Transplantation of Human Neural Precursor Cells in Matrigel Scaffolding Improves Outcome from Focal Cerebral Ischemia after Delayed Postischemic Treatment in Rats

Abstract

Transplantation of neural cells is a potential approach for the treatment of stroke, but the disruption of tissue architecture that accompanies stroke may limit the efficacy of transplantation. One strategy for enhancing the ability of transplants to restore brain structure and, thereby, function is to administer cells together with biomaterial scaffolding. We occluded the middle cerebral artery in adult rats and, 3 wks later, injected one of the following into the infarct cavity: (a) artificial cerebrospinal fluid, (b) Matrigel scaffolding, (c) human neuronal precursor cells, (d) scaffolding plus cells, or (e) cells cultured in and administered together with scaffolding. When tested up to 9 wks later, the latter group showed reduced infarct size, survival and neuronal differentiation of transplanted cells, and improved outcome on behavioral tests of sensorimotor and cognitive function. These results indicate that transplantation of human neural cells together with the scaffolding in which they are cultured has the potential to improve outcome from stroke, even when treatment is delayed for several weeks after the ischemic event.

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

“…These data now provide an impetus and opportunity to determine the extended utility of LIF signaling on NP cells to be used in neural cell-based therapies. Although others have used the NP cells we previously generated in animal models, the effect of LIF on these NP cells in vivo was not investigated [5]. Here both LIF À and LIF þ treated cells equally reduce infarct volumes in mouse models of stroke in as little as 24 hours postinjection (Fig.…”

“…We have previously derived a self-renewing but fate-restricted neural progenitor (NP) cell line from hESC that can generate highly enriched neuronal populations under specific conditions [2,3], thus serving as a potentially unlimited source of human neurons for both basic [4] and applied research [5]. This progenitor line has previously been used to study neurotoxicity, differentiation to specific neuronal phenotypes, drug screening, and transplantation experiments in rodent models of stroke [4,5].…”

“…We have previously derived a self-renewing but fate-restricted neural progenitor (NP) cell line from hESC that can generate highly enriched neuronal populations under specific conditions [2,3], thus serving as a potentially unlimited source of human neurons for both basic [4] and applied research [5]. This progenitor line has previously been used to study neurotoxicity, differentiation to specific neuronal phenotypes, drug screening, and transplantation experiments in rodent models of stroke [4,5]. However, the ultimate success of NP cell-based therapy in transplantation experiments may depend on identifying factors that enhance the capacity of these cells to expand in vitro and resisting suboptimal conditions such as the generation of reactive oxygen species (ROS) [6][7][8] and to survive and function in a diseased or injured niche.…”

Regenerative Medicine for Cerebral Infarction

“…Because brain tissue architecture is disrupted in the ischemic brain, the use of biodegradable scaffolds may help transplanted stem cells regenerate and/or restore damaged brain structures and functions, by affecting cell differentiation, morphology, adhesion, or gene expression (Kleinman & Martin, 2005;Steindler, 2002). Jin et al showed that transplantation of human neural precursor cells (NPCs) in Matrigel scaffolding at the time of transplantation partially improved therapeutic outcome compared to that of NPCs without Matrigel scaffolding, and that the use of NPC/Matrigel cultures dramatically improved the therapeutic effect (Jin et al, 2010). These reports indicate that, when using transplantation methods employing pre-treatment with GDNF, or Matrigel scaffolding, cytoprotective effects that enhance the survival rate of stem cells require time to develop in vitro before transplantation and that such development might be related to the enhanced cytoprotective effects observed after transplantation.…”

Neural Stem Cells: Exogenous and Endogenous Promising Therapies for Stroke

“…In an attempt to improve transplant survival and behavioral outcome, Jin et al found that intralesional transplantation of nestin/Sox2-immunopositive neuronal precursor cells (NPCs) derived from BG01 human embryonic stem cells 3 weeks after distal MCAO in rats reduced infarct volume and improved behavioral outcome 4-9 weeks post-transplant (Jin et al, 2010a). In another study, they found that the beneficial effects of transplantation occurred in both young adult (3-month-old) and aged (24-month-old) rats (Jin et al, 2010b).…”