Objective: To create a three dimensional (3D) long-living model of human tissue-engineered nigrostriatal pathway (TE-NSP) comprised of discrete somatic and axonal compartments recapitulating the native pathway.

Background: With the rising prevalence of Parkinson’s disease (PD) and the complexity associated with heterogeneity in PD, we need reliable tools to study pathophysiology changes at cellular and molecular levels. Although tissue engineered constructs are well-established in the field of regenerative medicine and drug discovery, maintaining long-lived neuronal culture conditions without glial support is very challenging. Here, we sought to build a long-living model of TE-NSP based on clinical criteria that recapitulates the human NSP.  The TE-NSP model holds great potential as a testbed to map out and understand chronic pathological events occurring in human DA neurons, thereby providing insight into human pathophysiology.

Method: TE-NSPs were fabricated using methacrylated hyaluronic acid (MeHA) hydrogel encasement filled with collagen/laminin solution that were used to seed two types of neuronal aggregates, namely, human iPSC-derived dopaminergic (DA) neurons and striatal medium spiny neurons (MSNs). These TE-NSPs were characterized for axonal growth, viability and histological analysis up to 6 months.

Results: TE-NSPs fabricated with an aggregate containing 220,000 human DA neurons demonstrated a maximum length of 2.5 and 3 cm in the absence and presence of MSNs respectively. The DA neurons in the TE-NSPs exhibited survival up to 6 months in vitro with robust dense TH+ axonal tracts and 90% cell viability. In contrast, the neuronal aggregates cultured on 2D surface showed a significantly slower growth rate achieving a maximum length of 0.5 cm and survival for 4 weeks signifying that the 3D hydrogel microcolumns provide a platform for long-term survival of dopaminergic neuronal cultures.

Conclusion: Recapitulating some aspects of neurodegeneration in human neuron systems is currently an unmet need, including the effects of aging. Therefore, a long-living 3D human TE-NSP model with two discrete neuronal populations holds great potential in understanding the role of aging disease mechanisms on the underlying neurodegenerative events associated with PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-long-living-human-tissue-engineered-nigrostriatal-pathway-as-a-testbed-to-study-parkinsons-disease/