Cells

Research

14 pages, 4051 KiB

Open AccessArticle

CXCL16/CXCR6 Axis in Adipocytes Differentiated from Human Adipose Derived Mesenchymal Stem Cells Regulates Macrophage Polarization

by Seung-Cheol Lee, Yoo-Jung Lee, Inho Choi, Min Kim and Jung-Suk Sung

Cells 2021, 10(12), 3410; https://doi.org/10.3390/cells10123410 - 3 Dec 2021

Cited by 5 | Viewed by 3474

Abstract

Adipocytes interact with adipose tissue macrophages (ATMs) that exist as a form of M2 macrophage in healthy adipose tissue and are polarized into M1 macrophages upon cellular stress. ATMs regulate adipose tissue inflammation by secreting cytokines, adipokines, and chemokines. CXC-motif receptor 6 (CXCR6) [...] Read more.

Adipocytes interact with adipose tissue macrophages (ATMs) that exist as a form of M2 macrophage in healthy adipose tissue and are polarized into M1 macrophages upon cellular stress. ATMs regulate adipose tissue inflammation by secreting cytokines, adipokines, and chemokines. CXC-motif receptor 6 (CXCR6) is the chemokine receptor and interactions with its specific ligand CXC-motif chemokine ligand 16 (CXCL16) modulate the migratory capacities of human adipose-derived mesenchymal stem cells (hADMSCs). CXCR6 is highly expressed on differentiated adipocytes that are non-migratory cells. To evaluate the underlying mechanisms of CXCR6 in adipocytes, THP-1 human monocytes that can be polarized into M1 or M2 macrophages were co-cultured with adipocytes. As results, expression levels of the M1 polarization-inducing factor were decreased, while those of the M2 polarization-inducing factor were significantly increased in differentiated adipocytes in a co-cultured environment with additional CXCL16 treatment. After CXCL16 treatment, the anti-inflammatory factors, including p38 MAPK ad ERK1/2, were upregulated, while the pro-inflammatory pathway mediated by Akt and NF-κB was downregulated in adipocytes in a co-cultured environment. These results revealed that the CXCL16/CXCR6 axis in adipocytes regulates M1 or M2 polarization and displays an immunosuppressive effect by modulating pro-inflammatory or anti-inflammatory pathways. Our results may provide an insight into a potential target as a regulator of the immune response via the CXCL16/CXCR6 axis in adipocytes. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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17 pages, 7310 KiB

Open AccessArticle

Bioprinting and Differentiation of Adipose-Derived Stromal Cell Spheroids for a 3D Breast Cancer-Adipose Tissue Model

by Hannes Horder, Mar Guaza Lasheras, Nadine Grummel, Ali Nadernezhad, Johannes Herbig, Süleyman Ergün, Jörg Teßmar, Jürgen Groll, Ben Fabry, Petra Bauer-Kreisel and Torsten Blunk

Cells 2021, 10(4), 803; https://doi.org/10.3390/cells10040803 - 3 Apr 2021

Cited by 47 | Viewed by 8804

Abstract

Biofabrication, including printing technologies, has emerged as a powerful approach to the design of disease models, such as in cancer research. In breast cancer, adipose tissue has been acknowledged as an important part of the tumor microenvironment favoring tumor progression. Therefore, in this [...] Read more.

Biofabrication, including printing technologies, has emerged as a powerful approach to the design of disease models, such as in cancer research. In breast cancer, adipose tissue has been acknowledged as an important part of the tumor microenvironment favoring tumor progression. Therefore, in this study, a 3D-printed breast cancer model for facilitating investigations into cancer cell-adipocyte interaction was developed. First, we focused on the printability of human adipose-derived stromal cell (ASC) spheroids in an extrusion-based bioprinting setup and the adipogenic differentiation within printed spheroids into adipose microtissues. The printing process was optimized in terms of spheroid viability and homogeneous spheroid distribution in a hyaluronic acid-based bioink. Adipogenic differentiation after printing was demonstrated by lipid accumulation, expression of adipogenic marker genes, and an adipogenic ECM profile. Subsequently, a breast cancer cell (MDA-MB-231) compartment was printed onto the adipose tissue constructs. After nine days of co-culture, we observed a cancer cell-induced reduction of the lipid content and a remodeling of the ECM within the adipose tissues, with increased fibronectin, collagen I and collagen VI expression. Together, our data demonstrate that 3D-printed breast cancer-adipose tissue models can recapitulate important aspects of the complex cell–cell and cell–matrix interplay within the tumor-stroma microenvironment. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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12 pages, 18910 KiB

