Human induced pluripotent stem cells in Parkinson's disease: A novel cell source of cell therapy and disease modeling

Highlights

• iPSCs are novel cell sources for cell therapy, drug screening and disease modeling.

• Virus-free approaches combined with small molecules promote reprogramming of iPSCs.

• Dopaminergic differentiation is improved by modulation of signaling pathways.

Abstract

Human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) are two novel cell sources for studying neurodegenerative diseases. Dopaminergic neurons derived from hiPSCs/hESCs have been implicated to be very useful in Parkinson's disease (PD) research, including cell replacement therapy, disease modeling and drug screening. Recently, great efforts have been made to improve the application of hiPSCs/hESCs in PD research. Considerable advances have been made in recent years, including advanced reprogramming strategies without the use of viruses or using fewer transcriptional factors, optimized methods for generating highly homogeneous neural progenitors with a larger proportion of mature dopaminergic neurons and better survival and integration after transplantation. Here we outline the progress that has been made in these aspects in recent years, particularly during the last year, and also discuss existing issues that need to be addressed.

Introduction

Parkinson's disease (PD) is the most common movement disorder in man. Loss of dopaminergic neurons in the substantia nigra pars compacta is the pathological hallmark of the disease. Therapies for PD have been mainly restricted to the relief of symptoms and there is still no effective and reliable model for studying the mechanisms of the disease.

Since the 1980s, several open-labeled trials have been performed to transplant human fetal dopaminergic neurons into the putamen and/or caudate nucleus as a replacement therapy to restore dopaminergic transmission (Lindvall et al., 1989, Sawle et al., 1992). Concrete evidence shows that neural transplants survive and become functional and integrated with the host brain neurons (Lindvall et al., 1994, Wenning et al., 1997). Fluoro-Dopa PET scans demonstrate that grafted neurons can actively take up dopamine, reflecting functional neurons in the transplant; the patients show benefits in general performance, reduced rigidity and increased speed of movement (Piccini et al., 1999, Piccini et al., 2000). Post-mortem studies of the brain tissues that received neural transplantation demonstrate the long-term survival of dopaminergic neurons, even longer than two decades post-operation (Fig. 1). These open-labeled clinical trials show that, when successful, dopaminergic neuron transplantation can be beneficial and promising to PD patients. However, two NIH-sponsored double-blind placebo trials failed to reach the primary outcome, i.e. a significant benefit to the patients (Freed et al., 2001, Olanow et al., 2003). Furthermore, a considerable number of transplanted patients developed clear adverse effects – graft-induced dyskinesia. After intensive debates on clinical trial designs of cell replacement therapy, including patient selection, graft tissue preparation and processing and optimization of surgical procedures, a new clinical trial (TRANSEURO) was established and is currently ongoing cross-continentally in multi-research and clinical centers (Barker et al., 2013). Success of this trial will have a major impact on neural transplantation with fetal dopaminergic tissues, and also with human embryonic stem cell (hESC)- and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons in future.

Embryonic stem cells (ESCs) provide hope for regenerative medicine, and have been proposed as a source of donor cells for replacement therapy in PD. ESCs are pluripotent; they have a wide differentiation potential to generate tissues and cells derived from all three embryonic germ layers. Mouse ESCs can be differentiated into dopaminergic neurons (Roy et al., 2006, Kawasaki et al., 2000) with efficient survival rates and can give rise to functional recovery after transplantation into the brains of rodent models of PD (Bjorklund et al., 2002, Kim et al., 2006). However, it has been difficult and complicated to generate high yields of dopaminergic neurons from hESCs with various differentiation protocols. Furthermore, following intra-cerebral transplantation, the survival of transplants and functional effects have not been satisfactory, even with reports of tumor or teratoma formation (Roy et al., 2006, Brederlau et al., 2006). HiPSCs (Park et al., 2008a) are promising potential cell sources for studying neurodegenerative diseases and may, in the future, be used for cell therapy as well. From the perspective of the differentiation potential, hiPSCs encounter similar problems to hESCs. The application of hiPSCs/hESCs in PD research has been substantially limited by the lack of effective protocols for differentiation and transplantation. A series of studies have been undertaken to optimize protocols of hiPSC/hESC differentiation and transplantation; although improvements have been made in the last few years, many problems still exist. Recently, a breakthrough of differentiating hESCs in vitro broke the deadlock (Fasano et al., 2010, Kirkeby et al., 2012). Here we will discuss advances that have been made in terms of dopaminergic conversion from hiPSCs/hESCs and transplantation studies in recent years and summarize the state-of-the-art development and prospects for effective and safe use of hiPSCs/hESCs for PD therapy in the future. We will keep to the following outline: hiPSCs/hESCs → neural progenitors → mature dopaminergic neurons → transplantation, and specify the progress that has been made in each of these aspects, including advanced reprogramming strategies without the use of viruses or using fewer transcriptional factors (Hiratsuka et al., 2011, Kim et al., 2009a, Rhee et al., 2011, Tsai et al., 2011), the optimal methods for generating highly homogeneous neural progenitors and a greater proportion of mature dopaminergic neurons (Kirkeby et al., 2012, Cooper et al., 2010, Chambers et al., 2009, Kriks et al., 2011, Morizane et al., 2010, Pang et al., 2011). Furthermore, we will focus on the survival, integration and safety issues regarding teratoma/tumor formation after intra-cerebral transplantation. This review will provide a timely highlight of recent advances and a better understanding of the use of hiPSCs/hESCs in cell therapy and in disease mechanism studies of PD for both clinical neurologists and researchers.