Effect of metformin on stem cells: Molecular mechanism and clinical prospect

Jiang, Linli; Liu, Lei

doi:10.4252/wjsc.v12.i12.1455

Cited by 38 publications

(21 citation statements)

References 125 publications

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“…The proliferation rate of stem cells plays an important role in maintaining the stem cell pool, stemness, and self-renewal capability. We observed that metformin inhibited the proliferation of ASCs without inducing any cytotoxic effect on ASCs, which agrees with other studies published on mice adipose-derived stem cells [ 28 ], stromal cells, and fibroblasts [ 38 , 39 ]. A recent study using adipose-derived stem cells from horses showed a pro-proliferative effect of metformin [ 27 ].…”

Section: Discussionsupporting

confidence: 92%

“…We observed that metformin significantly decreases the mitochondrial membrane potential and reactive oxygen species generation. In line with our data, earlier studies also reported that metformin decreases oxidative stress and improves the antioxidant expression in mouse embryonic fibroblasts [ 44 ], mouse ASCs [ 38 ], and human aortic endothelial cells [ 45 ]. Moreover, in agreement with our study, Chien-Hung Lin et al reported that metformin acts as a neuroprotective agent by reducing oxidative stress in human neural stem cells [ 46 ].…”

Section: Discussionsupporting

confidence: 92%

“…Moreover, in agreement with our study, Chien-Hung Lin et al reported that metformin acts as a neuroprotective agent by reducing oxidative stress in human neural stem cells [ 46 ]. Several other studies confirm that metformin acts as an antioxidant by reducing oxidative stress and increasing antioxidant enzyme expression, such as superoxide dismutase in mouse ASCs, murine C2C12 myoblasts, and circulating human endothelial progenitor cells [ 38 , 47 , 48 ]. Moreover, the study of Alejandro Martin-Montalvo et al supports our observation, demonstrating that metformin significantly inhibits the mitochondrial complex, inhibiting mitochondrial respiration in mice [ 49 ] The effects of metformin on reduced reactive oxygen species generation are possibly mediated by the increase in reduced glutathione [ 50 ] in a mechanism involving the redox-sensitive transcription factor Nrf2 [ 51 ].…”

Section: Discussionmentioning

confidence: 95%

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Metformin Improves Stemness of Human Adipose-Derived Stem Cells by Downmodulation of Mechanistic Target of Rapamycin (mTOR) and Extracellular Signal-Regulated Kinase (ERK) Signaling

et al. 2021

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Adipose tissue plays an important role in regulating metabolic homeostasis by storing excess fat and protecting other organs from lipotoxicity. Aging is associated with central fat redistribution, culminating in a decrease in insulin-sensitive subcutaneous and an increase in insulin-resistant visceral adipose depots. Adipose-derived stem cells (ASCs) play an important role in the regeneration of adipose tissue. Aged ASCs show decreased stemness and regenerative potential due to the accumulation of oxidative stress and mitochondrial dysfunction-related cell damage. Metformin is a well-established anti-diabetic drug that has shown anti-aging effects in different organisms and animal models. In this study, we analyzed the effect of metformin treatment on the stemness of human ASCs in cell culture and whole adipose tissue culture models. Our results demonstrate that metformin improves the stemness of ASCs, reducing their rate of proliferation and adipocyte differentiation. Investigating the possible underlying mechanism, we observed a decrease in the mTOR and ERK activity in metformin-treated ASCs. In addition, we observed an increase in autophagy activity upon metformin treatment. We conclude that metformin treatment improves ASCs stemness by reducing mTOR and ERK signaling and enhancing autophagy. Future in vivo evaluations in animal models and humans will pave the way for the clinical adaptation of this well-established drug for reviving the stemness of aged stem cells.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 95%

See 1 more Smart Citation

Metformin Improves Stemness of Human Adipose-Derived Stem Cells by Downmodulation of Mechanistic Target of Rapamycin (mTOR) and Extracellular Signal-Regulated Kinase (ERK) Signaling

et al. 2021

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“…We have previously demonstrated that the combination of natural molecules, for example, melatonin and vitamin D together with the adipogenic conditioned medium, can counteract the appearance of an adipogenic phenotype in ADSCs, instead stimulating osteogenic differentiation [32]. Moreover, metformin, widely known in the treatment of obesity-related diabetes, promotes stem cell differentiation [39]. In addition, metformin reduced the levels of TNF-α in obese mice, down-regulating NF-kB translocation into macrophages [40].…”

