Journal
CELL REPORTS
Volume 20, Issue 8, Pages 1964-1977Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.07.069
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Funding
- National Health and Medical Research Council Australia [APP1122974]
- Australian Research Council [130103131]
- CASS Foundation, Australia
- Victorian Government's Operational Infrastructure Support grant
- Natural Sciences and Engineering Research Council of Canada Postgraduate Scholarship Doctoral award
- NHMRC Career Development Fellowship
- Senior Medical Research Fellowship
- Australian Microscopy and Microanalysis Research Facility
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Stem cell transplants offer significant hope for brain repair following ischemic damage. Pre-clinical work suggests that therapeutic mechanisms may be multi-faceted, incorporating bone-fide circuit reconstruction by transplanted neurons, but also protection/regeneration of host circuitry. Here, we engineered hydrogel scaffolds to form bio-bridges'' within the necrotic lesion cavity, providing physical and trophic support to transplanted human embryonic stem cell-derived cortical progenitors, as well as residual host neurons. Scaffolds were fabricated by the self-assembly of peptides for a laminin-derived epitope (IKVAV), thereby mimicking the brain's major extracellular protein. Following focal ischemia in rats, scaffold-supported cell transplants induced progressive motor improvements over 9 months, compared to cell-or scaffold-only implants. These grafts were larger, exhibited greater neuronal differentiation, and showed enhanced electrophysiological properties reflective of mature, integrated neurons. Varying graft timing post-injury enabled us to attribute repair to both neuroprotection and circuit replacement. These findings highlight strategies to improve the efficiency of stem cell grafts for brain repair.
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