Modulation of reactive astrocytes upon cell transplantation for the treatment of SCI
Funded in: 2014, 2015, 2016
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Problem: Reactive astrocytes contribute to the formation of the glial scar, but they might also have beneficial effects on axonal growth.
Target: Improvement of stem cell replacement therapies in SCI combined with modulation of reactive astrogliosis (via inhibition of GSK-3).
Goal: A new therapeutic approaches for the treatment of SCI
Spinal cord transection leads to neurological dysfunction by the loss of central control of motor, sensory, and autonomic function below the injury site. Due to severe tissue damage and inflammation, reactive astrocytes together with other cells contribute to formation of the glial scar, the physical and chemical barrier representing the main obstacle and detrimental event for axon regrowth. Fundamental aspects of astrocytes contributing to scar formation remain poorly understood.
In spite of this widely accepted detrimental role of astrogliosis in SCI, several lines of evidence suggest that reactive astrocytes might have tissue-protective functions and beneficial effects on axonal growth specially in synergism with transplanted cells like human embryonic stem cells (hESCs) or induced pluripotent stem cells (ihPSC). As possible mechanism of action, the modification of inhibitory properties of reactive astrocytes is discussed.
The concept of the project is to improve the success of stem cell therapies using hESC and iPSC derived neural progenitors of SCI combining with modulation of reactive astrogliosis. By inducing astrogliosis using the recently developed inhibitor Ro3303544 of the glycogen synthase kinase 3 (GSK-3), the team expects that combinatorial therapy will be more efficient than cell therapy alone. This will contribute to the discovery of new combined therapies, resulting in reduced secondary tissue degeneration and improved functional outcome after SCI.