Open AccessArticle

D-Mannitol Induces a Brown Fat-like Phenotype via a β3-Adrenergic Receptor-Dependent Mechanism

by Hui-Jeon Jeon, Dong Kyu Choi, JaeHeon Choi, Seul Lee, Heejin Lee, Ji Hoon Yu and Sang-Hyun Min

Cells 2021, 10(4), 768; https://doi.org/10.3390/cells10040768 - 31 Mar 2021

Cited by 12 | Viewed by 4028

Abstract

The presence of brown adipocytes within white adipose tissue is associated with phenotypes that exhibit improved metabolism and proper body weight maintenance. Therefore, a variety of dietary agents that facilitate the browning of white adipocytes have been investigated. In this study, we screened [...] Read more.

The presence of brown adipocytes within white adipose tissue is associated with phenotypes that exhibit improved metabolism and proper body weight maintenance. Therefore, a variety of dietary agents that facilitate the browning of white adipocytes have been investigated. In this study, we screened a natural product library comprising 133 compounds with the potential to promote the browning of white adipocytes, and found that D-mannitol induces the browning of 3T3-L1 adipocytes by enhancing the expression of brown fat-specific genes and proteins, and upregulating lipid metabolism markers. D-mannitol also increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase 1 (ACC), suggesting a possible role in lipolysis and fat oxidation. Moreover, an increase in the expression of genes associated with D-mannitol-induced browning was strongly correlated with the activation of the β3-adrenergic receptor as well as AMPK, protein kinase A (PKA), and PPARγ coactivator 1α (PGC1α). D-mannitol effectively reduced the body weight of mice fed a high-fat diet, and increased the expression of β1-oxidation and energy expenditure markers, such as Cidea, carnitine palmityl transferase 1 (CPT1), uncoupling protein 1 (UCP1), PGC1α, and acyl-coenzyme A oxidase (ACOX1) in the inguinal white adipose tissue. Our findings suggest that D-mannitol plays a dual regulatory role by inducing the generation of a brown fat-like phenotype and enhancing lipid metabolism. These results indicate that D-mannitol can function as an anti-obesity supplement. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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35 pages, 10172 KiB

Open AccessArticle

Chemically Defined Xeno- and Serum-Free Cell Culture Medium to Grow Human Adipose Stem Cells

by Stefano Panella, Francesco Muoio, Valentin Jossen, Yves Harder, Regine Eibl-Schindler and Tiziano Tallone

Cells 2021, 10(2), 466; https://doi.org/10.3390/cells10020466 - 22 Feb 2021

Cited by 10 | Viewed by 5681

Abstract

Adipose tissue is an abundant source of stem cells. However, liposuction cannot yield cell quantities sufficient for direct applications in regenerative medicine. Therefore, the development of GMP-compliant ex vivo expansion protocols is required to ensure the production of a “cell drug” that is [...] Read more.

Adipose tissue is an abundant source of stem cells. However, liposuction cannot yield cell quantities sufficient for direct applications in regenerative medicine. Therefore, the development of GMP-compliant ex vivo expansion protocols is required to ensure the production of a “cell drug” that is safe, reproducible, and cost-effective. Thus, we developed our own basal defined xeno- and serum-free cell culture medium (UrSuppe), specifically formulated to grow human adipose stem cells (hASCs). With this medium, we can directly culture the stromal vascular fraction (SVF) cells in defined cell culture conditions to obtain hASCs. Cells proliferate while remaining undifferentiated, as shown by Flow Cytometry (FACS), Quantitative Reverse Transcription PCR (RT-qPCR) assays, and their secretion products. Using the UrSuppe cell culture medium, maximum cell densities between 0.51 and 0.80 × 10⁵ cells/cm² (=2.55–4.00 × 10⁵ cells/mL) were obtained. As the expansion of hASCs represents only the first step in a cell therapeutic protocol or further basic research studies, we formulated two chemically defined media to differentiate the expanded hASCs in white or beige/brown adipocytes. These new media could help translate research projects into the clinical application of hASCs and study ex vivo the biology in healthy and dysfunctional states of adipocytes and their precursors. Following the cell culture system developers’ practice and obvious reasons related to the formulas’ patentability, the defined media’s composition will not be disclosed in this study. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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13 pages, 2839 KiB

