Improvements in brain recovery observed in mouse models using genetically engineered stem cells
Researchers from UC Davis (CA, USA) have identified neuron interactions which offer a possible pathway for the development of therapies for human myelin diseases, including cerebral palsy and multiple sclerosis.
Led by principal investigator Wenbin Deng (UC Davis) the group report data demonstrating immature astroglial transplants, derived from human iPSCs, are highly protective against white matter injury, in addition to improving spatial learning and memory function in mouse models.
The group first generated immature astrocytes from human iPSCs and induced some to mature. The effects of immature versus mature astrocytes on myelin-producing oligodendrocytes were then compared. In cell culture, immature astrocytes were observed to better promote oligodendrocyte proliferation when compared with mature astrocytes. In addition, the investigators for the first time identified a factor secreted by immature astrocytes, tissue inhibitor of metalloproteinase-1 (TIMP-1), as important to astrocytes’ effects on oligodendrocytes.
Immature astrocytes were next implanted in mouse models of white matter damage from low blood flow. After 4 days, the density of myelinated axons was observed to be significantly higher in mice that received the astroglial implant secreting TIMP-1. If TIMP-1 secretion by astrocytes was inhibited before implantation, the positive effects on myelination did not occur, highlighting the factor’s importance in the protective influence of immature astrocytes. The factors collected from the immature iPSC-derived astrocytes, including TIMP-1, were subsequently concentrated and delivered intranasally to the mouse models, promoting proliferation of oligodendrocytes in the brain.
“This work has far-reaching implications in understanding the pathogenesis of white matter injury and is an important step toward developing treatment strategies based on astrocyte replacement,” explained Deng. “We believe that the human iPSC technology may one day be applied to patients and change the standard of care for treating central nervous system disorders in which myelin loss plays an important role. We are hopeful that his could lead to a promising therapy for premature brain injury, cerebral palsy, multiple sclerosis, spinal cord injury, white matter stroke and many neurodegenerative diseases.”
Written by Hannah Wilson