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: 3.98). 09/2010; 24(7):636-44. DOI: 10.1177/1545968310361958
Source: PubMed


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.
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    • "In addition, HS was used to culture ES cells and iPS cells, which retained their growth and pluripotent characteristics [38]. HS hydrogels also showed good performance in cell delivery and subsequent tissue repair in vivo [39]. "
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    • "In general, the concept of preconstructing neural circuits in vitro together with the associated implantation technology is naturally applicable for advances being made in stem cells research [39–43] and may begin to offer a new avenue for cell replacement strategies that aim to treat other CNS disorders which require the reestablishment of point-to-point contacts. Recently, hydrogels have been widely used as carriers for growth factors and cells [44, 45], but delivery of the constructs remains a difficulty [46]. The technology highlighted here would enable one to grow neural tissue/cells within a medium (such as a hydrogel) within a scaffold and displace this construct in vivo in a way that would not disturb the (pre)organisation/growth of the construct. "
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    ABSTRACT: Implanting pieces of tissue or scaffolding material into the mammalian central nervous system (CNS) is wrought with difficulties surrounding the size of tools needed to conduct such implants and the ability to maintain the orientation and integrity of the constructs during and after their transplantation. Here, novel technology has been developed that allows for the implantation of neural constructs or intact pieces of neural tissue into the CNS with low trauma. By "laying out" (instead of forcibly expelling) the implantable material from a thin walled glass capillary, this technology has the potential to enhance neural transplantation procedures by reducing trauma to the host brain during implantation and allowing for the implantation of engineered/dissected tissues or constructs in such a way that their orientation and integrity are maintained in the host. Such technology may be useful for treating various CNS disorders which require the reestablishment of point-to-point contacts (e.g., Parkinson's disease) across the adult CNS, an environment which is not normally permissive to axonal growth.
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