In vivo responses of neural progenitor cells to extracellular matrix signaling under pathological conditions

Abstract

The adult brain has an inherently low capacity for tissue regeneration, and neurons lost to disease or injuries are normally not replaced. This becomes especially apparent when stroke or brain trauma occurs. The discovery of neurogenesis and neural stem cells in the adult brain has opened up new avenues for treatment of the injured brain. In the adult brain, neural stem cells are present in two distinct neurogenic areas, the subventricular zone and the hippocampus. These neural stem cells are capable of generating new neu-rons throughout life. As these cells have been shown to respond to signals from the surrounding extracellular matrix, we were interested in how we can utilize these for the purpose of regenerating lost neurons. In paper I, we use an injectable self-assembling peptide amphiphile coupled to a migration-inducing peptide sequence derived from Tenascin-C, a glycoprotein natural occurring in the extracellular matrix of the neuro-genic areas. In this paper, we re-directed cells from their normal path, the rostral migra-tory stream, to migrate into the cortex using the Ten-C-peptide amphiphile. Further-more, this was done without causing an exacerbated glial response or glial scar. In paper II we used a similar biomaterial with another naturally occurring sequence, RGDS, de-rived from fibronectin. In this study, we were interested in the potential of the RGDS-peptide amphiphile as a possible cell scaffold for neural stem cell transplants. The in-troduction of a foreign material into the CNS can lead to a strong reactive gliosis re-sponse from endogenous astrocytes and microglia. Surprisingly, not only did the RGDS-peptide amphiphile not elicit a stronger glial response than the control needle wound injury, but it rather suppressed the reactivity of astrocytes and microglia. These results indicate great potential of the biomaterial for future use an artificial ECM for cell trans-plants in the CNS. In paper III, we were interested in the role of RHAMM, the receptor for hyaluronan, one of the most abundantly expressed glycosaminoglycans in the brain extracellular matrix, in stroke-induced neurogenesis. We observed RHAMM in both unlesioned and unlesioned animals being important for cell proliferation and neurogen-esis in both the SVZ and hippocampus of the adult brain.