Development of human umbilical cord mesenchymal stromal cell-based therapies for the treatment of encephalopathy of prematurity
This project focuses on the development of cell transplantation as a therapy for perinatal brain injury in the fetus and newborn associated with preterm birth. 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 stem 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. Current work using a human iPSC-derived brain organoid model in our lab allows us to validate our rodent findings and further our understanding of the therapeutic mechanism of EVs in human cells. Understanding these mechanisms will help in the understanding of the disease and in developing new therapeutic strategies.
Understanding reactive astrocytes in perinatal brain injury: potential as therapeutic target and diagnostic tool
(Brosius Lutz Group)
Reactive astrocytes are a well-accepted hallmark of injury to the developing human brain, but the specific role that these cells play in the disease pathogenesis of perinatal brain injury remains unknown. Studies in the injured 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 molecular identity of astrocytes in perinatal brain injury, the evolution of these reactive states, and their roles in disease is an essential step towards developing targeted treatment strategies to ameliorate disease outcomes.
We are characterizing astrocyte reactivity using single cell sequencing and spatial transcriptomics in rodent models of acute perinatal inflammatory/hypoxic brain injury and chronic gestational hypoxia. This work will provide mechanistic insight into the role of reactive astrocytes in disease pathophysiology. Furthermore, we are testing the feasibility of using peripherally detected fetal/neonatal astrocyte-derived extracellular vesicles as a biomarker of perinatal brain injury. This project is supported by a 2023 SNSF Ambizione Award. Work on this project is currently carried out by PhD students Marel Steinfort and Emma Liedtke.
Mechanisms underlying predisposition to chronic disease in adulthood following intrauterine growth restriction (IUGR)
This is a collaborative project between our lab and the Department of Nephrology at the Insel Hospital (Prof. Uyen Huynh-Do, Stefan Rudloff, PhD) focusing on long-term sequelae of IUGR and their underlying mechanisms. The project involves experiments in a mouse model of IUGR, multi-omics sequencing, and work with human samples. Our lab’s role in the project focuses on long-term effects of IUGR on the brain. This project is led in our lab by Amanda Brosius Lutz, MD PhD.
