E3 ligase activity of Carboxyl terminus of Hsc70 interacting protein (CHIP) in Wharton's jelly derived mesenchymal stem cells improves their persistence under hyperglycemic stress and promotes the prophylactic effects against diabetic cardiac damages

Bioengineering & Translational Medicine

Marthandam Asokan Shibu¹  Jayasimha R. Daddam¹  Chih‐Yang Huang¹  Ayaz Ali²  Wei‐Wen Kuo²  Vijaya Padma Viswanadha³  Michael Y. C. Chen⁴  Tsung‐Jung Ho⁵  Jeng‐Fan Lo⁶  Chia‐Hua Kuo⁷ 

[1] Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation Hualien Taiwan;Department of Biological Science and Technology China Medical University Taichung Taiwan;Department of Biotechnology Bharathiar University Coimbatore India;Department of Cardiology Buddhist Tzu Chi General Hospital Hualien Taiwan;Department of Chinese Medicine Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University Hualien Taiwan;Institute of Oral Biology, National Yang‐Ming University Taipei Taiwan;Laboratory of Exercise Biochemistry University of Taipei Taipei Taiwan;

关键词: apoptosis;    carboxyl terminus of Hsc70 interacting protein;    diabetes;    phosphatase and tensin homolog;    Wharton's jelly derived mesenchymal stem cells;   

DOI  :  10.1002/btm2.10234

来源: DOAJ

【 摘 要 】

Abstract Recent studies indicate that umbilical cord stem cells are cytoprotective against several disorders. One critical limitation in using stem cells is reduction in their viability under stressful conditions, such as diabetes. However, the molecular intricacies responsible for diabetic conditions are not fully elucidated. In this study, we found that high glucose (HG) conditions induced loss of chaperone homeostasis, stabilized PTEN, triggered the downstream signaling cascade, and induced apoptosis and oxidative stress in Wharton's jelly derived mesenchymal stem cells (WJMSCs). Increased Carboxyl terminus of Hsc70 interacting protein (CHIP) expression promoted phosphatase and tensin homolog (PTEN) degradation via the ubiquitin‐proteasome system and shortened its half‐life during HG stress. Docking studies confirmed the interaction of CHIP with PTEN and FOXO3a with the Bim promoter region. Further, it was found that the chaperone system is involved in CHIP‐mediated PTEN proteasomal degradation. CHIP depletion stabilizes PTEN whereas PTEN inhibition showed an inverse effect. CHIP overactivation suppressed the binding of FOXO3a with bim. Coculturing CHIP overexpressed WJMSCs suppressed HG‐induced apoptosis and oxidative stress in embryo derived cardiac cell lines. CHIP overexpressing and PTEN silenced WJMSCs ameliorated diabetic effects in streptozotocin (STZ) induced diabetic rats and further improved their body weight and heart weight, and rescued from hyperglycemia‐induced cardiac injury. Considering these, the current study suggests that CHIP confers resistance to apoptosis and acts as a potentiation factor in WJMSCs to provide protection from degenerative effects of diabetes.

【 授权许可】

Unknown