Section: Discussionmentioning

confidence: 99%

Metformin and Vitamin D Modulate Inflammation and Autophagy during Adipose-Derived Stem Cell Differentiation

Cruciani

Garroni

Pala

et al. 2021

IJMS

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Adipose-derived stem cells (ADSCs) came out from the regenerative medicine landscape for their ability to differentiate into several phenotypes, contributing to tissue regeneration both in vitro and in vivo. Dysregulation in stem cell recruitment and differentiation during adipogenesis is linked to a chronic low-grade inflammation and macrophage infiltration inside the adipose tissue, insulin resistance, cardiovascular disease and obesity. In the present paper we aimed to evaluate the role of metformin and vitamin D, alone or in combination, in modulating inflammation and autophagy in ADSCs during adipogenic commitment. ADSCs were cultured for 21 days in the presence of a specific adipogenic differentiation medium, together with metformin, or vitamin D, or both. We then analyzed the expression of FoxO1 and Heat Shock Proteins (HSP) and the secretion of proinflammatory cytokines IL-6 and TNF-α by ELISA. Autophagy was also assessed by specific Western blot analysis of ATG12, LC3B I, and LC3B II expression. Our results showed the ability of the conditioned media to modulate adipogenic differentiation, finely tuning the inflammatory response and autophagy. We observed a modulation in HSP mRNA levels, and a significant downregulation in cytokine secretion. Taken together, our findings suggest the possible application of these molecules in clinical practice to counteract uncontrolled lipogenesis and prevent obesity and obesity-related metabolic disorders.

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“…It exerts this action via the AMPK signaling pathway. It is suggested that metformin promotes the differentiation of gastric epithelial progenitor cells into parietal cells secreting hydrochloric acid by activating AMPK, which may be of key importance in the prevention of gastric cancer [9]. M. Kodali et al (2021) investigated the effect of metformin administered by oral gavage at a dose of 100 mg / kg once daily for 5 days a week for 10 weeks in 18-month-old (late middle age) mice.…”

Section: Organ Systemsmentioning

confidence: 99%

Anti-aging properties of metformin

Łopuszyńska

Pawlicki

Kozioł

et al. 2021

J Educ Health Sport

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Introduction: Life expectancy of human population is being constantly prolonged, hence there is a lot of research into drug that will prevent the effects of aging. There are many reports that metformin, which is a drug used in type 2 diabetes, has anti-aging effects. It belongs to the group of biguanides and has been used since the 1950s. It is a relatively safe, cheap and effective drug, which makes it a promising subject for many studies. The purpose of this review is to present the latest developments in this field. Material and methods: PubMed scientific base was searched using following keywords: metformin, aging, anti-aging, in years 2017-2021. Results: Numerous studies show that metformin has an impact on aging through the nutrient pathway, AMPK signaling pathway, and its effects on reactive oxygen species. In addition, it has an anti-cancer effect, inhibiting, among others, rectal cancer cells and p53 mutant colon cancer. Research in rodents has shown that this drug has anti-aging effects on many organs, including the CNS, ovaries, prostate, heart muscle and skin. Conclusions: Metformin, which is the most commonly used oral drug in type 2 diabetes, has many other mechanisms of action. Its anti-aging effect works on many organs in our bodies, which gives hope to find an anti-aging substance. However, multicentre, randomized trials are needed to determine the exact anti-aging dose, its possible side effects, and effects on various organisms.

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Effect of metformin on stem cells: Molecular mechanism and clinical prospect

Cited by 38 publications

References 125 publications

Metformin Improves Stemness of Human Adipose-Derived Stem Cells by Downmodulation of Mechanistic Target of Rapamycin (mTOR) and Extracellular Signal-Regulated Kinase (ERK) Signaling

Metformin Improves Stemness of Human Adipose-Derived Stem Cells by Downmodulation of Mechanistic Target of Rapamycin (mTOR) and Extracellular Signal-Regulated Kinase (ERK) Signaling

Metformin and Vitamin D Modulate Inflammation and Autophagy during Adipose-Derived Stem Cell Differentiation

Anti-aging properties of metformin

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