Three-dimensional bioactive scaffolds hold great promise as substrates for generating tissue from stem cells in vitro and for promoting tissue regeneration in vivo. As reported in Science, Silva and colleagues have developed a remarkable new nanofibre matrix that assembles spontaneously when it comes into contact with cells, and can be engineered to promote neuronal differentiation.

The authors constructed a molecule called IKVAV-PA, which included the five-amino-acid motif IKVAV (isoleucine–lysine–valine–alanine–valine). This motif occurs in the extracellular matrix component laminin, and it has been shown to induce and direct the growth of neurites. The IKVAV-PA molecules carried a net negative charge, and mutual repulsion prevented them from aggregating in solution at pH 7.4. However, when they were exposed to positive ions — for example, in living tissue — they formed nanofibres and assembled into a gel-like matrix.

The authors added mouse neural progenitor cells to a solution of IKVAV-PA, prompting the formation of a matrix that encapsulated the cells. The resulting scaffold had a high water content, which allowed efficient diffusion of nutrients. A high proportion of the progenitors differentiated rapidly into neurons, as indicated by the expression of specific marker genes and neurite outgrowth. By contrast, there was little evidence of astrocytic differentiation. A control molecule — EQS-PA — in which the laminin motif was replaced by the non-physiological sequence glutamic acid–glutamine–serine (EQS), was also capable of self-assembly, but failed to induce neuronal differentiation.

Interestingly, the IKVAV-PA nanofibres were also effective at promoting neuronal differentiation when they were presented to neural progenitors as a two-dimensional substrate on a culture dish. The authors proposed that the key to the success of the matrix is the high density of IKVAV epitope that is presented to the cells, rather than the three-dimensional conformation. A soluble IKVAV peptide added to an EQS-PA matrix was far less efficient at stimulating neuronal differentiation than the IKVAV-PA scaffold, indicating that the epitope needs to be integrated into the nanofibres to be appropriately presented.

Silva et al. found that the matrix could also be induced to assemble if it was injected into tissue, raising the tantalizing possibility that it could be used to stimulate the regeneration of injured nerves in vivo. As the matrix assembles on contact with tissue, it could be injected as a fluid at the injury site, which would be far less invasive than implanting a pre-formed scaffold. Also, because the IKVAV-PA scaffold seems to suppress astrocytic differentiation, it is unlikely to exacerbate the injury by inducing glial scar formation. Further investigations should uncover the full potential of this intriguing material.