Shear Containment of BDNF within Molecular Hydrogels Promotes Human Stem Cell Engraftment and Postinfarction Remodeling in Stroke

Abstract

Improved control over spatiotemporal delivery of growth factors is needed to enhance tissue repair. Current methods are limited-requiring invasive procedures, poor tissue targeting, and/or limited control over dosage and duration. Incorporation into implantable biomaterials enables stabilized delivery and avoids burst release/fluctuating doses. Here, the physical forces of fibrils formed by self-assembly of epitope-containing peptides are exploited. This biomimetic hydrogel is loaded with neurotrophic factor BDNF via a shear-induced gel-solution transition, unique to noncovalent hydrogels. This results in a biomaterial with three desirable features: a nanofibrillar scaffold, presentation of a laminin epitope, and slow release of BDNF. In a stroke-injury model, synergistic actions of this trimodal strategy on the integration of transplanted human neural progenitor cells, and protection of peri-infarct tissue are identified. These BDNF-functionalized hydrogels promote the integration of transplanted human embryonic stem cell-derived neural progenitors-resulting in larger grafts with greater cortical differentiation, appropriate for neuronal replacement. Furthermore, BDNF promotes the infiltration of host endothelial cells into the graft to augment vascularization of the graft, and adjacent penumbra tissue. These findings demonstrate the benefits of multifaceted tissue-specific hydrogels to provide biomimetics of the host tissue, while sustain protein delivery, to promote endogenous and graft-derived tissue repair. Self-Assembling PeptidesThe ORCID identification number(s) for the author(s) of this article can be found under https://doi.

Cytotoxic T cells swarm by homotypic chemokine signalling

“…Fourier transform infrared (FTIR), circular dichroism (CD) spectroscopy, and transmission electron microscopy were performed to verify synthesis and structure of the desired nanofibrillar structure (data not shown). CCL3 was loaded within the molecular hydrogel via our recent shear-containment methodology (Nisbet D. R.;.…”

Harnessing stem cells and biomaterials to promote neural repair

“…GDNF mixed directly into a collagen hydrogel with primary dopaminergic neurons resulted in dramatic increases in dopaminergic cell survival and host tissue reinnervation (Moriarty et al ., ). We recently demonstrated the benefit of delivering BDNF within an IKVAV SAP hydrogel to promote the survival and differentiation of human ESC‐derived cortical progenitors in a stroke model, also demonstrating increased vascularization of the graft and protection of the host tissue compared to BDNF delivery in the absence of the scaffold (Nisbet et al ., ). A limitation of this approach, however, is that the exact duration and level of delivery are dependent on the interactions between the specific protein and the specific material – and are not inherently optimized.…”

“…In this context, a non-degradable scaffold that provides a bridging network for the support of axonal regeneration may be more optimal. The requirements for stroke are similarwhere decreasing the lesion volume can result in significant functional improvement through the support of both endogenous and grafted cells (Somaa et al, 2017;Nisbet et al, 2018;Tuladhar et al, 2018). In the context of more discrete injuries such as PD and Huntington's disease, a scaffold that provides physical and chemical support for the survival and differentiation of cells upon implantation, but then slowly degrades once the cells have appropriately integrated within the host circuitry, may be a desirable alternative.…”

Cell and Tissue Instructive Materials for Central Nervous System Repair

“…Adding to their capacity of shaping the stroke environment by tailored presentation of bioactive factors, cell-and tissue-instructive hydrogels have also to be compliant with the mechanical properties of brain tissue as this feature is known to heavily influence cell fate. [172,173] Nisbet et al [174] utilized a Fmoc-IKVAV SAPNS shear-loading BDNF and encapsulating human embryonic stem cells (hESCs) to study if the controlled release of this neurotrophin would act in conjunction with these cells and the CTIM in the remodeling of poststroke environment. This approach proved to be suitable for the integration of transplanted cells into host tissue and remarkably the majority of hESCs in the SAPNS + BDNF group acquired cortical identity.…”