Chaperone-assisted E3 ligase-engineered mesenchymal stem cells target hyperglycemia-induced p53 for ubiquitination and proteasomal degradation ameliorates self-renewal

TL;DR

This study shows that increasing CHIP in stem cells can reverse the harmful effects of high blood sugar on their self-renewal ability.

Contribution

The study reveals that CHIP regulates hyperglycemia-induced p53 degradation to restore stem cell self-renewal.

Findings

Hyperglycemia reduces CHIP and promotes p53 accumulation, impairing stemness in WJMSCs.

CHIP overexpression decreases phosphorylated p53 levels and enhances self-renewal factors.

CHIP facilitates ubiquitination and proteasomal degradation of p53, rescuing stem cell function.

Abstract

Stem cell therapies may potentially be used in regenerative and reconstructive medicine due to their ability for self-renewal and differentiation. Stressful conditions, such as hyperglycemia, adversely affect stem cell functions, impairing their function and promoting differentiation by opposing self-renewal. The carboxyl terminus of HSP70 interacting protein (CHIP), which is a cochaperone and E3 ligase, maintains protein homeostasis and performs quality control of the cell via ubiquitylation. However, the role of CHIP in regulating stemness remains unknown.

Hyperglycemia downregulated CHIP-induced p53, arrested the cell cycle at the gap (G1) phase, and promoted the loss of stemness in WJMSCs. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, immunofluorescence, and cell cycle analysis showed that CHIP-overexpressing WJMSCs downregulated the expression of phosphorylated p53 and shortened its half-life while enhancing self-renewal factors. Additionally, co-IP and Western blotting revealed that CHIP promoted the ubiquitination and proteasomal degradation of hyperglycemia-induced p53 through the chaperone system.

CHIP may promote ubiquitin-mediated proteasomal degradation of hyperglycemia-induced p53 rescues self-renewal genes, which can maintain the long-term undifferentiated state of WJMSCs. CHIP may be an alternative therapeutic option in regenerative medicine for hyperglycemic-related complications in diabetes.

The online version contains supplementary material available at 10.1186/s40659-025-00604-7.

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