Cortical Reshaping and Functional Recovery Induced by Silk Fibroin Hydrogels-Encapsulated Stem Cells Implanted in Stroke Animals

Abstract

The restitution of damaged circuitry and functional remodeling of peri-injured areas constitute two main mechanisms for sustaining recovery of the brain after stroke. In this study, a silk fibroin-based biomaterial efficiently supports the survival of intracerebrally implanted mesenchymal stem cells (mSCs) and increases functional outcomes over time in a model of cortical stroke that affects the forepaw sensory and motor representations. We show that the functional mechanisms underlying recovery are related to a substantial preservation of cortical tissue in the first days after mSCs-polymer implantation, followed by delayed cortical plasticity that involved a progressive functional disconnection between the forepaw sensory (FLs1) and caudal motor (cFLm1) representations and an emergent sensory activity in peri-lesional areas belonging to cFLm1. Our results provide evidence that mSCs integrated into silk fibroin hydrogels attenuate the cerebral damage after brain infarction inducing a delayed cortical plasticity in the peri-lesional tissue, this later a functional change described during spontaneous or training rehabilitation-induced recovery. This study shows that brain remapping and sustained recovery were experimentally favored using a stem cell-biomaterial-based approach.

Combined Adipose Tissue-Derived Mesenchymal Stem Cell Therapy and Rehabilitation in Experimental Stroke

“…Neuroprotection may also be a prerequisite for delayed cortical plasticity and functional recovery. In the elegant work of Fernández-García et al (69), transplantation of mesenchymal stem cells alone into stroke mice was not effective as these animals showed permanent sensorimotor deficits in the grid walking test. However, when cells where encapsulated in silk fibroin hydrogel, significant cortical neuroprotection was observed, leading to delayed remapping of forelimb representations and a behavioral recovery similar to that associated with rehabilitation.…”

Biomimetic Approaches for Separated Regeneration of Sensory and Motor Fibers in Amputee People: Necessary Conditions for Functional Integration of Sensory–Motor Prostheses With the Peripheral Nerves

“…Considering that not all biomaterials accomplish for the strict requirements of the nervous system, silk appears as a very promising solution (Zhang et al, 2012). Because of its high biocompatibility and excellent mechanical properties (Heim et al, 2009), silk is currently being explored for the development of many new therapies (Vepari and Kaplan, 2007;Fernández-García et al, 2018). Furthermore, the possibility of producing regenerated silk fibers [artificially spun fibers, from a solution of natural silk protein (Madurga et al, 2017b)] led to the generation of high-performance silk fibroin fibers with a wide range of geometries, which, in addition, can be functionalized (Madurga et al, 2017a).…”

Biomaterials to Neuroprotect the Stroke Brain: A Large Opportunity for Narrow Time Windows

“…(C) At the top, representative coronal brain sections from two mice stained with TTC (2,3,5-triphenyltetrazolium chloride) 24 h after MCA occlusion at distal level respect the Circle of Willis. In this specific stroke model, the infarct area (in a white colour) is mainly restricted to the cortex (scale bar 0.5 cm) [83][84][85]. In the middle, as part of the inflammatory response, an intense astrogliosis (Glial Fibrillary Acidic Protein staining) can usually be detected in the infarcted hemisphere in relation to the contralateral hemisphere (scale bars 700 µm and 100 µm, respectively).…”

“…This strategy reduces invasiveness, prevents subsequent damage of viable functional tissue, and is very appropriate for cell encapsulation. Different hydrogel-based biomaterials have been implanted in the striatum [84,159], in the stroke cavity [160,161], or epicortically above the brain's surface [162,163]. A priori, the implantation of static hydrogels could be more able to treat focal injuries, although alternative approaches should be explored for global damage caused by severe stroke or neurodegenerative disorders, affecting several brain structures, such as the cortex, hippocampus, and striatum (e.g., Alzheimer's disease).…”

“…Thus, in the context of cellular therapies, it is possible to tune the polymer concentration and cross-linking density to select the mechanical properties of a hydrogel and its level of graft integration with the recipient [175]. For example, it is feasible to create highly compartmentalized hydrogels with very strict barriers to prevent donor cell-host cell contact, thus avoiding the entrance of inflammatory and harmful signals, which are usually present in the damaged tissues, towards the encapsulated cells [84]. Alternatively, it is possible to design more open systems to achieve large-scale integration between donor and host components [176].…”