Open AccessArticle

Multiplex Analysis of Adipose-Derived Stem Cell (ASC) Immunophenotype Adaption to In Vitro Expansion

by Qiuyue Peng, Martyna Duda, Guoqiang Ren, Zongzhe Xuan, Cristian Pablo Pennisi, Simone Riis Porsborg, Trine Fink and Vladimir Zachar

Cells 2021, 10(2), 218; https://doi.org/10.3390/cells10020218 - 22 Jan 2021

Cited by 6 | Viewed by 3058

Abstract

In order to enhance the therapeutic potential, it is important that sufficient knowledge regarding the dynamic changes of adipose-derived stem cell (ASC) immunophenotypical and biological properties during in vitro growth is available. Consequently, we embarked on a study to follow the evolution of [...] Read more.

In order to enhance the therapeutic potential, it is important that sufficient knowledge regarding the dynamic changes of adipose-derived stem cell (ASC) immunophenotypical and biological properties during in vitro growth is available. Consequently, we embarked on a study to follow the evolution of highly defined cell subsets from three unrelated donors in the course of eight passages on tissue culture polystyrene. The co-expression patterns were defined by panels encompassing seven and five cell surface markers, including CD34, CD146, CD166, CD200, CD248, CD271, and CD274 and CD29, CD31, CD36, CD201, and Stro-1, respectively. The analysis was performed using multichromatic flow cytometry. We observed a major paradigm shift, where the CD166-CD34⁺ combination which was found across all cell subsets early in the culture was replaced by the CD166⁺ phenotype as the population homogeneity increased with time. At all analysis points, the cultures were dominated by a few major clones that were highly prevalent in most of the donors. The selection process resulted in two predominant clones in the larger panel (CD166⁺CD34⁻CD146⁻CD271⁻ CD274⁻CD248⁻CD200⁻ and CD166⁺CD34⁺ CD146⁻CD271⁻CD274⁻CD248⁻CD200⁻) and one clone in the smaller panel (CD29⁺CD201⁺CD36⁻ Stro-1⁻ CD31⁻). The minor subsets, including CD166⁺CD34⁻CD146⁻CD271⁺CD274⁻CD248⁻CD200⁻ and CD166⁺CD34⁺CD146⁺CD271⁻CD274⁻CD248⁻CD200⁻, and CD29⁺CD201⁻CD36⁻Stro-1⁻CD31⁻, CD29⁺CD201⁺CD36⁻Stro-1⁺CD31⁻, and CD29⁺CD201⁺CD36⁺Stro-1⁻CD31⁻, in the seven and five marker panels, respectively, were, on the other, hand highly fluctuating and donor-dependent. The results demonstrate that only a limited number of phenotypical repertoires are possible in ASC cultures. Marked differences in their relative occurrence between distinct individuals underscore the need for potency standardization of different ASC preparation to improve the clinical outcome. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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15 pages, 3519 KiB

Open AccessArticle

Human Adipose-Derived Stem Cells in Madelung’s Disease: Morphological and Functional Characterization

by Federica Caponnetto, Ivana Manini, Michela Bulfoni, Nicola Zingaretti, Giovanni Miotti, Carla Di Loreto, Daniela Cesselli, Laura Mariuzzi and Pier Camillo Parodi

Cells 2021, 10(1), 44; https://doi.org/10.3390/cells10010044 - 30 Dec 2020

Cited by 7 | Viewed by 2749

Abstract

Madelung Disease (MD) is a syndrome characterized by the accumulation of aberrant symmetric adipose tissue deposits. The etiology of this disease is yet to be elucidated, even though the presence of comorbidities, either genetic or environmental, has been reported. For this reason, establishing [...] Read more.

