Systematic optimization of an engineered hydrogel allows for selective control of human neural stem cell survival and differentiation after transplantation in the stroke brain

Abstract

Stem cell therapies have shown promise in promoting recovery in stroke but have been limited by poor cell survival and differentiation. We have developed a hyaluronic acid (HA)-based self-polymerizing hydrogel that serves as a platform for adhesion of structural motifs and a depot release for growth factors to promote transplant stem cell survival and differentiation. We took an iterative approach in optimizing the complex combination of mechanical, biochemical and biological properties of an HA cell scaffold. First, we optimized stiffness for a minimal reaction of adjacent brain to the transplant. Next hydrogel crosslinkers sensitive to matrix metalloproteinases (MMP) were incorporated as they promoted vascularization. Finally, candidate adhesion motifs and growth factors were systemically changed in vitro using a design of experiment approach to optimize stem cell survival or proliferation. The optimized HA hydrogel, tested in vivo, promoted survival of encapsulated human neural progenitor cells (iPS-NPCs) after transplantation into the stroke core and differentially tuned transplanted cell fate through the promotion of glial, neuronal or immature/progenitor states. This HA hydrogel can be tracked in vivo with MRI. A hydrogel can serve as a therapeutic adjunct in a stem cell therapy through selective control of stem cell survival and differentiation in vivo.

Mechanical Stimulation of Cells Through Scaffold Design for Tissue Engineering

“…Stem cells in these diferent biomaterials had a diverse behaviour related with mechanical properties of the scafold and conirm that stifness is an important factor [37].…”

“…For example, Moshayedi et al [37] developed a hydrogel material to control neural cells fate in vivo. In this study, an injectable hydrogel was designed and showed to promote survival and diferentiation towards immature states of human neural progenitor cells.…”

Harnessing the Potential of Biomaterials for Brain Repair after Stroke

“…Many factors can control cell fate, yet few have been tested in combination with cell delivery in a hydrogel delivery system for stroke. Moshayedi et al (2016) encapsulated hiPSC-derived NPCs in HA gels modified with MMP-cleavable sequences for degradation in the brain, as well as soluble factors, BDNF and BMP4, and adhesive laminin peptides, YIGSR and IKVAV (Moshayedi et al, 2016). The authors found that after injection of the hydrogel with cells into the stroke-injured mouse brain, BDNF and BMP4 promoted astrocytic differentiation whereas the laminin sequences promoted neuronal differentiation.…”

“…The differentiation of cells cultured on fibrous scaffolds can be controlled by tuning the thickness of the fibers; rat NSCs cultured on polyethersulfone fiber meshes differentiate preferentially into oligodendrocytes on smaller diameter fibers and into neurons on wider diameter fibers (Christopherson et al, 2009). Others have seen an increase in NSC differentiation in vivo with the use of HA hydrogels (Lam et al, 2014;Führmann et al, 2016;Moshayedi et al, 2016).…”

“…The material should be biocompatible with brain tissue, which is more sensitive to mechanical and environmental stresses than other tissues (Saxena and Caroni, 2011). For maximum biocompatibility, the mechanical properties of the material should be similar to those of brain tissue, as stiffer materials lead to increased gliosis and worsened outcomes, whereas materials softer than the host tissue lead to poor material stability at the implant site (Moshayedi et al, 2016;Spencer et al, 2017). Due to the confined space of the skull the material must also be minimally swelling to avoid compressing the brain tissue and increasing intracranial pressure.…”