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

Ayaz Ali; Wei-Wen Kuo; Chia-Hua Kuo; Jeng-Fan Lo; Michael Y C Chen; Jayasimha R Daddam; Tsung-Jung Ho; Vijaya Padma Viswanadha; Marthandam Asokan Shibu; Chih-Yang Huang

doi:10.1002/btm2.10234

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

Bioeng Transl Med. 2021 Jun 11;6(3):e10234. doi: 10.1002/btm2.10234. eCollection 2021 Sep.

Authors

Ayaz Ali¹, Wei-Wen Kuo^{1

2}, Chia-Hua Kuo³, Jeng-Fan Lo⁴, Michael Y C Chen⁵, Jayasimha R Daddam⁶, Tsung-Jung Ho^{7

8}, Vijaya Padma Viswanadha⁹, Marthandam Asokan Shibu⁶, Chih-Yang Huang^{6

10

11

12

13}

Affiliations

¹ Department of Biological Science and Technology China Medical University Taichung Taiwan.
² Ph.D. Program for Biotechnology Industry, China Medical University Taichung Taiwan.
³ Laboratory of Exercise Biochemistry University of Taipei Taipei Taiwan.
⁴ Institute of Oral Biology, National Yang-Ming University Taipei Taiwan.
⁵ Department of Cardiology Buddhist Tzu Chi General Hospital Hualien Taiwan.
⁶ Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation Hualien Taiwan.
⁷ Department of Chinese Medicine Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University Hualien Taiwan.
⁸ Integration Center of Traditional Chinese and Modern Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation Hualien Taiwan.
⁹ Department of Biotechnology Bharathiar University Coimbatore India.
¹⁰ Graduate Institute of Biomedical Sciences, China Medical University Taichung Taiwan.
¹¹ Department of Medical Research China Medical University Hospital, China Medical University Taichung Taiwan.
¹² Department of Biotechnology Asia University Taichung Taiwan.
¹³ Center of General Education, Buddhist Tzu Chi Medical Foundation Tzu Chi University of Science and Technology Hualien Taiwan.

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.

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