Madelung Disease (MD) is a syndrome characterized by the accumulation of aberrant symmetric adipose tissue deposits. The etiology of this disease is yet to be elucidated, even though the presence of comorbidities, either genetic or environmental, has been reported. For this reason, establishing an in vitro model for MD is considered crucial to get insights into its physiopathology. We previously established a protocol for isolation and culture of stem cells from diseased tissues. Therefore, we isolated human adipose-derived stem cells (ASC) from MD patients and compared these cells with those isolated from healthy subjects in terms of surface phenotype, growth kinetic, adipogenic differentiation potential, and molecular alterations. Moreover, we evaluated the ability of the MD-ASC secretome to affect healthy ASC. The results reported a difference in the growth kinetic and surface markers of MD-ASC compared to healthy ASC but not in adipogenic differentiation. The most commonly described mitochondrial mutations were not observed. Still, MD-ASC secretome was able to shift the healthy ASC phenotype to an MD phenotype. This work provides evidence of the possibility of exploiting a patient-based in vitro model for better understanding MD pathophysiology, possibly favoring the development of novel target therapies. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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17 pages, 5233 KiB

Open AccessFeature PaperArticle

The Primary Cilium of Adipose Progenitors Is Necessary for Their Differentiation into Cancer-Associated Fibroblasts that Promote Migration of Breast Cancer Cells In Vitro

by Pascal Peraldi, Annie Ladoux, Sophie Giorgetti-Peraldi and Christian Dani

Cells 2020, 9(10), 2251; https://doi.org/10.3390/cells9102251 - 8 Oct 2020

Cited by 4 | Viewed by 2614

Abstract

Cancer associated fibroblasts (CAFs) are central elements of the microenvironment that control tumor development. In breast cancer, CAFs can originate from adipose progenitors (APs). We, and others, have shown that the primary cilium, an antenna-shaped organelle, controls several aspects of APs’ biology. We [...] Read more.

Cancer associated fibroblasts (CAFs) are central elements of the microenvironment that control tumor development. In breast cancer, CAFs can originate from adipose progenitors (APs). We, and others, have shown that the primary cilium, an antenna-shaped organelle, controls several aspects of APs’ biology. We studied the conversion of human APs into CAFs by breast cancer cell lines (BCCs). Deletion of the cilium of APs by a pharmacological inhibitor, or by siRNA, allow us to demonstrate that the cilium is necessary for the differentiation of APs into CAFs. BCCs increase production of TGF-β1 by APs, which is a known inducer of CAFs. Pharmacological inhibition of TGF-β1 signaling in APs prevents their conversion into CAFs. Since we previously showed that deletion of the APs’ cilium inhibits TGF-β1 signaling, we propose that BCCs induce TGF-β1 production in Aps, which binds to the primary cilium of Aps and leads to their differentiation into CAFs. Inhibition of APs conversion into CAFs induces a loss in some of the biological effects of CAFs since deletion of the cilium of APs decreases their effect on the migration of BCCs. This is the first observation of a function of the cilium of APs in their conversion into CAFs, and its consequences on BCCs. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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17 pages, 1568 KiB

Open AccessArticle

Short-Term Rapamycin Preconditioning Diminishes Therapeutic Efficacy of Human Adipose-Derived Stem Cells in a Murine Model of Multiple Sclerosis

by Rachel M. Wise, Mark A. A. Harrison, Brianne N. Sullivan, Sara Al-Ghadban, Sarah J. Aleman, Amber T. Vinluan, Emily R. Monaco, Umberto M. Donato, India A. Pursell and Bruce A. Bunnell

Cells 2020, 9(10), 2218; https://doi.org/10.3390/cells9102218 - 30 Sep 2020

Cited by 6 | Viewed by 3488

Abstract

Human adipose-derived stem cells (ASCs) show immense promise for treating inflammatory diseases, attributed primarily to their potent paracrine signaling. Previous investigations demonstrated that short-term Rapamycin preconditioning of bone marrow-derived stem cells (BMSCs) elevated secretion of prostaglandin E2, a pleiotropic molecule with therapeutic effects [...] Read more.

