Abstract: SA-PO436
Metformin Improves Dysfunction of Mesenchymal Stem Cells Associated with CKD via Protection from Senescence
Session Information
- Development and Regenerative Medicine
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 500 Development, Stem Cells, and Regenerative Medicine
Authors
- Noh, Hyunjin, Soon Chun Hyang Univ., Seoul, Korea (the Republic of)
- Yu, Mi ra, Soon Chun Hyang University, Seoul, Korea (the Republic of)
- Kim, Hyoshik, Soon Chun Hyang Univ., Seoul, Korea (the Republic of)
- Kwon, Soon hyo, Soon Chun Hyang Univ., Seoul, Korea (the Republic of)
Background
Mesenchymal stem cells (MSC) are promising source of cell-based regenerative therapy; however, adequate cell functionality is a critical factor for the success of autotransplantation. We previously reported a functional incompetence of CKD (chronic kidney disease) MSC.
Methods
In this study, we investigated the effects of metformin on CKD-associated cellular senescence using MSC isolated from sham operated and subtotal nephrectomized mice and further explored the protective role of metformin-treated CKD MSC in renal progression using unilateral ureteral obstruction (UUO) model and in vitro co-culture system.
Results
When compared to normal MSC, MSC isolated from CKD mice displayed reduced proliferation and early senescence as determined by enlarged cell morphology, increased oxidative stress, accumulation of DNA damage response marker p53 binding protein 1 (53BP1), phospho p53, p16INK4a, and b-gal expression, and decreased cyclin-dependent kinase 4 (CDK4) and cyclin D. CKD MSC exhibited activation of NFκB resulting in expression of senescence-associated secretory phenotype (SASP) factors such as MCP-1, TNF-α, IL-6, and IL-1β compared to normal MSC. All of these changes were significantly prevented by metformin treatment. In vivo, metformin-treated CKD MSC attenuated inflammation and fibrosis in UUO kidney as compared to CKD MSC. Co-culture of LPS-treated HK2 cells with normal MSC almost completely rescued LPS-induced tubular expression of MCP-1 and TNF-α. Of note, metformin-treated CKD MSC markedly decreased tubular expression of MCP-1 and TNF-α when compared to CKD MSC suggesting paracrine action of CKD MSC enhanced by metformin treatment.
Conclusion
Taken together, our data suggest that metformin prevents cellular senescence of CKD MSC and improves their renoprotective effects.
Funding
- Government Support - Non-U.S.