Enhancement of Polysialic Acid Expression Improves Function of Embryonic Stem-Derived Dopamine Neuron Grafts in Parkinsonian Mice

Center for Stem Cell Biology, Developmental Biology Program, and Cell Biology Program, Sloan-Kettering Institute for Cancer Research, New York, New York, USA.
STEM CELLS TRANSLATIONAL MEDICINE (Impact Factor: 5.71). 12/2013; 3(1). DOI: 10.5966/sctm.2013-0084
Source: PubMed


There has been considerable progress in obtaining engraftable embryonic stem (ES) cell-derived midbrain dopamine neurons for cell replacement therapy in models of Parkinson's disease; however, limited integration and striatal reinnervation of ES-derived grafts remain a major challenge for future clinical translation. In this paper, we show that enhanced expression of polysialic acid results in improved graft efficiency in correcting behavioral deficits in Parkinsonian mice. This result is accompanied by two potentially relevant cellular changes: greater survival of transplanted ES-derived dopamine neurons and robust sprouting of tyrosine hydroxylase-positive processes into host tissue. Because the procedures used to enhance polysialic acid are easily translated to other cell types and species, this approach may represent a general strategy to improve graft integration in cell-based therapies.

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Available from: Yosif Ganat, Sep 29, 2015
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    • "It has long been known that the aged brain lacks many support factors found in younger brains (Collier et al., 1999, 2005; Ling et al., 2000), and is generally considered to be an impoverished or hostile environment for grafted embryonic neurons. Many researchers continue to explore methods of increasing survival of grafted DA neurons for PD (e.g.: Büchele et al., 2014; Chermenina et al., 2014; Battista et al., 2014), irrespective of host age. However, the purpose here was to determine if cell replacement therapy in the aged parkinsonian rat is equally therapeutic as in a younger cohort when the challenge of limited survival of grafted cells is overcome. "
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    ABSTRACT: Advanced age is the primary risk factor for Parkinson disease (PD). In PD patients and rodent models of PD, advanced age is associated with inferior symptomatic benefit following intrastriatal grafting of embryonic dopamine (DA) neurons, a pattern believed to result from decreased survival and reinnervation provided by grafted neurons in the aged host. To help understand the capacity of the aged, parkinsonian striatum to be remodeled with new DA terminals, we used a grafting model and examined whether increasing the number of grafted DA neurons in aged rats would translate to enhanced behavioral recovery. Young (3 mo), middle-aged (15 mo), and aged (22 mo) parkinsonian rats were grafted with proportionately increasing numbers of embryonic ventral mesencephalic (VM) cells to evaluate whether the limitations of the graft environment in subjects of advancing age can be offset by increased numbers of transplanted neurons. Despite robust survival of grafted neurons in aged rats, reinnervation of striatal neurons remained inferior and amelioration of levodopa-induced dyskinesias (LID) was delayed or absent. This study demonstrates that: 1) counter to previous evidence, under certain conditions the aged striatum can support robust survival of grafted DA neurons; and 2) unknown factors associated with the aged striatum result in inferior integration of graft and host, and continue to present obstacles to full therapeutic efficacy of DA cell-based therapy in this model of aging. Copyright © 2015. Published by Elsevier Inc.
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    ABSTRACT: Motoneurons (MNs) derived from mouse embryonic stem cells (ESCs) begin to express low levels of polysialic acid (PSA) at the time when they acquire an ability to migrate and extend neurites. PSA is known to promote cell migration and process outgrowth/guidance in the developing nervous system. To test if experimentally enhanced expression of PSA would augment these cellular events, the PSA-synthesizing polysialyltransferase was introduced into ESCs. In culture, the resulting higher PSA expression specifically increased neurite outgrowth and cell migration from differentiated embryoid bodies. In addition, the MN population obtained after sorting for HB9::GFP expression showed enhanced survival as well as extensive neurite outgrowth. Following transplantation of ESC-derived MNs into an adult sciatic nerve devoid of endogenous axons, the PSA augmentation increased the numbers of axons growing toward the denervated muscles. Migration of some transplanted cells inside the nerve toward muscle was also enhanced. Moreover, higher PSA expression selectively affected target innervation. It produced greater numbers of neuromuscular junctions in a predominantly fast twitch muscle and had no effect in a slow twitch muscle. These findings suggest that engineering of PSA expression in ESC could serve as an enhancement for MN cell therapy.
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