Dopaminergic Neurons Transplanted Using Cell‐Instructive Biomaterials Alleviate Parkinsonism in Rodents

Abstract

Cell replacement therapy (CRT) is a promising treatment for degenerative disorders, such as Parkinson's disease (PD). However, CRT is in general hindered by poor graft survival, limited cell dispersion, modest cell integration, and delayed therapeutic efficacy. These challenges need to be addressed to enhance the clinical translation of CRT. Here, key bioactive factors that increase the survival and dispersion of human pluripotent stem cell-derived midbrain dopaminergic (mDA) neurons, the primary type of cells lost in PD, are identified. mDA neurons cotransplanted with survival and dispersion factors within a protective hyaluronic acid hydrogel, optimized for controlled factor release and cell spread, alleviate disease symptoms in PD model rats. Importantly, treatment benefits correlate with increased graft survival, dispersion, and integration. Optimally engineered cell-instructive transplantation platforms thus offer promise for enhancing CRT in PD and potentially a range of degenerative diseases or trauma.

A hierarchically ordered compacted coil scaffold for tissue regeneration

“…Cell therapy, especially stem-cell transplantation, has attracted extensive attention as a promising treatment for many diseases since the day it was proposed [1][2][3][4][5][6] . In the typical process of cell transplantation, donor tissue is dissociated into individual cells, and then a proper scaffold is needed to support cell growth, differentiation or functionalization in vitro.…”

Advanced Materials to Enhance Central Nervous System Tissue Modeling and Cell Therapy

“…[106][107][108] Conversely, mDA neuron grafts in PD rodent models displayed enhanced cell survival and innervation if transplanted within a 3D hydrogel scaffold containing trophic cues. [109] Advantageously, materials can be engineered to exhibit a diverse range of chemical and physical properties that can be customized for a specific purpose, CQA and implantation region in the CNS, as we describe next.…”

“…D) HNCAM+ cells (green) implanted in a hyaluronic acid gel functionalized with growth factors (panels g and i) displayed increased graft area and cell innervation post‐implantation into the striatum of a rat model of Parkinson's disease compared to cells implanted in PBS (panels h and j) and corresponding quantification of graft area (panel k); Adapted with permission. [ 109 ] Copyright 2018, Wiley‐VCH.…”

Cell and Tissue Instructive Materials for Central Nervous System Repair

“…[232] Adil and co-workers devised a HA-based CTIM for the transplantation of previously differentiated dopaminergic neurons into a parkinsonian rat model. [233] By including GDNF, HGF, and Ephrin-B2, the authors intended to increase the dispersity and survival of transplanted cells (mimicking their in vitro results) with the final aim of impacting the progression of the disease. Animals receiving this CTIM showed signs of improved motor function, being it correlated with both increased innervation and synaptic integration of the graft.…”

“…Notably, injection of composite scaffolds into the injured brain of parkinsonian mice improved the survival and integration of cell grafts and reinnervation of the striatum, an effect that was potentiated with the delivery of GDNF 232. Adil and co‐workers devised a HA‐based CTIM for the transplantation of previously differentiated dopaminergic neurons into a parkinsonian rat model 233. By including GDNF, HGF, and Ephrin‐B2, the authors intended to increase the dispersity and survival of transplanted cells (mimicking their in vitro results) with the final aim of impacting the progression of the disease.…”