Role of Fibrinogen on neural stem cell differentiation in the context of neural stem cell transplantation
Funded in: 2019, 2020, 2021
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Problem: Survival and differentiation of transplanted stem cells is strongly influenced by the local environment
Target: By depleting fibrinogen we will study the effects of this blood protein on human neural stem cell identity and their integration into the lesion area
Goal: Discovering mechanisms applicable to control neural stem cell fate and functions to promote repair
Transplantation of neural stem cells has shown promise in improving tissue sparing, myelination of spared fibers, and the formation of new connections from transplanted neurons in animal models of spinal cord injury. Human neural stem cells derived from induced pluripotent stem cells might therefore be useful for regeneration after injury. The survival and differentiation of transplanted stem cells is strongly influenced by the local environment that is dramatically changed after spinal cord injury. After injury, the blood-brain-barrier breaks down and blood proteins enter into the lesion site. One of the blood-derived proteins that accumulates around sites of spinal cord injury is the protein fibrinogen, the major architectural protein component of blood clots.
Previous studies have suggested that fibrinogen can inhibit axonal regeneration and contributes to astrocyte scar formation. These studies were done in vitro using mouse neurons or astrocytes. Whether the same signaling pathways are important in human cells and whether these signaling pathways influence the differentiation of human neural stem cells derived from induced pluripotent stem cells has not been investigated.
The scientists will investigate the behavior of human stem cells transplanted into mice after spinal cord injury. By depleting the blood-derived protein fibrinogen they will also study the effects of this blood protein on human neural stem cell identity and their integration into the lesion area. This study will shed light on the role of a changed environment after spinal cord injury on the cell fate of human neural stem cells, potentially discovering mechanisms applicable to control neural stem cell fate and functions to promote repair after spinal cord injury.