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, Nebraska, USA
| | - Qiang Li
- Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, Nebraska, USA
| | - Yuguo Lei
- Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, Nebraska, USA.,Mary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, Nebraska, USA.,Fred &Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA
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Nishio M, Nakahara M, Yuo A, Saeki K. Human pluripotent stem cells: Towards therapeutic development for the treatment of lifestyle diseases. World J Stem Cells 2016; 8:56-61. [PMID: 26981171 PMCID: PMC4766251 DOI: 10.4252/wjsc.v8.i2.56] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 10/09/2015] [Accepted: 01/11/2016] [Indexed: 02/06/2023] Open
Abstract
There are two types of human pluripotent stem cells: Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), both of which launched themselves on clinical trials after having taken measures to overcome problems: Blocking rejections by immunosuppressants regarding ESCs and minimizing the risk of tumorigenicity by depleting exogenous gene components regarding iPSCs. It is generally assumed that clinical applications of human pluripotent stem cells should be limited to those cases where there are no alternative measures for treatments because of the risk in transplanting those cells to living bodies. Regarding lifestyle diseases, we have already several therapeutic options, and thus, development of human pluripotent stem cell-based therapeutics tends to be avoided. Nevertheless, human pluripotent stem cells can contribute to the development of new therapeutics in this field. As we will show, there is a case where only a short-term presence of human pluripotent stem-derived cells can exert long-term therapeutic effects even after they are rejected. In those cases, immunologically rejections of ESC- or allogenic iPSC-derived cells may produce beneficial outcomes by nullifying the risk of tumorigenesis without deterioration of therapeutic effects. Another utility of human pluripotent stem cells is the provision of an innovative tool for drug discovery that are otherwise unavailable. For example, clinical specimens of human classical brown adipocytes (BAs), which has been attracting a great deal of attention as a new target of drug discovery for the treatment of metabolic disorders, are unobtainable from living individuals due to scarcity, fragility and ethical problems. However, BA can easily be produced from human pluripotent stem cells. In this review, we will contemplate potential contribution of human pluripotent stem cells to therapeutic development for lifestyle diseases.
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Unser AM, Mooney B, Corr DT, Tseng YH, Xie Y. 3D brown adipogenesis to create "Brown-Fat-in-Microstrands". Biomaterials 2015; 75:123-134. [PMID: 26496384 DOI: 10.1016/j.biomaterials.2015.10.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 10/05/2015] [Accepted: 10/06/2015] [Indexed: 01/19/2023]
Abstract
The ability of brown adipocytes (fat cells) to dissipate energy as heat shows great promise for the treatment of obesity and other metabolic disorders. Employing pluripotent stem cells, with an emphasis on directed differentiation, may overcome many issues currently associated with primary fat cell cultures. In addition, three-dimensional (3D) cell culture systems are needed to better understand the role of brown adipocytes in energy balance and treating obesity. To address this need, we created 3D "Brown-Fat-in-Microstrands" by microfluidic synthesis of alginate hydrogel microstrands that encapsulated cells and directly induced cell differentiation into brown adipocytes, using mouse embryonic stem cells (ESCs) as a model of pluripotent stem cells, and brown preadipocytes as a positive control. Brown adipocyte differentiation within microstrands was confirmed by immunocytochemistry and qPCR analysis of the expression of the brown adipocyte-defining marker uncoupling protein 1 (UCP1), as well as other general adipocyte markers. Cells within microstrands were responsive to a β-adrenergic agonist with an increase in gene expression of thermogenic UCP1, indicating that these "Brown-Fat-in-Microstrands" are functional. The ability to create "Brown-Fat-in-Microstrands" from pluripotent stem cells opens up a new arena to understanding brown adipogenesis and its implications in obesity and metabolic disorders.
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Affiliation(s)
- Andrea M Unser
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA
| | - Bridget Mooney
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA
| | - David T Corr
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA
| | - Yu-Hua Tseng
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Yubing Xie
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA.
