Adipose-derived stem cells alleviate acute pancreatitis by inhibiting ferroptosis and oxidative damage in canines.

Abstract

<h4>Background</h4>Acute pancreatitis (AP) is a common exocrine pancreatic disease that can lead to systemic inflammatory response syndrome and multiorgan failure in canines. The therapeutic benefits of adipose-derived stem cells (ADSCs) and conditioned medium (CM) and the role in ferroptosis regulation in managing AP in canines (dogs) were investigated in this study.<h4>Methods</h4>Sixteen dogs were randomly divided into a control (CON), AP, ADSC, or ADSC-CM group. The AP model was established by injecting the dogs with sodium taurocholate (5%, 0.1 mL/kg) and trypsin (3500 U/kg) via the pancreaticobiliary duct. ADSCs (1 × 10⁶/kg) and CM (0.1 mL/kg) were injected intravenously 6 h after surgery, and the roles on ferroptosis and oxidative stress were analyzed. The changing patterns of ferroptosis and oxidative stress were determined in vitro using a lipopolysaccharideinduced cellular inflammation model of AR42J.<h4>Results</h4>Ferroptosis occurred in the pancreas during AP, as evidenced by significant iron accumulation, suppressed glutathione peroxidase (GPx)4 expression, and increased transferrin receptor-1 (TFR1), and ferritin heavy chain expression. Treatment with ADSCs and ADSC-CM led to pathological remission and effectively restored abnormal amylase and lipase levels. ADSC-CM showed ferroptosis-alleviating effects similar to that of ADSCs, with reduced iron accumulation and increased GPx4 expression. Furthermore, ADSCs could promote the nuclear translocation of nuclear factor erythroid 2-related factor 2 and initiate the transcription of detoxification enzymes to protect the pancreas from oxidative damage.<h4>Conclusions</h4>ADSCs can protect the pancreas of dogs by inhibiting ferroptosis and oxidative stress via paracrine function, indicating immense potential as a therapeutic target for treating AP.