Stem Cell Grafting Improves Both Motor and Cognitive Impairments in a Genetic Model of Parkinson's Disease, the Aphakia (ak) Mouse

Abstract

Stem cell-based cell replacement of lost midbrain dopamine (mDA) neurons is a potential therapy for Parkinson’s disease (PD). Toward this goal, it is critical to optimize various aspects of cell transplantation and to assess functional recovery through behavioral tests in validated animal model(s) of PD. At present, cell transplantation studies are being done almost exclusively in neurotoxin-based animal models, because few genetic models of PD exhibit robust mDA neuronal loss. Here, we used a genetic model of PD, the aphakia mouse, which demonstrates selective degeneration of mDA neurons in the substantia nigra. We systematically investigated the functional effects of transplanting embryonic stem cell derived cells at different stages of in vitro differentiation; embryoid body (EB), neural progenitor (NP), and neuronal differentiated (ND) stages. We found that transplantation of NP cells yielded the best outcomes for both survival and behavioral improvement while transplantation of EB and ND cells resulted in high teratoma-like tumor formation and poor survival, respectively. In behavioral paradigms specific to basal ganglia, the NP cells group prominently improved motor behavioral defects 1 and 2 months post transplantation. Furthermore, we found that NP cells transplantation also improved cognitive impairments of aphakia mice, as examined by the passive avoidance task. Importantly, these graft-induced functional improvements well correlated with survival of tyrosine hydroxylase-positive DA neurons. Taken together, we propose that the aphakia mouse can serve as a novel and useful platform for cell transplantation studies to assess both neurological and cognitive improvements and that NP stage cells represent an optimal stage for transplantation.

Genetic strategies to investigate neuronal circuit properties using stem cell-derived neurons

“…In the hopes of curing or providing therapeutic measures for damaged and diseased nervous tissue, significant interest has been placed in developing stem cell-based therapies for common neurological disorders (Babaei et al, 2012; Chen and Blurton-Jones, 2012; Lescaudron et al, 2012; Moon et al, 2012). Early attempts in animal models were aimed at transplanting pure populations of ESCs directly into damaged or diseased brain tissue (Deacon et al, 1998; Bjorklund et al, 2002; Erdo et al, 2004), with the intent of providing a source of renewable cells capable of functionally integrating into existing circuits.…”

“…First, transplantation of pluripotent stem cells into the brains of animals can lead to restrictively high incidence of teratomas (Bjorklund et al, 2002; Erdo et al, 2004); in some cases, 25% or more of all grafts can result in undifferentiated brain tumors (Garcia et al, 2012). In attempt to avoid teratoma formation, efforts next turned toward transplantation of adult and fetal neural stem cells (NSCs) (Fainstein et al, 2012; Moon et al, 2012; Muneton-Gomez et al, 2012). With putative lineage restriction, NSCs were considered to have potential as a renewable source of neuronal and glial subtypes, without the attendant risk of teratoma formation.…”

“…Cellular approaches aimed at understanding and treating neurological diseases have ranged from the direct transplantation of embryonic, neuronal, and fetal stem cells (Bjorklund et al, 2002; Erdo et al, 2004; Hattiangady et al, 2007; Kauhausen et al, 2012; Moon et al, 2012) in rodent models, to the in vitro generation and investigation of induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) from affected patients' tissues (Takahashi and Yamanaka, 2006; Takahashi et al, 2007; Han et al, 2012; Ring et al, 2012; Thier et al, 2012). Although induced stem cells have yielded valuable in vitro models of several neurological disorders (Camnasio et al, 2012; Israel et al, 2012; Ooi et al, 2012; Yagi et al, 2012), numerous studies have identified major challenges that have hindered transplantation efforts.…”

Improvement of Neurological Dysfunctions in Aphakia Mice, a Model of Parkinson’s Disease, after Transplantation of ES Cell-Derived Dopaminergic Neuronal Precursors

“…Unlike many other genetic models of PD [3, 4], aphakia mice show selective degeneration of the substantia nigra dopaminergic neurons [1, 5 – 7] as in the case of human diseases, accompanied by behavioral deficits, which can be reversed by pharmacological treatment [2] or cell transplantation [8, 9]. Here, we describe the generation of dopaminergic neuronal precursors from mouse embryonic stem cells for transplantation, stereotaxic surgery of aphakia mice to deliver dopaminergic neuronal precursors into the striatum, and the behavioral analyses of the transplanted aphakia mice using various assays such as challenging beam test and pole test.…”

124I-PET Assessment of Human Sodium Iodide Symporter Reporter Gene Activity for Highly Sensitive In Vivo Monitoring of Teratoma Formation in Mice

“…Aiming at replacing functional tissues, cardiomyocytes, dopaminergic neurons and chondrocytes have been generated successfully in vitro from ESC [1][2][3] and iPSC [4][5][6] or directly from fibroblasts [7][8][9]. Thereby, therapeutic effects on ischemic cardiomyopathy, Parkinson's disease and osteoarthritis were reported in small animal studies respectively [10][11][12]. Pivotal studies have already transferred the concept of human ESC-derived neural cells into clinical application [13], and the first study to apply human iPSCderived retinal pigment epithelium cell sheets is about to start [14].…”