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12
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Unser AM, Tian Y, Xie Y. Opportunities and challenges in three-dimensional brown adipogenesis of stem cells. Biotechnol Adv 2015; 33:962-79. [PMID: 26231586 DOI: 10.1016/j.biotechadv.2015.07.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 07/07/2015] [Accepted: 07/23/2015] [Indexed: 12/21/2022]
Abstract
The formation of brown adipose tissue (BAT) via brown adipogenesis has become a notable process due to its ability to expend energy as heat with implications in the treatment of metabolic disorders and obesity. With the advent of complexity within white adipose tissue (WAT) along with inducible brown adipocytes (also known as brite and beige), there has been a surge in deciphering adipocyte biology as well as in vivo adipogenic microenvironments. A therapeutic outcome would benefit from understanding early events in brown adipogenesis, which can be accomplished by studying cellular differentiation. Pluripotent stem cells are an efficient model for differentiation and have been directed towards both white adipogenic and brown adipogenic lineages. The stem cell microenvironment greatly contributes to terminal cell fate and as such, has been mimicked extensively by various polymers including those that can form 3D hydrogel constructs capable of biochemical and/or mechanical modifications and modulations. Using bioengineering approaches towards the creation of 3D cell culture arrangements is more beneficial than traditional 2D culture in that it better recapitulates the native tissue biochemically and biomechanically. In addition, such an approach could potentially protect the tissue formed from necrosis and allow for more efficient implantation. In this review, we highlight the promise of brown adipocytes with a focus on brown adipogenic differentiation of stem cells using bioengineering approaches, along with potential challenges and opportunities that arise when considering the energy expenditure of BAT for prospective therapeutics.
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Affiliation(s)
- Andrea M Unser
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road Albany, NY 12203, USA
| | - Yangzi Tian
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road Albany, NY 12203, USA
| | - Yubing Xie
- Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road Albany, NY 12203, USA.
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Okla M, Ha JH, Temel RE, Chung S. BMP7 drives human adipogenic stem cells into metabolically active beige adipocytes. Lipids 2014; 50:111-20. [PMID: 25534037 DOI: 10.1007/s11745-014-3981-9] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 12/08/2014] [Indexed: 12/21/2022]
Abstract
Adult humans have a substantial amount of inducible-brown (or beige) fat, which is associated with increased energy expenditure and reduced weight gain via thermogenesis. Despite the identification of key regulators of beige adipogenesis, impacts of dietary factors on adaptive thermogenesis are largely unknown, partly due to a lack of validated human cell models. Bone morphogenetic protein 7 (BMP7) is known to promote brown adipogenesis in rodent and human progenitor cells. However, controversy still surrounds the cellular identity in BMP7-mediated transition of white to brown adipocytes. The aim of this study was to confirm BMP7-derived human adipocytes as a relevant in vitro model of human beige adipocyte by verifying the cellular lineage and metabolic activity. In this study, we hypothesized that pre-exposure of the stromal vascular (SV) fraction of primary human adipogenic precursor cells (hASC) to BMP7 would convert metabolically active brown adipocytes. Our results showed that exposure of hASC to human BMP7 was associated with significant escalation of (1) UCP1 gene expression, a signature gene of brown adipocytes, (2) beige specific marker gene expression (i.e., CD137 and TMEM26), (3) glucose and fatty acid uptake, and (4) basal and cAMP-stimulated oxygen consumption rate compared to white adipocyte control. Taken together, we demonstrated that BMP7 mediates conversion of hASC into metabolically active beige adipocytes. By confirming the cellular identity and metabolic activity, this BMP7-induced human beige adipocytes from hASC should aid in the discovery and assessment of bioactive molecules to promote adaptive thermogenesis.
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Affiliation(s)
- Meshail Okla
- Department of Nutrition and Health Sciences, University of Nebraska, 316G Ruth Leverton Hall, Lincoln, NE, 68583, USA
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Abstract
Adipose cells are an important source of mesenchymal stem cells and are important for direct use in research on lipid metabolism and obesity. In addition to use of primary cultures, there is increasing interest in other sources of larger numbers of cells, using approaches including induced pluripotent stem cell differentiation and viral immortalisation.
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