# 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.

## Key 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.