Bioactive Nanofibers Induce Neural Transdifferentiation of Human Bone Marrow Mesenchymal Stem Cells

Abstract

The combination of biomaterials with stem cells is a promising therapeutic strategy to repair traumatic injuries in the central nervous system, and human bone marrow mesenchymal stem cells (BMSCs) offer a clinically translatable option among other possible sources of stem cells. We report here on the use of a supramolecular bioactive material based on a peptide amphiphile (PA), displaying a laminin-mimetic IKVAV sequence to drive neural transdifferentiation of human BMSCs. The IKVAV-PA self-assembles into supramolecular nanofibers that induce neuroectodermal lineage commitment after 1 week, as evidenced by the upregulation of the neural progenitor gene nestin (NES) and glial fibrillary acidic protein (GFAP). After 2 weeks, the bioactive IKVAV-PA nanofibers induce significantly higher expression of neuronal markers β-III tubulin (TUJ-1), microtubule-associated protein-2 (MAP-2), and neuronal nuclei (NEUN), as well as the extracellular matrix laminin (LMN). Furthermore, the human BMSCs exposed to the biomaterial reveal a polarized cytoskeletal architecture and a decrease in cellular size, resembling neuron-like cells. We conclude that the investigated supramolecular biomaterial opens the opportunity to transdifferentiate adult human BMSCs into neuronal lineage.

Cross-Linked Self-Assembling Peptides and Their Post-Assembly Functionalization via One-Pot and In Situ Gelation System

“…However, despite the fact that self-assembling peptides (SAPs) can self-assemble into high-aspect-ratio nanofibers resembling nanofibrous ECMs [14][15][16][17][18], the practical application of such nanomaterials has been limited due to their intrinsic instability, low-performance, and low-strain/stress response [19]. Further, the incorporation of functional motifs into SAP nanostructures has generally been limited to bioactive peptides tethered to the C-or N-terminal of an SAP sequence during solid-phase peptide synthesis [20][21][22][23][24][25][26][27][28]. Additionally, the presence of functional motifs, bringing additional hydrophobic and charged interactions, could potentially influence the self-assembly process of the SAP molecules, resulting in the formation of an altered nanostructures [29] and consequently posing limits to their potential functionalization [20,30].…”

Design of materials with supramolecular polymers

“…Also depending on peptide sequence and solvent conditions, the amphiphilic monomers can form a range of architectures that include spherical micelles [73] , cylindrical fibers [65] , flat belts [74] , and twisted ribbons [75] . These primarily filamentous structures are highly reminiscent of structures present in the natural extracellular matrix (ECM) of cells and as demonstrated by extensive research over the past two decades an ideal platform to create supramolecular polymers for cell signaling in regenerative medicine through the presentation of biological cues by the peptide-based terminal segment of monomers [ [40] , [41] , [42] , [43] , [44] , [46] , [47] , [48] , [49] , 52 , 65 , [76] , [77] , [78] , [79] ].…”

“…Peptide amphiphile monomers that create filament-like supramolecular polymers, were reported by our laboratory in 2001 [65] , and continue to provide unique opportunities for biomedical applications [ 39 , 40 , 42 , 44 , 46 , [48] , [49] , [50] , 77 , 79 , [94] , [95] , [96] , [97] ] and development of novel materials that include robotic soft materials [ 34 , 35 ]. In one recent example, we demonstrated the importance of dynamic behavior in supramolecular polymers to enhance bioactivity, by developing sulfated glycopeptide amphiphile monomers.…”

Recent Progress in the Design and Application of Supramolecular Peptide Hydrogels in Cancer Therapy

“…For instance, Stupp and coworkers incorporated a laminin-mimetic IKVAV sequence into their peptide amphiphile design (C 16 V 2 A 2 E 4 GIKVAV), creating a supramolecular hydrogel for neural transdifferentiation. [123] Yang and colleagues modified their peptide hydrogelator with folic acid (FA) to generate FA-functionalized hydrogel, which significantly improved the retention and survival of pluripotent stem (iPS) cells. [124] Li and colleagues reported a new peptide gelator (Nap-FFRGD) to encapsulate vascular endothelial growth factor (VEGF), and the resulting hydrogel enhanced blood capillary density in mice.…”