MSCs Deliver Hypoxia-Treated Mitochondria Reprogramming Acinar Metabolism to Alleviate Severe Acute Pancreatitis Injury.

Zhengyu Hu, Dongyan Wang, Jian Gong, Yan Li, Zhilong Ma, Tingyi Luo, Xuyang Jia, Yihai Shi, Zhenshun Song

Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2023;10(25):e2207691

PMID: 37409821

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Abstract

Mitochondrial function impairment due to abnormal opening of the mitochondrial permeability transition pore (MPTP) is considered the central event in acute pancreatitis; however, therapeutic choices for this condition remain controversial. Mesenchymal stem cells (MSCs) are a family member of stem cells with immunomodulatory and anti-inflammatory capabilities that can mitigate damage in experimental pancreatitis. Here, it is shown that MSCs deliver hypoxia-treated functional mitochondria to damaged pancreatic acinar cells (PACs) via extracellular vesicles (EVs), which reverse the metabolic function of PACs, maintain ATP supply, and exhibit an excellent injury-inhibiting effect. Mechanistically, hypoxia inhibits superoxide accumulation in the mitochondria of MSCs and upregulates the membrane potential, which is internalized into PACs via EVs, thus, remodeling the metabolic state. In addition, cargocytes constructed via stem cell denucleation as mitochondrial vectors are shown to exert similar therapeutic effects to MSCs. These findings reveal an important mechanism underlying the role of mitochondria in MSC therapy and offer the possibility of applying mitochondrial therapy to patients with severe acute pancreatitis.

Address: Department of Hepatopancreatobiliary Surgery, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China.; Department of General Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.; Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230032, China.; Department of Gastroenterology, Shanghai Pudong New Area Gongli Hospital, Shanghai, 200135, China.; Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.

DOI: 10.1002/advs.202207691

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MeSH Terms: Acinar Cells, Acute Disease, Adenosine Triphosphate, Bile Acids and Salts, Cell Hypoxia, Cellular Reprogramming, Extracellular Vesicles, Membrane Potential, Mitochondrial, Mesenchymal Stem Cells, Mitochondria, Mitochondrial Permeability Transition Pore, Pancreas, Pancreatitis, Paracrine Communication, Superoxides, Umbilical Cord, Humans