Intranasal mesenchymal stem cell therapy to boost myelination after encephalopathy of prematurity
Josine E G Vaes1,2, Caren M van Kammen1, Chloe Trayford3
1Department for Developmental Origins of Disease, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Insights
Mesenchymal stem cells (MSCs) delivered intranasally show promise in treating encephalopathy of prematurity (EoP). This therapy improved myelination and neuroinflammation in a mouse model, offering hope for preterm infants.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Developmental Biology
Background:
- Encephalopathy of prematurity (EoP) causes neurodevelopmental issues in preterm infants.
- Diffuse white matter injury (dWMI) is a common form of EoP, linked to impaired oligodendrocyte (OL) maturation.
- Current treatments for dWMI are lacking.
Purpose of the Study:
- To investigate the therapeutic potential of intranasal mesenchymal stem cell (MSC) therapy for dWMI.
- To develop and utilize a double-hit dWMI mouse model mimicking clinical scenarios.
Main Methods:
- A double-hit dWMI mouse model was created using postnatal systemic inflammation and hypoxia-ischemia.
- Intranasal MSC administration was employed to assess therapeutic effects.
- Coculture systems and analysis of secreted factors (IGF1, EGF, LIF, IL11) were used to elucidate mechanisms.
Main Results:
- Intranasal MSCs migrated to the injured brain, improving myelination and functional outcomes.
- MSC therapy reduced neuroinflammation and rescued OL maturation in the dWMI model.
- MSCs secrete factors that promote OL maturation and reduce neuroinflammation, adapting their secretome to the injury environment.
Conclusions:
- The developed mouse model effectively mimics clinical EoP and dWMI.
- Intranasal MSC delivery is a promising strategy to restore myelination and improve neurodevelopmental outcomes in preterm infants.
- MSC-derived factors play a key role in neuroprotection and regeneration after dWMI.
Abstract:
Encephalopathy of prematurity (EoP) is a common cause of long-term neurodevelopmental morbidity in extreme preterm infants. Diffuse white matter injury (dWMI) is currently the most commonly observed form of EoP. Impaired maturation of oligodendrocytes (OLs) is the main underlying pathophysiological mechanism. No therapies are currently available to combat dWMI. Intranasal application of mesenchymal stem cells (MSCs) is a promising therapeutic option to boost neuroregeneration after injury. Here, we developed a double-hit dWMI mouse model and investigated the therapeutic potential of intranasal MSC therapy. Postnatal systemic inflammation and hypoxia-ischemia led to transient deficits in cortical myelination and OL maturation, functional deficits and neuroinflammation. Intranasal MSCs migrated dispersedly into the injured brain and potently improved myelination and functional outcome, dampened cerebral inflammationand rescued OL maturation after dWMI. Cocultures of MSCs with primary microglia or OLs show that MSCs secrete factors that directly promote OL maturation and dampen neuroinflammation. We show that MSCs adapt their secretome after ex vivo exposure to dWMI milieu and identified several factors including IGF1, EGF, LIF, and IL11 that potently boost OL maturation. Additionally, we showed that MSC-treated dWMI brains express different levels of these beneficial secreted factors. In conclusion, the combination of postnatal systemic inflammation and hypoxia-ischemia leads to a pattern of developmental brain abnormalities that mimics the clinical situation. Intranasal delivery of MSCs, that secrete several beneficial factors in situ, is a promising strategy to restore myelination after dWMI and subsequently improve the neurodevelopmental outcome of extreme preterm infants in the future.
