Article

Hydrogel Matrix to Support Stem Cell Survival After Brain Transplantation in Stroke

David Geffen School of Medicine at UCLA, Los Angeles, CA 98895, USA.
Neurorehabilitation and neural repair (Impact Factor: 4.62). 09/2010; 24(7):636-44. DOI: 10.1177/1545968310361958
Source: PubMed

ABSTRACT Stroke is a leading cause of adult disability. Stem/progenitor cell transplantation improves recovery after stroke in rodent models. These studies have 2 main limitations to clinical translation. First, most of the cells in stem/progenitor transplants die after brain transplantation. Second, intraparenchymal approaches target transplants to normal brain adjacent to the stroke, which is the site of the most extensive natural recovery in humans. Transplantation may damage this tissue. The stroke cavity provides an ideal target for transplantation because it is a compartmentalized region of necrosis, can accept a high volume transplant without tissue damage, and lies directly adjacent to the most plastic brain area in stroke. However, direct transplantation into the stroke cavity has caused massive death in the transplant. To overcome these limitations, the authors tested stem/progenitor transplants within a specific biopolymer hydrogel matrix to create a favorable environment for transplantation into the infarct cavity after stroke, and they tested this in comparison to stem cell injection without hydrogel support. A biopolymer hydrogel composed of cross-linked hyaluronan and heparin sulfate significantly promoted the survival of 2 different neural progenitor cell lines in vitro in conditions of stress and in vivo into the infarct cavity. Quantitative analysis of the transplant and surrounding tissue indicates diminished inflammatory infiltration of the graft with the hydrogel transplant. This result indicates that altering the local environment in stem cell transplantation enhances survival and diminishes cell stress. Stem cell transplantation into the infarct cavity within a pro-survival hydrogel matrix may provide a translational therapy for stroke recovery.

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    • "Among these various modifications, thiol-modified HA hydrogels have favorable properties for use with cell transplantation , including excellent biocompatibility and ease of injection [4]. For the delivery of neural stem cells, reports have shown that an HA-based hydrogel composed of cross-linked thiol-modified heparin, gelatin, and HA significantly promoted the survival of neural progenitor cell (NPC) lines in vitro and in vivo after delivery into the ischemic stroke cavity in mouse brain [5], and improve the survival of several NPC lines in either immunodeficient or immunocompetent animals [6]. Once transplanted, the microenvironment of the scaffolded, encapsulated cells may become subject to changes due to interactions either between stem cells and the gel or between the gel and the surrounding host tissue. "
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    ABSTRACT: Composite hyaluronic acid (HA) hydrogels containing gelatin are used in regenerative medicine as tissue-mimicking scaffolds for improving stem cell survival. Once implanted, it is assumed that these biomaterials disintegrate over time, but at present there is no non-invasive imaging technique available with which such degradation can be directly monitored in vivo. We show here the potential of chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) as a label-free non-invasive imaging technique to monitor dynamic changes in scaffold composition in vivo. The CEST properties of the three individual hydrogel components (HA, GelinS, and polyethylene glycol diacrylate) were first measured in vitro. The complete hydrogel was then injected into the brain of immunodeficient rag2−/− mice and CEST MR images were obtained at day 1 and 7 post-transplantation. In vitro, GelinS gave the strongest CEST signal at 3.6 ppm offset from the water peak, originating from the amide protons present in gelatin. In vivo, a significant decrease in CEST signal was observed at 1 week post-implantation. These results were consistent with the biodegradation of the GelinS component, as validated by fluorescent microscopy of implanted hydrogels containing Alexa Fluor 488-labeled GelinS. Our label-free imaging approach should be useful for further development of hydrogel formulations with improved composition and stability.
    Biomaterials 02/2015; 42. DOI:10.1016/j.biomaterials.2014.11.050 · 8.31 Impact Factor
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    • "For treatment of neurological disorders, most studies have focused on in vitro studies [12]. A recent study reported a positive effect of an HA hydrogel on the survival of NSCs transplanted into the cavity of stroked rat brain, although the protective effect was modest (the average number of surviving cells increased to 8000 from 4000 after scaffolding), especially considering the large quantity of cells initially injected (1 Â 10 5 , survival rate was then 8% vs. 4%, hydrogel vs. cells-only) [16]. The goal of our study was to optimize the hydrogel injection procedure and to perform a systematic serial study of its pro-survival effects for three different stem cell types in vivo. "
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    ABSTRACT: Successful cell-based therapy of neurological disorders is highly dependent on the survival of transplanted stem cells, with the overall graft survival of naked, unprotected cells in general remaining poor. We investigated the use of an injectable hyaluronic acid (HA) hydrogel for enhancement of survival of transplanted mouse C17.2 cells, human neural progenitor cells (ReNcells), and human glial-restricted precursors (GRPs). The gelation properties of the HA hydrogel were first characterized and optimized for intracerebral injection, resulting in a 25 min delayed-injection after mixing of the hydrogel components. Using bioluminescence imaging (BLI) as a non-invasive readout of cell survival, we found that the hydrogel can protect xenografted cells as evidenced by the prolonged survival of C17.2 cells implanted in immunocompetent rats (p < 0.01 at day 12). The survival of human ReNcells and human GRPs implanted in the brain of immunocompetent or immunodeficient mice was also significantly improved after hydrogel scaffolding (ReNcells, p < 0.05 at day 5; GRPs, p < 0.05 at day 7). However, an inflammatory response could be noted two weeks after injection of hydrogel into immunocompetent mice brains. We conclude that hydrogel scaffolding increases the survival of engrafted neural stem cells, justifying further optimization of hydrogel compositions.
    Biomaterials 04/2013; 34(22). DOI:10.1016/j.biomaterials.2013.03.095 · 8.31 Impact Factor
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    • "Finally, the use of transplantion auxiliaries as well as appropriate dosing of iPSCs should also be estimated carefully. Ischemic sites are associated with massive necrosis with poor blood supply and deficient extracellular support, so scaffolds such as Hydrogel Matrix and fibrin glue are presumed to promote formation of reciprocal connections between graft and host, and favorable results have been reported (Park et al., 2002; Zhong et al., 2010). With respect to dosing, the best approach is to extrapolate the dose from rodents to humans based on weight or brain size. "
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    ABSTRACT: Despite dramatic advancements in medical and surgical care, effective clinical therapies for ischemic stroke are limited. Stem-cell transplantation has emerged as a potential therapeutic approach for cell replacement in ischemic brain injuries. Inducible pluripotent stem cells (iPSCs) have become an alternative cell source for transplantation. They possess efficient capacities for neural differentiation without ethical and immune-rejection concerns. Substantial function of iPSCs in pre-clinical models of ischemic brain injury has been observed. However, several problems remain regarding the treatment of ischemic stroke with iPSCs: tumorigenicity, poor iPSC derivation methods, and undefined delivery variables. With the development of iPSC research, safer and more effective strategies will be achieved for highly effective and tumor-free cell treatment of ischemic stroke.
    Reviews in the neurosciences 08/2012; 23(4):393-402. DOI:10.1515/revneuro-2012-0042 · 3.31 Impact Factor
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