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

Chinnapaka, Somaiah; Yang, Katherine S.; Flowers, Quinn; Faisal, Minhal; Nerone, Wayne Vincent; Rubin, J. Peter; Ejaz, Asim

doi:10.3390/biomedicines9121782

Cited by 13 publications

(11 citation statements)

References 58 publications

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“…However, our findings of the maintained immunomodulatory features of dASCs agree with the results of a previous study on age-matched diabetic and nondiabetic donors. 41 It has been reported that metformin, a diabetic drug, improves the stemness, 84 and immunomodulatory potential, 85 of nondiabetic ASCs. The diabetic donors in the present study were administered different therapeutic regimens for T2D and the unknown effect(s) of medications on ASC functions could be a study limitation that needs to be taken into account in the future.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory Functions of Adipose Mesenchymal Stromal/Stem Cell Derived From Donors With Type 2 Diabetes and Obesity on CD4 T Cells

et al. 2023

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For adipose stromal/stem cell (ASCs)-based immunomodulatory therapies, it is important to study how donor characteristics, such as obesity and type 2 diabetes (T2D), influence ASCs efficacy. Here, ASCs were obtained from two groups, donors and T2D and obesity (dASCs) or nondiabetic donors with normal-weight (ndASCs), and then cultured with anti-CD3/CD28-stimulated allogeneic CD4 T cells. ASCs were studied for the expression of the immunomodulators CD54, CD274, and indoleamine 2, 3 dioxygenase 1 (IDO) in inflammatory conditions. CD4 T cells cultured alone or in cocultures were assessed to evaluate proliferation, activation marker surface expression, apoptosis, the regulatory T cells (Tregs; CD4 + CD25 high FOXP3 +) frequency, and intracellular cytokine expression using flow cytometry. Modulation of T-cell subset cytokines was explored via ELISA. In inflammatory conditions, the expression of CD54, CD274 and IDO was significantly upregulated in ASCs, with no significant differences between ndASCs and dASCs. dASCs retained the potential to significantly suppress CD4 T-cell proliferation, with a slightly weaker inhibitory effect than ndASCs, which was associated with significantly reduced abilities to decrease IL-2 production and increase IL-8 levels in cocultures. Such attenuated potentials were significantly correlated with increasing body mass index. dASCs and ndASCs comparably reduced CD4 T-cell viability, HLA-DR expression, and interferon-gamma production and conversely increased CD69 expression, the Tregs percentage, and IL-17A production. Considerable amounts of the immunomodulators prostaglandin E2 (PGE2) and IL-6 were detected in the conditioned medium of cocultures. These findings suggest that ASCs obtained from donors with T2D and obesity are receptive to the inflammatory environment and able to modulate CD4 T cells accordingly.

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Section: Discussionmentioning

confidence: 99%

Immunomodulatory Functions of Adipose Mesenchymal Stromal/Stem Cell Derived From Donors With Type 2 Diabetes and Obesity on CD4 T Cells

et al. 2023

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“…Adipose tissue, particularly adipose-derived stem cells (ASCs), have been implicated as a significant contributor to inflammation during the aging process [ 21 , 32 ]. Hyperactivity of mitochondria is linked to detrimental ROS levels, inflammation, and reduced adipogenesis [ 21 , 33 ]. In this study, we analyzed the ROS levels in freshly isolated ASCs ex vivo among our young and aged mice cohorts.…”

Section: Resultsmentioning

confidence: 99%

“…Increased mitochondrial activity and ROS productions lead to the loss of quiescence, stemness, and increased differentiation of ASCs [ 21 , 33 , 34 ]. We compared the mitochondrial activity by measuring the mitochondrial membrane potential (TMRM staining) of freshly isolated CD34 + ASCs ex vivo in the subcutaneous and visceral adipose depots of young and aged mice.…”

Section: Resultsmentioning

confidence: 99%

“…ASCs are distinguished by their impressive capacity to multiply and transform into fat cells, thereby facilitating the repair or replacement of damaged or diminished fat tissue. However, this property of stemness in ASCs is detrimentally affected by both aging and obesity [ 33 ]. As people grow older, there is a noticeable decrease in ASCs’ ability to rejuvenate themselves and turn into fat cells, which is characterized by reduced proliferation potential, altered gene expression, and hindered differentiation capabilities [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

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Caloric restriction mitigates age-associated senescence characteristics in subcutaneous adipose tissue-derived stem cells

Chinnapaka,

Malekzadeh,

Tirmizi

et al. 2024

Aging

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Adipose tissue regulates metabolic balance, but aging disrupts it, shifting fat from insulin-sensitive subcutaneous to insulin-resistant visceral depots, impacting overall metabolic health. Adipose-derived stem cells (ASCs) are crucial for tissue regeneration, but aging diminishes their stemness and regeneration potential. Our findings reveal that aging is associated with a decrease in subcutaneous adipose tissue mass and an increase in the visceral fat depots mass. Aging is associated with increase in adipose tissue fibrosis but no significant change in adipocyte size was observed with age. Long term caloric restriction failed to prevent fibrotic changes but resulted in significant decrease in adipocytes size. Aged subcutaneous ASCs displayed an increased production of ROS. Using mitochondrial membrane activity as an indicator of stem cell quiescence and senescence, we observed a significant decrease in quiescence ASCs with age exclusively in subcutaneous adipose depot. In addition, aged subcutaneous adipose tissue accumulated more senescent ASCs having defective autophagy activity. However, long-term caloric restriction leads to a reduction in mitochondrial activity in ASCs. Furthermore, caloric restriction prevents the accumulation of senescent cells and helps retain autophagy activity in aging ASCs. These results suggest that caloric restriction and caloric restriction mimetics hold promise as a potential strategy to rejuvenate the stemness of aged ASCs. Further investigations, including in vivo evaluations using controlled interventions in animals and human studies, will be necessary to validate these findings and establish the clinical potential of this well-established approach for enhancing the stemness of aged stem cells.

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“…Recent studies reveal that aging and obesity are closely related to the loss of stemness properties in adipose stem cells. Chinnapaka et al showed that metformin improved the stemness of human adipose-derived stem cells by downregulating the mTOR and ERK signaling 85 . Age-related adipose tissue dysfunction caused by stress-induced senescence of adipose stromal cells was ameliorated by metformin treatment 86 .…”

Section: Clinical Applicationsmentioning

confidence: 99%

Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms

et al. 2022

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Aging is a natural process, which plays a critical role in the pathogenesis of a variety of diseases, i.e., aging-related diseases, such as diabetes, osteoarthritis, Alzheimer disease, cardiovascular diseases, cancers, obesity and other metabolic abnormalities. Metformin, the most widely used antidiabetic drug, has been reported to delay aging and display protective effect on attenuating progression of various aging-related diseases by impacting key hallmark events of aging, including dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, altered intercellular communication, telomere attrition, genomic instability, epigenetic alterations, stem cell exhaustion and cellular senescence. In this review, we provide updated information and knowledge on applications of metformin in prevention and treatment of aging and aging-related diseases. We focus our discussions on the roles and underlying mechanisms of metformin in modulating aging and treating aging-related diseases.

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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

Cited by 13 publications

References 58 publications

Immunomodulatory Functions of Adipose Mesenchymal Stromal/Stem Cell Derived From Donors With Type 2 Diabetes and Obesity on CD4 T Cells

Immunomodulatory Functions of Adipose Mesenchymal Stromal/Stem Cell Derived From Donors With Type 2 Diabetes and Obesity on CD4 T Cells

Caloric restriction mitigates age-associated senescence characteristics in subcutaneous adipose tissue-derived stem cells

Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms

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