Development of stem cell-based therapies for the treatment of encephalopathy of prematurity
The development of cell transplantation as a therapy for perinatal hypoxic of preterm birth-related brain injury in the fetus and newborn is our research focus. Encephalopathy of prematurity leads to severe neonatal morbidity and mortality and to long-term neurological deficits. Etiologies mainly include hypoxia-ischemia due to reduced cerebral blood flow and maternal/fetal infection and inflammation. The damage is characterized by the degeneration of the white and grey matter, mostly due to maturation arrest of oligodendrocyte progenitor cells (OPC), followed by myelination disturbances and neuronal degeneration.
Perinatal tissues have gained increasing interest as sources of stem cells, due to their availability, minimally-invasive collection, and low immunogenicity. Mesenchymal stromal cells (MSC) derived from perinatal tissues are recognized as promising tools in regenerative medicine through their immunomodulatory, anti-microbial and anti-inflammatory capacities. Their mechanisms of action are attributed to the cells’ secretome rather than to their differentiation and replacement capacities.
We investigate the potential of human umbilical cord tissue-derived stromal/stem cells as a cell graft in perinatal brain injury using various in vitro and in vivo models. Noninvasive protocols, like the intranasal application, have been successfully evaluated by the group. Standardized sensorimotor behavioral tests show stem cell transplantations’ effects on brain function. Our specific interest is in the mechanisms leading to the injury and to neuroregeneration in order to develop an optimal therapy for perinatal brain injury.
Characterization of extracellular vesicles derived from human umbilical cord mesenchymal stromal cells
Extracellular vesicles (EV) are small vesicles secreted by the cells and contain proteins, lipids, and nucleic acids, which they transfer from cell to cell. Extracellular vesicles show therapeutic effects that reflect the characteristics of their cells of origin. The administration of extracellular vesicles derived from mesenchymal stromal/stem cells (MSC-EV) has been shown to promote neuroregeneration in various disease models. Their cargo, specifically micro RNAs (miRNAs), has increased interest in their regulatory functions in brain development and neurological disorders. In animal models of neurodegenerative disorders, the administrations of MSC-EVs contributed to neural repair and functional recovery.
EV derived from perinatal MSC contain a molecular cargo, including miRNAs, that interferes with pathways involved in hypoxia/ischemia and inflammation, leading to the attenuation of neurodegenerative diseases such as perinatal white matter disease. We are focusing on small EVs (sEVs) derived from the umbilical cord’s matrix (Wharton’s jelly, WJ) and characterize their cargo, esp. the miRNAs and proteins. Differential expression (DE) of disease-related genes, proteins and miRNAs are analyzed in our preterm neonatal models to confirm disease-specific targets and pathways involved in the pathophysiology. Loss- and gain-of-function studies serve as proof-of-principle for the mechanisms of action in the neonatal brain injury disease models for the molecules found to be associated with the EV. Understanding these mechanisms will help in the understanding of the disease and in developing new therapeutic strategies.
Role of astrocyte polarization on the development of white matter injury as a consequence of preterm birth
Reactive astrocytes are a well-accepted hallmark of injury to the developing human brain, but their specific roles in the disease pathogenesis of perinatal brain injury remain unknown. Studies in the mature brain highlight the formation of molecularly distinct reactive astrocyte states with contrasting roles after injury, some capable of mediating brain repair and others with toxic functions. Deciphering the reactivity states of astrocytes in perinatal brain injury, the evolution of these states, and their roles in disease outcomes is an essential step towards enabling improved recovery of the injured prenatal brain.
To prove that astrocytes in the developing brain exhibit heterogeneous and region-dependent reactivity in response to acute and chronic perinatal brain insults, we characterize astrocyte reactivity across brain regions in acute and chronic perinatal brain injury using single cell transcriptomics and rodent models of acute perinatal inflammatory/hypoxic injury, and chronic gestational hypoxia. This line of research will shed light on mechanistic commonalities and differences in reactive astrocyte states following acute and chronic perinatal insults. The results will be validated in human post-mortem fetal/neonatal brains with acute perinatal and chronic gestational brain injury through a collaboration with the University of California, San Francisco (USA).
To test if inflammatory astrocytes expressing C3 are necessary and sufficient to drive the disruption of myelination in perinatal white matter injury, we are assessing myelination after constitutive and temporally controlled blockade of inflammatory astrocyte formation in rodent models of acute perinatal inflammatory/hypoxic injury. Inhibiting the formation/reversal of this reactive astrocyte subtype could become a therapeutic goal.
Furthermore, we are testing the diagnostic potential of peripherally detected fetal/perinatal astrocyte-derived exosomes as a biomarker of astrocyte reactivity using astrocyte-specific exosome in vitro and in vivo models. If the development of a method for remote monitoring of fetal and neonatal astrocyte reactivity is successful, this biomarker approach could be used to inform treatment/delivery decisions during the course of pregnancies complicated by conditions endangering fetal brain health.
