Gelatin methacryloyl hydrogel as a potential scaffold for cell transplantation for Huntington’s disease

Abstract Cell replacement therapy is a promising strategy for treating Huntington’s disease. Advances in cell reprogramming now allow the generation of clinically relevant cells; however, conventional delivery methods can compromise long-term cell survival and maturation. Hydrogels have emerged as supportive three-dimensional scaffolds that better mimic the in vivo environment. This study examined whether encapsulating human-induced lateral ganglionic eminence precursor cells (hiLGEPs) in gelatin methacryloyl (GelMA) hydrogel enhanced differentiation after transplantation into the striatum of the quinolinic acid lesion rat model of Huntington’s disease. hiLGEPs were delivered either in cell culture medium (n = 5) or in a pre-crosslinked GelMA solution (n = 4) prior to transplantation. GelMA was polymerised in situ using a visible-light optical fibre system, and grafts were assessed 4 weeks later. Transplanted cells survived in all animals. Notably, GelMA-encapsulated hiLGEPs produced significantly more protein gene product 9.5 (PGP9.5+) neurons than those delivered in cell culture medium. Transplanted cells in both groups differentiated into microtubule-associated protein 2 (MAP2+) and GABA+ phenotypes, with no detectable differences in graft volume. These findings provide the first evidence that encapsulating hiLGEPs in GelMA enhances early neuronal differentiation following transplantation, supporting GelMA hydrogel as a promising delivery scaffold for cell replacement therapy in Huntington’s disease.