Human adipose-derived stem cells (ASCs) show immense promise for treating inflammatory diseases, attributed primarily to their potent paracrine signaling. Previous investigations demonstrated that short-term Rapamycin preconditioning of bone marrow-derived stem cells (BMSCs) elevated secretion of prostaglandin E2, a pleiotropic molecule with therapeutic effects in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), and enhanced immunosuppressive capacity in vitro. However, this has yet to be examined in ASCs. The present study examined the therapeutic potential of short-term Rapamycin-preconditioned ASCs in the EAE model. Animals were treated at peak disease with control ASCs (EAE-ASCs), Rapa-preconditioned ASCs (EAE-Rapa-ASCs), or vehicle control (EAE). Results show that EAE-ASCs improved clinical disease scores and elevated intact myelin compared to both EAE and EAE-Rapa-ASC animals. These results correlated with augmented CD4⁺ T helper (T_h) and T regulatory (T_reg) cell populations in the spinal cord, and increased gene expression of interleukin-10 (IL-10), an anti-inflammatory cytokine. Conversely, EAE-Rapa-ASC mice showed no improvement in clinical disease scores, reduced myelin levels, and significantly less T_h and T_reg cells in the spinal cord. These findings suggest that short-term Rapamycin preconditioning reduces the therapeutic efficacy of ASCs when applied to late-stage EAE. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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20 pages, 7660 KiB

Open AccessArticle

Ischemia-Like Stress Conditions Stimulate Trophic Activities of Adipose-Derived Stromal/Stem Cells

by Julia Bachmann, Elias Ehlert, Matthias Becker, Christoph Otto, Katrin Radeloff, Torsten Blunk and Petra Bauer-Kreisel

Cells 2020, 9(9), 1935; https://doi.org/10.3390/cells9091935 - 21 Aug 2020

Cited by 9 | Viewed by 4285

Abstract

Adipose-derived stromal/stem cells (ASCs) have been shown to exert regenerative functions, which are mainly attributed to the secretion of trophic factors. Upon transplantation, ASCs are facing an ischemic environment characterized by oxygen and nutrient deprivation. However, current knowledge on the secretion capacity of [...] Read more.

Adipose-derived stromal/stem cells (ASCs) have been shown to exert regenerative functions, which are mainly attributed to the secretion of trophic factors. Upon transplantation, ASCs are facing an ischemic environment characterized by oxygen and nutrient deprivation. However, current knowledge on the secretion capacity of ASCs under such conditions is limited. Thus, the present study focused on the secretory function of ASCs under glucose and oxygen deprivation as major components of ischemia. After exposure to glucose/oxygen deprivation, ASCs maintained distinct viability, but the metabolic activity was greatly reduced by glucose limitation. ASCs were able to secrete a broad panel of factors under glucose/oxygen deprivation as revealed by a cytokine antibody array. Quantification of selected factors by ELISA demonstrated that glucose deprivation in combination with hypoxia led to markedly higher secretion levels of the angiogenic and anti-apoptotic factors IL-6, VEGF, and stanniocalcin-1 as compared to the hypoxic condition alone. A conditioned medium of glucose/oxygen-deprived ASCs promoted the viability and tube formation of endothelial cells, and the proliferation and migration of fibroblasts. These findings indicate that ASCs are stimulated by ischemia-like stress conditions to secrete trophic factors and would be able to exert their beneficial function in an ischemic environment. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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27 pages, 5800 KiB

Open AccessArticle

Beneficial Effect of IL-4 and SDF-1 on Myogenic Potential of Mouse and Human Adipose Tissue-Derived Stromal Cells

by Karolina Archacka, Joanna Bem, Edyta Brzoska, Areta M. Czerwinska, Iwona Grabowska, Paulina Kasprzycka, Dzesika Hoinkis, Katarzyna Siennicka, Zygmunt Pojda, Patrycja Bernas, Robert Binkowski, Kinga Jastrzebska, Aleksandra Kupiec, Malgorzata Malesza, Emilia Michalczewska, Marta Soszynska, Katarzyna Ilach, Wladyslawa Streminska and Maria A. Ciemerych

Cells 2020, 9(6), 1479; https://doi.org/10.3390/cells9061479 - 17 Jun 2020

Cited by 12 | Viewed by 3419

Abstract

Under physiological conditions skeletal muscle regeneration depends on the satellite cells. After injury these cells become activated, proliferate, and differentiate into myofibers reconstructing damaged tissue. Under pathological conditions satellite cells are not sufficient to support regeneration. For this reason, other cells are sought [...] Read more.

