Semaphorin 3C Released from a Biocompatible Hydrogel Guides and Promotes Axonal Growth of Rodent and Human Dopaminergic Neurons

Abstract

Cell therapy in experimental models of Parkinson's disease replaces the lost dopamine neurons (DAN), but we still need improved methods to guide dopaminergic axons (DAx) of grafted neurons to make proper connections. The protein Semaphorin 3C (Sema3C) attracts DAN axons and enhances their growth. In this work, we show that the hydrogel PuraMatrix, a self-assembling peptide-based matrix, incorporates Sema3C and releases it steadily during 4 weeks. We also tested if hydrogel-delivered Sema3C attracts DAx using a system of rat midbrain explants embedded in collagen gels. We show that Sema3C released by this hydrogel attracts DAx, in a similar way to pretectum, which is known to attract growing DAN axons. We assessed the effect of Sema3C on the growth of DAx using microfluidic devices. DAN from rat midbrain or those differentiated from human embryonic stem cells showed enhanced axonal extension when exposed to hydrogel-released Sema3C, similar to soluble Sema3C. Notably, DAN of human origin express the cognate Sema3C receptors, Neuropilin1 and Neuropilin2. These results show that PuraMatrix is able to incorporate and release Sema3C, and such delivery guides and promotes the axonal growth of DAN. This biocompatible hydrogel might be useful as a Sema3C carrier for in vivo studies in parkinsonian animal models.

Roles of Semaphorins in Neurodegenerative Diseases

“…Paradoxically, the Sema3A found to promote neurodegeneration in PD pathogenesis, at the same time may be useful for steam cell transplantation therapy in PD patients [96][97][98][99]. Given that semaphorins participate in the formation of the nigrostriatal pathway during prenatal development, they have also been proposed to guide axons to their appropriate targets after possible cell replacement therapy with dopaminergic neurons [96,[100][101][102][103][104][105].…”

“…Sema3C, besides increasing length, also attracts axons, whereas Sema3F produces either no effect or axon repulsion [96,97]. Semaphorin axonal guidance results are promising toward the recovery of parkinsonian symptoms in transplanted PD animal models [98,99]. Therefore, even though semaphorins may be directly involved in promoting PD neurodegeneration, they could also be a strategy to restore the dopaminergic function by providing axon guidance cues after embryonic stem cell intranigral transplantation.…”

Semaphorin 3C and Its Receptors in Cancer and Cancer Stem-Like Cells

“…Sema3C functions as an axon attractant in migrating cortical axons, whereas Sema3A functions as a repellant [ 18 ]. Sema3C also promotes axonal growth of dopaminergic neurons in humans and rats [ 19 , 20 ], is essential for cortical and hippocampal neuron polarization and migration [ 21 , 22 , 23 ], and helps guide motor neurons to their targets [ 24 , 25 ], revealing a diverse range of neuronal projections that Sema3C regulates.…”

Multi-compartmental biomaterial scaffolds for patterning neural tissue organoids in models of neurodevelopment and tissue regeneration

“… 11 , 15 Hydrogels functionalized with axonal guidance molecules may enhance cellular attachment, migration, differentiation, and axonal extension, and hydrogels seeded with diseased cells can replicate innate pathological features of diseases like Alzheimer’s and Parkinson’s disease. 2 – 4 , 16 Characteristics like biomaterial stiffness, density, and cross-linking capability can influence cell differentiation and function, 17 and a wide array of tissue types and cell states may be achieved with the choice of biomaterial, either by means of intrinsic cell signals or by means of various growth factors and differentiation factors that can be supplied within the biomaterials.…”