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Cell reprogramming using extracellular vesicles from differentiating stem cells into white/beige adipocytes.

ABSTRACT: Stem cell-derived extracellular vesicles (EVs) offer alternative approaches to stem cell-based therapy for regenerative medicine. In this study, stem cell EVs derived during differentiation are developed to use as cell-free therapeutic systems by inducing tissue-specific differentiation. EVs are isolated from human adipose-derived stem cells (HASCs) during white and beige adipogenic differentiation (D-EV and BD-EV, respectively) via tangential flow filtration. D-EV and BD-EV can successfully differentiate HASCs into white and beige adipocytes, respectively. D-EV are transplanted with collagen/methylcellulose hydrogels on the backs of BALB/c mice, and they produce numerous lipid droplets in injected sites. Treatments of BD-EV attenuate diet-induced obesity through browning of adipose tissue in mice. Furthermore, high-fat diet-induced hepatic steatosis and glucose tolerance are improved by BD-EV treatment. miRNAs are responsible for the observed effects of BD-EV. These results reveal that secreted EVs during stem cell differentiation into white adipocytes or beige adipocytes can promote cell reprogramming.

SUBMITTER: Jung YJ

PROVIDER: S-EPMC7096171 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Cell reprogramming using extracellular vesicles from differentiating stem cells into white/beige adipocytes.

Jung Youn Jae YJ Kim Hark Kyun HK Cho Yoonsuk Y Choi Ji Suk JS Woo Chang Hee CH Lee Kyoung Soo KS Sul Jae Hoon JH Lee Chan Mi CM Han Jihoon J Park Jae Hyung JH Jo Dong-Gyu DG Cho Yong Woo YW

Science advances 20200325 13

Stem cell-derived extracellular vesicles (EVs) offer alternative approaches to stem cell-based therapy for regenerative medicine. In this study, stem cell EVs derived during differentiation are developed to use as cell-free therapeutic systems by inducing tissue-specific differentiation. EVs are isolated from human adipose-derived stem cells (HASCs) during white and beige adipogenic differentiation (D-EV and BD-EV, respectively) via tangential flow filtration. D-EV and BD-EV can successfully dif ...[more]

PMID: 32232152

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Project description:Promoting white-to-beige adipocyte transition is a promising approach for obesity treatment. Although Liensinine (Lie), a kind of isoquinoline alkaloid, has been reported to affect white-to-beige adipocyte transition, its effects on inhibiting beige adipocytes recovering to white adipocytes and maintaining the characteristics of beige adipocyte remain unclear. Therefore, we explored the effects and underlying mechanism of Lie on beige adipocyte maintenance in vitro and in vivo. Here, we first demonstrated that after white adipocytes turned to beige adipocytes by rosiglitazone (Rosi) stimuli, beige adipocytes gradually lost their characteristics and returned to white adipocytes again once Rosi was withdrawn. We found that Lie retained high levels of uncoupling protein 1 (UCP1) and mitochondrial oxidative phosphorylation complex I, II, III, IV and V (COX I-V), oxygen consumption rate (OCR) after Rosi withdrawal. In addition, after Rosi withdrawal, the beige-to-white adipocyte transition was coupled to mitophagy, while Lie inhibited mitophagy flux by promoting the accumulation of pro-cathepsin B (pro-CTSB), pro-cathepsin D (pro-CTSD) and pro-cathepsin L (pro-CTSL), ultimately maintaining the beige adipocytes characteristics in vitro. Moreover, through blocking mitophagy flux, Lie significantly retained the molecular characteristics of beige adipocyte, reduced body weight gain rate and enhanced energy expenditure after stimuli withdrawal in vivo. Together, our data showed that Lie inhibited lysosomal cathepsin activity by promoting the accumulation of pro-CTSB, pro-CTSD and pro-CTSL, which subsequently inhibited mitophagy flux, and ultimately inhibited the beige adipocytes recovering to white adipocytes and maintained the characteristics of beige adipocyte after stimuli withdrawal. In conclusion, by blocking lysosome-mediated mitophagy, Lie inhibits beige adipocytes recovering to white adipocytes and may be a potential candidate for preventing high fat diet induced obesity.

Project description:The stemness maintenance of adipose-derived stem cells (ADSCs) is important for adipose homeostasis and energy balance. Programmed cell death 4 (Pdcd4) has been demonstrated to be involved in the development of obesity, but its possible roles in ADSC function and adipogenic capacity remain unclear. In this study, we demonstrate that Pdcd4 is a key controller that limits the self-renewal and white-to-beige transdifferentiation of ADSCs. Pdcd4 deficiency in mice caused stemness enhancement of ADSCs as evidenced by increased expression of CD105, CD90, Nanog and Oct4 on ADSCs, together with enhanced in situ proliferation in adipose tissues. Pdcd4 deficiency promoted proliferation, colony formation of ADSCs and drove more ADSCs entering the S phase accompanied by AKT activation and cyclinD1 upregulation. Blockade of AKT signaling in Pdcd4-deficient ADSCs led to a marked decline in cyclinD1, S-phase entry and cell proliferation, revealing AKT as a target for repressing ADSC self-renewal by Pdcd4. Intriguingly, depletion of Pdcd4 promoted the transdifferentiation of ADSCs into beige adipocytes. A reduction in lipid contents and expression levels of white adipocyte markers including C/EBPα, PPAR-γ, adiponectin and αP2 was detected in Pdcd4-deficient ADSCs during white adipogenic differentiation, substituted by typical beige adipocyte characteristics including small, multilocular lipid droplets and UCP1 expression. More lactate produced by Pdcd4-deficient ADSCs might be an important contributor to the expression of UCP1 and white-to-beige transdifferentiation. In addition, an elevation of UCP1 expression was confirmed in white adipose tissues from Pdcd4-deficient mice upon high-fat diet, which displayed increased energy expenditure and resistance to obesity as compared with wild-type obese mice. These findings provide evidences that Pdcd4 produces unfavorable influences on ADSC stemness, which contribute to adipose dysfunction, obesity and metabolic syndromes, thereby proposing Pdcd4 as a potential intervening target for regulating ADSC function.

Dataset Information

Cell reprogramming using extracellular vesicles from differentiating stem cells into white/beige adipocytes.

Publications

Cell reprogramming using extracellular vesicles from differentiating stem cells into white/beige adipocytes.

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