ω-3 polyunsaturated fatty acids direct differentiation of the membrane phenotype in mesenchymal stem cells to potentiate osteogenesis

Levental, Kandice R.; Surma, Michał A.; Skinkle, Allison D.; Lorent, Joseph H.; Zhou, Yong; Klose, Christian; Chang, Jeffrey T.; Hancock, John F.; Levental, Ilya

doi:10.1126/sciadv.aao1193

Cited by 113 publications

(127 citation statements)

References 82 publications

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“…DHA supplementation enhances Akt activation at plasma membrane and thereby potentiates osteogenic differentiation. 222 Long-term and high-dose treatment of inflammatory diseases with Dex facilitates apoptosis of BMMSCs, leading to bone loss and associated metabolic bone diseases. 223,224 These effects can be eliminated by EPA via activating autophagy and suppressing apoptosis of BMMSCs.…”

Section: Fatty Acids As Positive Activators Of Bmmscsmentioning

confidence: 99%

Therapeutic potentials and modulatory mechanisms of fatty acids in bone

et al. 2019

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Bone metabolism is a lifelong process that includes bone formation and resorption. Osteoblasts and osteoclasts are the predominant cell types associated with bone metabolism, which is facilitated by other cells such as bone marrow mesenchymal stem cells (BMMSCs), osteocytes and chondrocytes. As an important component in our daily diet, fatty acids are mainly categorized as long‐chain fatty acids including polyunsaturated fatty acids (LCPUFAs), monounsaturated fatty acids (LCMUFAs), saturated fatty acids (LCSFAs), medium‐/short‐chain fatty acids (MCFAs/SCFAs) as well as their metabolites. Fatty acids are closely associated with bone metabolism and associated bone disorders. In this review, we summarized the important roles and potential therapeutic implications of fatty acids in multiple bone disorders, reviewed the diverse range of critical effects displayed by fatty acids on bone metabolism, and elucidated their modulatory roles and mechanisms on specific bone cell types. The evidence supporting close implications of fatty acids in bone metabolism and disorders suggests fatty acids as potential therapeutic and nutritional agents for the treatment and prevention of metabolic bone diseases.

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Section: Fatty Acids As Positive Activators Of Bmmscsmentioning

confidence: 99%

Therapeutic potentials and modulatory mechanisms of fatty acids in bone

et al. 2019

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“…An elegant strategy to yield compartment systems with more complex composition is based on the generation of cell‐derived giant plasma membrane vesicles (GPMVs) . The membrane and internal composition directly mirror the composition of the cells from which they originated, except for larger cellular organelles and intracellular structures (e.g., nuclei, Golgi apparatus, vesicles) .…”

Section: Introductionmentioning

confidence: 99%

Bioinspired Molecular Factories with Architecture and In Vivo Functionalities as Cell Mimics

et al. 2020

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Despite huge need in the medical domain and significant development efforts, artificial cells to date have limited composition and functionality. Although some artificial cells have proven successful for producing therapeutics or performing in vitro specific reactions, they have not been investigated in vivo to determine whether they preserve their architecture and functionality while avoiding toxicity. Here, these limitations are overcome and customizable cell mimic is achieved—molecular factories (MFs)—by supplementing giant plasma membrane vesicles derived from donor cells with nanometer‐sized artificial organelles (AOs). MFs inherit the donor cell's natural cytoplasm and membrane, while the AOs house reactive components and provide cell‐like architecture and functionality. It is demonstrated that reactions inside AOs take place in a close‐to‐nature environment due to the unprecedented level of complexity in the composition of the MFs. It is further demonstrated that in a zebrafish vertebrate animal model, these cell mimics show no apparent toxicity and retain their integrity and function. The unique advantages of highly varied composition, multicompartmentalized architecture, and preserved functionality in vivo open new biological avenues ranging from the study of biorelevant processes in robust cell‐like environments to the production of specific bioactive compounds.

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“…2 Dysregulation of this balance is linked to pathophysiologic states. 8,9 In addition, sphingosine-1-phosphate, ceramide-1-phosphate, and ω-3 polyunsaturated fatty acids have been shown to regulate the differentiation of MSCs, [10][11][12] but the detailed mechanisms of MSC differentiation are not fully understood. 3,4 Although each lineage-specific factor is needed for fate determination, the exact governing mechanism is not clearly defined.…”

Section: Introductionmentioning

confidence: 99%

“…When MSCs differentiate into osteoblasts, gangliosides GD1a and GM1 are increased, and they promote osteogenic differentiation. 8,9 In addition, sphingosine-1-phosphate, ceramide-1-phosphate, and ω-3 polyunsaturated fatty acids have been shown to regulate the differentiation of MSCs, [10][11][12] but the detailed mechanisms of MSC differentiation are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Glucosylceramide synthase regulates adipo‐osteogenic differentiation through synergistic activation of PPARγ with GlcCer

et al. 2019

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Abbreviations: A/B, N-terminal regulatory domain; AIM, adipogenic induction medium; ALP, alkaline phosphatase; AMP-DNM, N-(5-adamantane-1-ylmethoxy-pentyl)-deoxynojirimycin; aP2, adipocyte protein 2; ATF2, activating transcription factor 2; BMP2, bone morphogenetic protein 2; BV, bone volume; C/EBPα, CCAAT-enhancer binding protein α AbstractDysregulation of the adipo-osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and osteoporosis. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation; however, the detailed underlying mechanisms are largely unknown. Here, we demonstrate that glucosylceramide (GlcCer) and its synthase, glucosylceramide synthase (GCS), are key determinants of MSC differentiation into adipocytes or osteoblasts. GCS expression was increased during adipogenesis and decreased during osteogenesis. Targeting GCS using RNA interference or a chemical inhibitor enhanced osteogenesis and inhibited adipogenesis by controlling the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ). Treatment with GlcCer sufficiently rescued adipogenesis and inhibited osteogenesis in GCS knockdown MSCs. Mechanistically, GlcCer interacted directly with PPARγ through A/B domain and synergistically enhanced rosiglitazone-induced PPARγ activation without changing PPARγ expression, thereby treatment with exogenous GlcCer increased adipogenesis and inhibited osteogenesis. Animal studies demonstrated that inhibiting GCS reduced adipocyte formation in white adipose tissues under normal chow diet and high-fat diet feeding and accelerated bone repair in a calvarial defect model. Taken together, our findings identify a novel lipid metabolic regulator for the control of MSC differentiation and may have important therapeutic implications.

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ω-3 polyunsaturated fatty acids direct differentiation of the membrane phenotype in mesenchymal stem cells to potentiate osteogenesis

Abstract: Dietary lipids change membrane phenotypes, which can be used to affect lineage specification in stem cells.

Cited by 113 publications

References 82 publications

Therapeutic potentials and modulatory mechanisms of fatty acids in bone

Therapeutic potentials and modulatory mechanisms of fatty acids in bone

Bioinspired Molecular Factories with Architecture and In Vivo Functionalities as Cell Mimics

Glucosylceramide synthase regulates adipo‐osteogenic differentiation through synergistic activation of PPARγ with GlcCer

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