A Hyaluronan-Based Injectable Hydrogel Improves the Survival and Integration of Stem Cell Progeny following Transplantation

Abstract

SummaryThe utility of stem cells and their progeny in adult transplantation models has been limited by poor survival and integration. We designed an injectable and bioresorbable hydrogel blend of hyaluronan and methylcellulose (HAMC) and tested it with two cell types in two animal models, thereby gaining an understanding of its general applicability for enhanced cell distribution, survival, integration, and functional repair relative to conventional cell delivery in saline. HAMC improves cell survival and integration of retinal stem cell (RSC)-derived rods in the retina. The pro-survival mechanism of HAMC is ascribed to the interaction of the CD44 receptor with HA. Transient disruption of the retinal outer limiting membrane, combined with HAMC delivery, results in significantly improved rod survival and visual function. HAMC also improves the distribution, viability, and functional repair of neural stem and progenitor cells (NSCs). The HAMC delivery system improves cell transplantation efficacy in two CNS models, suggesting broad applicability.

Harnessing the Potential of Biomaterials for Brain Repair after Stroke

“…Yet, some materials or chemistries necessary for controlled drug release are incompatible with cell delivery due to degradation by-products or harsh fabrication conditions (Bible et al, 2012;Pakulska et al, 2013). For cell delivery, the material must be cytocompatible, able to promote cell adhesion to prevent anoikis, able to provide good cell distribution in order to prevent cell aggregation (often observed with transplants in saline; Ballios et al, 2015), and degradable. Topographical features, bioactive ligands, or drugs incorporated into the material can be used to guide cell behavior and fate.…”

“…The infarct provides a convenient space for delivery of a relatively large volume of cells, avoiding damage to nearby intact tissue while also localizing cells to the potentially salvageable tissue in the peri-infarct (Zhong et al, 2010;Willing and Shahaduzzaman, 2013;Ballios et al, 2015). Smith et al compared cell transplantation to the intracerebroventricular or intraparenchymal peri-infarct locations and after 14 weeks only found surviving cells when delivered into the intraparenchymal peri-infarct (Smith et al, 2012).…”

“…If injected in a saline solution, cells can backflow out of the brain tissue through the needle tract made by the injection (Ballios et al, 2015). A hydrogel system that can gel in situ is ideal as it provides an injectable material that becomes more viscous once in the brain and retains cells at the infarct site.…”

“…A hydrogel system that can gel in situ is ideal as it provides an injectable material that becomes more viscous once in the brain and retains cells at the infarct site. Studies directly comparing cell transplantation with and without a hydrogel carrier have reported a higher number of cells in the brain immediately following injection with the use of a hydrogel (Ballios et al, 2015;Cai et al, 2015), which is attributed to increased cell retention. HAMC, which is shear-thinning and inverse-thermal gelling, allows cells to be injected through a fine-gage needle into the brain where it will gel to localize cells to the injury site (Ballios et al, 2015;Payne et al, 2017).…”

Biomaterial applications in neural therapy and repair

“…In addition to ECM hydrogels, natural polymers like hyaluronic acid (HA) [70,71], fibrin [72], HAmethylcellulose (HAMC) [73], chitosan [74,75], and collagen [76] have been used extensively to deliver cells or molecules in the CNS. Collagen is a popular material used in biomedical applications since it is the most abundant protein and main component of peripheral ECM in mammalian tissues.…”