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Thrombin-preconditioned mesenchymal stromal cell-derived extracellular vesicles attenuate experimental necrotizing
Sein Hwang1,2, Se In Sung2,3, Young Eun Kim2
1Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06355, Republic of Korea.
Stem Cell Research & Therapy
|February 28, 2025
Summary
Thrombin-preconditioned mesenchymal stromal cell-derived extracellular vesicles (thMSC-EVs) show promise for treating necrotizing enterocolitis (NEC) in preterm infants. These vesicles improved cell viability and reduced inflammation in NEC models, suggesting significant therapeutic potential.
Area of Science:
- Neonatal Medicine
- Gastroenterology
- Regenerative Medicine
Background:
- Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease affecting preterm infants with no established treatment.
- Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) show potential for neonatal tissue injury repair.
- Thrombin-preconditioned MSC-EVs (thMSC-EVs) were previously found to protect against other neonatal injuries.
Purpose of the Study:
- To evaluate the therapeutic potential of thMSC-EVs in preclinical models of NEC.
- To compare the efficacy of thMSC-EVs against naïve MSC-EVs in NEC models.
- To investigate the mechanisms underlying the protective effects of thMSC-EVs.
Main Methods:
- In vitro studies used hyperosmotic, ischemic, and hypothermic (HIT)-stressed IEC-6 cells and LPS-treated macrophages to assess thMSC-EVs and naïve MSC-EVs.
- In vivo studies induced NEC in mouse pups, followed by daily intraperitoneal administration of thMSC-EVs and subsequent macroscopic, histological, and biochemical assessments.
- NEC mouse-derived organoids were established to evaluate thMSC-EVs' effects on mature enterocytes, with proteomic analysis of EVs.
Main Results:
- thMSC-EVs significantly improved cell viability in HIT-stressed cells and modulated cytokine profiles in macrophages compared to naïve MSC-EVs.
- In vivo, thMSC-EVs attenuated NEC symptoms, reduced intestinal damage, retained stem cell markers, and showed increased localization in NEC-affected intestines.
- Organoid studies revealed thMSC-EVs increased specific stem cell markers (OLFM4, claudin-4) and reduced stress markers, with proteomic analysis indicating enrichment in anti-apoptotic, anti-inflammatory, and Wnt signaling pathways.
Conclusions:
- thMSC-EVs demonstrated significant tissue-protective effects in preclinical NEC models.
- These vesicles improved cellular viability, reduced apoptosis, attenuated inflammation, and upregulated key intestinal stem cell markers.
- thMSC-EVs represent a promising therapeutic candidate for necrotizing enterocolitis in preterm infants.