Under physiological conditions skeletal muscle regeneration depends on the satellite cells. After injury these cells become activated, proliferate, and differentiate into myofibers reconstructing damaged tissue. Under pathological conditions satellite cells are not sufficient to support regeneration. For this reason, other cells are sought to be used in cell therapies, and different factors are tested as a tool to improve the regenerative potential of such cells. Many studies are conducted using animal cells, omitting the necessity to learn about human cells and compare them to animal ones. Here, we analyze and compare the impact of IL-4 and SDF-1, factors chosen by us on the basis of their ability to support myogenic differentiation and cell migration, at mouse and human adipose tissue-derived stromal cells (ADSCs). Importantly, we documented that mouse and human ADSCs differ in certain reactions to IL-4 and SDF-1. In general, the selected factors impacted transcriptome of ADSCs and improved migration and fusion ability of cells in vitro. In vivo, after transplantation into injured muscles, mouse ADSCs more eagerly participated in new myofiber formation than the human ones. However, regardless of the origin, ADSCs alleviated immune response and supported muscle reconstruction, and cytokine treatment enhanced these effects. Thus, we documented that the presence of ADSCs improves skeletal muscle regeneration and this influence could be increased by cell pretreatment with IL-4 and SDF-1. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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16 pages, 3006 KiB

Open AccessArticle

Allogeneic ADSCs Induce the Production of Alloreactive Memory-CD8 T Cells through HLA-ABC Antigens

by Sung-Ho Chang, Hyun Je Kim and Chung-Gyu Park

Cells 2020, 9(5), 1246; https://doi.org/10.3390/cells9051246 - 18 May 2020

Cited by 10 | Viewed by 3429

Abstract

We investigated the immunogenicity of allogeneic human adipose-derived mesenchymal stem cells (ADSCs) through the production of alloreactive-CD8 T and -memory CD8 T cells, based on their human leukocyte antigen (HLA) expression. In surface antigen analysis, ADSCs do not express co-stimulatory molecules, but expresses [...] Read more.

We investigated the immunogenicity of allogeneic human adipose-derived mesenchymal stem cells (ADSCs) through the production of alloreactive-CD8 T and -memory CD8 T cells, based on their human leukocyte antigen (HLA) expression. In surface antigen analysis, ADSCs do not express co-stimulatory molecules, but expresses HLA-ABC, which is further increased by exposure to the pro-inflammatory cytokines as well as IFN-γ alone. For immunogenicity analysis, allogeneic ADSCs cultured in xenofree medium (XF-ADSCs) were incubated with the recipient immune cells for allogeneic–antigen stimulation. As a result, XF-ADSCs induced IFN-γ and IL-17A release by alloreactive-CD8 T cells and the production of alloreactive-CD8 T cell through a direct pathway, although they have immunomodulatory activity. In the analysis of alloreactive memory CD8 T cells, XF-ADSCs also significantly induced the production of CFSE-low-CD8 TEM and -CD8 TCM cells. However, HLA-blocking antibodies significantly inhibited the production of CFSE-low memory-CD8 T cells, indicating that HLAs are the main antigens responsible for the development of allogeneic ADSCs’ immunogenicity. These results suggested that HLA surface antigens expressed in allogeneic MSCs should be solved in order to address concerns related to the immunogenicity problem. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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25 pages, 47197 KiB

Open AccessArticle

FTO Intronic SNP Strongly Influences Human Neck Adipocyte Browning Determined by Tissue and PPARγ Specific Regulation: A Transcriptome Analysis

by Beáta B. Tóth, Rini Arianti, Abhirup Shaw, Attila Vámos, Zoltán Veréb, Szilárd Póliska, Ferenc Győry, Zsolt Bacso, László Fésüs and Endre Kristóf

Cells 2020, 9(4), 987; https://doi.org/10.3390/cells9040987 - 16 Apr 2020

Cited by 21 | Viewed by 4744

Abstract

Brown adipocytes, abundant in deep-neck (DN) area in humans, are thermogenic with anti-obesity potential. FTO pro-obesity rs1421085 T-to-C single-nucleotide polymorphism (SNP) shifts differentiation program towards white adipocytes in subcutaneous fat. Human adipose-derived stromal cells were obtained from subcutaneous neck (SC) and DN fat [...] Read more.

