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Hypoxic Preconditioning Enhances the Potential of Mesenchymal Stem Cells to Treat Neonatal Hypoxic-Ischemic Brain
Sara T De Palma1, Eva C Hermans1, Tatiana M Shamorkina2,3
1Department for Developmental Origins of Disease, University Medical Center Utrecht Brain Center and Wilhelmina Children's Hospital (S.T.D.P., E.C.H., C.H.A.N., C.G.M.d.T.), Utrecht University, the Netherlands.
Insights
Hypoxic preconditioning enhances mesenchymal stem cell (MSC) therapy for neonatal brain injury. This method boosts MSC migration and neuroregeneration, improving outcomes in a mouse model.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Stem Cell Biology
Background:
- Neonatal hypoxic-ischemic (HI) brain injury causes significant long-term neurological deficits.
- Current treatments for HI brain injury are limited, highlighting the need for novel therapeutic strategies.
- Mesenchymal stem cell (MSC) therapy shows promise for promoting neuroregeneration after HI injury, with ongoing research focused on optimizing MSC potential.
Purpose of the Study:
- To investigate the efficacy of hypoxic preconditioning of MSCs in enhancing therapeutic outcomes for neonatal HI brain injury.
- To evaluate whether preconditioning MSCs under hypoxia improves their migratory and neuroregenerative capacities.
Main Methods:
- Neonatal HI brain injury was induced in C57Bl/6 mice.
- MSCs were cultured under hypoxic (HP-MSCs) or normoxic conditions.
- HP-MSCs or normoxic-preconditioned MSCs were administered intranasally 10 days post-HI.
- MSC migration, lesion size, sensorimotor function, neuroinflammation, and neural stem cell differentiation were assessed.
- Proteomic profiling of MSCs was performed.
Main Results:
- Intranasally administered HP-MSCs significantly reduced lesion size and sensorimotor impairments compared to normoxic-preconditioned MSCs.
- Hypoxic preconditioning enhanced MSC migration both in vitro and in vivo to the injured brain hemisphere.
- HP-MSCs promoted neural stem cell differentiation into more complex neurons in vitro.
- Hypoxic preconditioning increased the abundance of extracellular matrix remodeling proteins in MSCs.
Conclusions:
- Hypoxic preconditioning of MSCs enhances their therapeutic efficacy in a mouse model of neonatal HI brain injury.
- The improved therapeutic potential is attributed to increased MSC migratory and neuroregenerative capacities.
- This study provides a novel strategy for optimizing MSC-based therapies for neonatal brain injury.
Background:
Neonatal hypoxic-ischemic (HI) brain injury is one of the leading causes of long-term neurological morbidity in newborns. Current treatment options for HI brain injury are limited, but mesenchymal stem cell (MSC) therapy is a promising strategy to boost neuroregeneration after injury. Optimization strategies to further enhance the potential of MSCs are under development. The current study aimed to test the potency of hypoxic preconditioning of MSCs to enhance the therapeutic efficacy in a mouse model of neonatal HI injury.
Methods:
HI was induced on postnatal day 9 in C57Bl/6 mouse pups. MSCs were cultured under hypoxic (hypoxic-preconditioned MSCs [HP-MSCs], 1% O2) or normoxic-control (normoxic-preconditioned MSCs [NP-MSCs], 21% O2) conditions for 24 hours before use. At 10 days after HI, HP-MSCs, NP-MSCs, or vehicle were intranasally administered. Gold nanoparticle-labeled MSCs were used to assess MSC migration 24 hours after intranasal administration. At 28 days post-HI, lesion size, sensorimotor outcome, and neuroinflammation were assessed by hematoxylin and eosin staining, cylinder rearing task, and ionized calcium-binding adapter molecule 1 (IBA1) staining, respectively. In vitro, the effect of HP-MSCs was studied on transwell migration, neural stem cell differentiation and microglia activation, and the MSC intracellular proteomic content was profiled using quantitative Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).
Results:
Intranasally administered HP-MSCs were superior to NP-MSCs in reducing lesion size and sensorimotor impairments post-HI. Moreover, hypoxic preconditioning enhanced MSC migration in an in vitro set-up, and in vivo to the lesioned hemisphere after intranasal application. In addition, HP-MSCs enhanced neural stem cell differentiation into more complex neurons in vitro but had similar anti-inflammatory effects compared with NP-MSCs. Lastly, hypoxic preconditioning led to elevated abundances of proteins in MSCs related to extracellular matrix remodeling.
Conclusions:
This study shows for the first time that hypoxic preconditioning enhanced the therapeutic efficacy of MSC therapy in a mouse model of neonatal HI brain injury by increasing the migratory and neuroregenerative capacity of MSCs.
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