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Thrombin Preconditioning Improves the Therapeutic Efficacy of Mesenchymal Stem Cells in Severe Intraventricular
So Yeon Jung1,2, Young Eun Kim3,4, Won Soon Park1,3,4
1Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
Insights
Thrombin preconditioning enhances mesenchymal stem cell (MSC) therapy for severe neonatal intraventricular hemorrhage (IVH). This improved MSC treatment reduced brain injury and improved neurobehavioral function in a rat model.
Area of Science:
- Neonatal Neurology
- Regenerative Medicine
- Stem Cell Therapy
Background:
- Severe intraventricular hemorrhage (IVH) in preterm infants leads to significant mortality and morbidity.
- Mesenchymal stem cell (MSC) transplantation is a potential therapy, but enhanced efficacy is needed.
- Thrombin preconditioning is explored as a method to improve MSC therapeutic potential.
Purpose of the Study:
- To investigate if thrombin preconditioning enhances the therapeutic efficacy of human Wharton's jelly-derived MSCs for severe neonatal IVH.
- To evaluate the effects of thrombin-preconditioned MSCs on brain injury and neurobehavioral outcomes in a rat model of IVH.
Main Methods:
- Severe neonatal IVH was induced in Sprague-Dawley rats.
- Rats received either naïve MSCs or thrombin-preconditioned MSCs via intraventricular transplantation.
- In vivo MRI, behavioral tests, and histological/biochemical analyses were performed to assess outcomes.
Main Results:
- Thrombin-preconditioned MSC transplantation significantly reduced IVH-induced ventricular dilatation compared to naïve MSCs.
- Preconditioned MSCs attenuated reactive gliosis, cell death, microglial activation, and inflammatory cytokine levels.
- Sensorimotor and memory functions were significantly improved in rats treated with thrombin-preconditioned MSCs.
Conclusions:
- Thrombin preconditioning significantly enhances the therapeutic potential of MSCs for neonatal IVH.
- This enhanced therapy effectively attenuates brain injury, including ventricular dilatation, gliosis, cell death, and inflammation.
- Thrombin-preconditioned MSC transplantation offers a more effective treatment for neurobehavioral functional impairment following severe IVH.
Abstract:
Severe intraventricular hemorrhage (IVH) remains a major cause of high mortality and morbidity in extremely preterm infants. Mesenchymal stem cell (MSC) transplantation is a possible therapeutic option, and development of therapeutics with enhanced efficacy is necessary. This study investigated whether thrombin preconditioning improves the therapeutic efficacy of human Wharton's jelly-derived MSC transplantation for severe neonatal IVH, using a rat model. Severe neonatal IVH was induced by injecting 150 μL blood into each lateral ventricle on postnatal day (P) 4 in Sprague-Dawley rats. After 2 days (P6), naïve MSCs or thrombin-preconditioned MSCs (1 × 105/10 μL) were transplanted intraventricularly. After behavioral tests, brain tissues and cerebrospinal fluid of P35 rats were obtained for histological and biochemical analyses, respectively. Thrombin-preconditioned MSC transplantation significantly reduced IVH-induced ventricular dilatation on in vivo magnetic resonance imaging, which was coincident with attenuations of reactive gliosis, cell death, and the number of activated microglia and levels of inflammatory cytokines after IVH induction, compared to naïve MSC transplantation. In the behavioral tests, the sensorimotor and memory functions significantly improved after transplantation of thrombin-preconditioned MSCs, compared to naïve MSCs. Overall, thrombin preconditioning significantly improves the therapeutic potential and more effectively attenuates brain injury, including progressive ventricular dilatation, gliosis, cell death, inflammation, and neurobehavioral functional impairment, in newborn rats with induced severe IVH than does naïve MSC transplantation.