Brown adipocytes, abundant in deep-neck (DN) area in humans, are thermogenic with anti-obesity potential. FTO pro-obesity rs1421085 T-to-C single-nucleotide polymorphism (SNP) shifts differentiation program towards white adipocytes in subcutaneous fat. Human adipose-derived stromal cells were obtained from subcutaneous neck (SC) and DN fat of nine donors, of which 3-3 carried risk-free (T/T), heterozygous or obesity-risk (C/C) FTO genotypes. They were differentiated to white and brown (long-term Peroxisome proliferator-activated receptor gamma (PPARγ) stimulation) adipocytes; then, global RNA sequencing was performed and differentially expressed genes (DEGs) were compared. DN and SC progenitors had similar adipocyte differentiation potential but differed in DEGs. DN adipocytes displayed higher browning features according to ProFAT or BATLAS scores and characteristic DEG patterns revealing associated pathways which were highly expressed (thermogenesis, interferon, cytokine, and retinoic acid, with UCP1 and BMP4 as prominent network stabilizers) or downregulated (particularly extracellular matrix remodeling) compared to SC ones. Part of DEGs in either DN or SC browning was PPARγ-dependent. Presence of the FTO obesity-risk allele suppressed the expression of mitochondrial and thermogenesis genes with a striking resemblance between affected pathways and those appearing in ProFAT and BATLAS, underlining the importance of metabolic and mitochondrial pathways in thermogenesis. Among overlapping regulatory influences that determine browning and thermogenic potential of neck adipocytes, FTO genetic background has a thus far not recognized prominence. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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13 pages, 2790 KiB

Open AccessArticle

Increase in Leptin and PPAR-γ Gene Expression in Lipedema Adipocytes Differentiated in vitro from Adipose-Derived Stem Cells

by Sara Al-Ghadban, Zaidmara T. Diaz, Hallie J. Singer, Karya B. Mert and Bruce A. Bunnell

Cells 2020, 9(2), 430; https://doi.org/10.3390/cells9020430 - 12 Feb 2020

Cited by 29 | Viewed by 7902

Abstract

Lipedema is a painful loose connective tissue disorder characterized by a bilaterally symmetrical fat deposition in the lower extremities. The goal of this study was to characterize the adipose-derived stem cells (ASCs) of healthy and lipedema patients by the expression of stemness markers [...] Read more.

Lipedema is a painful loose connective tissue disorder characterized by a bilaterally symmetrical fat deposition in the lower extremities. The goal of this study was to characterize the adipose-derived stem cells (ASCs) of healthy and lipedema patients by the expression of stemness markers and the adipogenic and osteogenic differentiation potential. Forty patients, 20 healthy and 20 with lipedema, participated in this study. The stromal vascular fraction (SVF) was obtained from subcutaneous thigh (SVF-T) and abdomen (SVF-A) fat and plated for ASCs characterization. The data show a similar expression of mesenchymal markers, a significant increase in colonies (p < 0.05) and no change in the proliferation rate in ASCs isolated from the SVF-T or SVF-A of lipedema patients compared with healthy patients. The leptin gene expression was significantly increased in lipedema adipocytes differentiated from ASCs-T (p = 0.04) and the PPAR-γ expression was significantly increased in lipedema adipocytes differentiated from ASCs-A (p = 0.03) compared to the corresponding cells from healthy patients. No significant changes in the expression of genes associated with inflammation were detected in lipedema ASCs or differentiated adipocytes. These results suggest that lipedema ASCs isolated from SVF-T and SVF-A have a higher adipogenic differentiation potential compared to healthy ASCs. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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Review

Jump to: Research, Other

19 pages, 3178 KiB

Open AccessReview

Human Adipose-Derived Stromal/Stem Cell Culture and Analysis Methods for Adipose Tissue Modeling In Vitro: A Systematic Review

by Peyton Gibler, Jeffrey Gimble, Katie Hamel, Emma Rogers, Michael Henderson, Xiying Wu, Spencer Olesky and Trivia Frazier

Cells 2021, 10(6), 1378; https://doi.org/10.3390/cells10061378 - 3 Jun 2021

Cited by 12 | Viewed by 7005

Abstract

Human adipose-derived stromal/stem cells (hASC) are widely used for in vitro modeling of physiologically relevant human adipose tissue. These models are useful for the development of tissue constructs for soft tissue regeneration and 3-dimensional (3D) microphysiological systems (MPS) for drug discovery. In this [...] Read more.

