Encapsulation of MSCs and GDNF in an Injectable Nanoreinforced Supramolecular Hydrogel for Brain Tissue Engineering

The co-administration
of glial cell line-derived neurotrophic factor
(GDNF) and mesenchymal stem cells (MSCs) in hydrogels (HGs) has emerged
as a powerful strategy to enhance the efficient integration of transplanted
cells in Parkinson’s disease (PD). This strategy could be improved
by controlling the cellular microenvironment and biomolecule release
and better mimicking the complex properties of the brain tissue. Here,
we develop and characterize a drug delivery system for brain repair
where MSCs and GDNF are included in a nanoparticle-modified supramolecular
guest–host HA HG. In this system, the nanoparticles act as
both carriers for the GDNF and active physical crosslinkers of the
HG. The multifunctional HG is mechanically compatible with brain tissue
and easily injectable. It also protects GDNF from degradation and
achieves its controlled release over time. The cytocompatibility studies
show that the developed biomaterial provides a friendly environment
for MSCs and presents good compatibility with PC12 cells. Finally,
using RNA-sequencing (RNA-seq), we investigated how the three-dimensional
(3D) environment, provided by the nanostructured HG, impacted the
encapsulated cells. The transcriptome analysis supports the beneficial
effect of including MSCs in the nanoreinforced HG. An enhancement
in the anti-inflammatory effect of MSCs was observed, as well as a
differentiation of the MSCs toward a neuron-like cell type. In summary,
the suitable strength, excellent self-healing properties, good biocompatibility,
and ability to boost MSC regenerative potential make this nanoreinforced
HG a good candidate for drug and cell administration to the brain.