Metformin inhibits chronic kidney disease‐induced DNA damage and senescence of mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSCs) are promising source of cell‐based regenerative therapy. In consideration of the risk of allosensitization, autologous MSC‐based therapy is preferred over allogenic transplantation in patients with chronic kidney disease (CKD). However, it remains uncertain whether adequate cell functionality is maintained under uremic conditions. As chronic inflammation and oxidative stress in CKD may lead to the accumulation of senescent cells, we investigated cellular senescence of CKD MSCs and determined the effects of metformin on CKD‐associated cellular senescence in bone marrow MSCs from sham‐operated and subtotal nephrectomized mice and further explored in adipose tissue‐derived MSCs from healthy kidney donors and patients with CKD. CKD MSCs showed reduced proliferation, accelerated senescence, and increased DNA damage as compared to control MSCs. These changes were significantly attenuated following metformin treatment. Lipopolysaccharide and transforming growth factor β1‐treated HK2 cells showed lower tubular expression of proinflammatory and fibrogenesis markers upon co‐culture with metformin‐treated CKD MSCs than with untreated CKD MSCs, suggestive of enhanced paracrine action of CKD MSCs mediated by metformin. In unilateral ureteral obstruction kidneys, metformin‐treated CKD MSCs more effectively attenuated inflammation and fibrosis as compared to untreated CKD MSCs. Thus, metformin preconditioning may exhibit a therapeutic benefit by targeting accelerated senescence of CKD MSCs.

Metformin attenuates silica-induced pulmonary fibrosis via AMPK signaling

“…Metformin, a widely used miracle drug, is well known for treating type 2 diabetes. However, with advances in epidemiological and experimental researches, growing evidence suggests that metformin has multiple benefits in various diseases, including fibrotic diseases [ 55 – 57 ]. For example, metformin was found to alter the fate of myofibroblasts by inducing lipogenic differentiation and inhibit TGF-β1-stimulated myogenic differentiation [ 58 ].…”

Proteomic and Biological Analysis of the Effects of Metformin Senomorphics on the Mesenchymal Stromal Cells

“…There are several findings that demonstrate the consequences of metformin treatment on MSCs biology. In a mouse model of kidney disease, a short pulse of metformin inhibited the acute senescence of bone marrow MSCs (Kim et al, 2021). Others have shown that metformin reduces the level of ROS and the onset of senescence in mouse adipose-derived MSCs (Marycz et al, 2016).…”

“…Several studies evaluated the effects of metformin on MSCs biology. Metformin treatment protects MSCs from DNA damage events, delays senescence, reduces their level of reactive oxygen species, and promotes differentiation phenomena (Gu et al, 2017;Kuang et al, 2020;Kim et al, 2021). Additionally, metformin may enhance the immunomodulatory potential of MSCs (Park et al, 2019).…”

Metformin Attenuates Silica-induced Pulmonary Fibrosis via AMPK Signaling

“…Metformin, a widely used miracle drug, is well known for treating type 2 diabetes. However, with advances in epidemiological and experimental researches, growing evidence suggests that metformin has multiple bene ts in various diseases, including brotic diseases [43][44][45]. For example, metformin was found to alter the fate of myo broblasts by inducing lipogenic differentiation and inhibit TGF-β1-stimulated myogenic differentiation [46].…”