Human adipose-derived stromal/stem cells (hASC) are widely used for in vitro modeling of physiologically relevant human adipose tissue. These models are useful for the development of tissue constructs for soft tissue regeneration and 3-dimensional (3D) microphysiological systems (MPS) for drug discovery. In this systematic review, we report on the current state of hASC culture and assessment methods for adipose tissue engineering using 3D MPS. Our search efforts resulted in the identification of 184 independent records, of which 27 were determined to be most relevant to the goals of the present review. Our results demonstrate a lack of consensus on methods for hASC culture and assessment for the production of physiologically relevant in vitro models of human adipose tissue. Few studies have assessed the impact of different 3D culture conditions on hASC adipogenesis. Additionally, there has been a limited use of assays for characterizing the functionality of adipose tissue in vitro. Results from this study suggest the need for more standardized culture methods and further analysis on in vitro tissue functionality. These will be necessary to validate the utility of 3D MPS as an in vitro model to reduce, refine, and replace in vivo experiments in the drug discovery regulatory process. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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21 pages, 1522 KiB

Open AccessReview

Modeling Adipogenesis: Current and Future Perspective

by Hisham F. Bahmad, Reem Daouk, Joseph Azar, Jiranuwat Sapudom, Jeremy C. M. Teo, Wassim Abou-Kheir and Mohamed Al-Sayegh

Cells 2020, 9(10), 2326; https://doi.org/10.3390/cells9102326 - 20 Oct 2020

Cited by 45 | Viewed by 9102

Abstract

Adipose tissue is contemplated as a dynamic organ that plays key roles in the human body. Adipogenesis is the process by which adipocytes develop from adipose-derived stem cells to form the adipose tissue. Adipose-derived stem cells’ differentiation serves well beyond the simple goal [...] Read more.

Adipose tissue is contemplated as a dynamic organ that plays key roles in the human body. Adipogenesis is the process by which adipocytes develop from adipose-derived stem cells to form the adipose tissue. Adipose-derived stem cells’ differentiation serves well beyond the simple goal of producing new adipocytes. Indeed, with the current immense biotechnological advances, the most critical role of adipose-derived stem cells remains their tremendous potential in the field of regenerative medicine. This review focuses on examining the physiological importance of adipogenesis, the current approaches that are employed to model this tightly controlled phenomenon, and the crucial role of adipogenesis in elucidating the pathophysiology and potential treatment modalities of human diseases. The future of adipogenesis is centered around its crucial role in regenerative and personalized medicine. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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Other

Jump to: Research, Review

16 pages, 1255 KiB

Open AccessLetter

Epigenetic Regulation of Neuregulin-1 Tunes White Adipose Stem Cell Differentiation

by Alyssa D. Cordero, Evan C. Callihan, Rana Said, Yasir Alowais, Emily S. Paffhausen and John R. Bracht

Cells 2020, 9(5), 1148; https://doi.org/10.3390/cells9051148 - 7 May 2020

Cited by 3 | Viewed by 3390

Abstract

Expansion of subcutaneous adipose tissue by differentiation of new adipocytes has been linked to improvements in metabolic health. However, an expandability limit has been observed wherein new adipocytes cannot be produced, the existing adipocytes become enlarged (hypertrophic) and lipids spill over into ectopic [...] Read more.

Expansion of subcutaneous adipose tissue by differentiation of new adipocytes has been linked to improvements in metabolic health. However, an expandability limit has been observed wherein new adipocytes cannot be produced, the existing adipocytes become enlarged (hypertrophic) and lipids spill over into ectopic sites. Inappropriate ectopic storage of these surplus lipids in liver, muscle, and visceral depots has been linked with metabolic dysfunction. Here we show that Neuregulin-1 (NRG1) serves as a regulator of adipogenic differentiation in subcutaneous primary human stem cells. We further demonstrate that DNA methylation modulates NRG1 expression in these cells, and a 3-day exposure of stem cells to a recombinant NRG1 peptide fragment is sufficient to reprogram adipogenic cellular differentiation to higher levels. These results define a novel molecular adipogenic rheostat with potential implications for the expansion of adipose tissue in vivo. Full article

(This article belongs to the Special Issue Human Adipose Stem Cells)

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