Abstract
In patients with Parkinson's disease (PD), stem cells can serve as therapeutic agents to restore or regenerate injured nervous system. Here, we differentiated two types of stem cells; mouse embryonic stem cells (mESCs) and protein-based iPS cells (P-iPSCs) generated by non-viral methods, into midbrain dopaminergic (mDA) neurons, and then compared the efficiency of DA neuron differentiation from these two cell types. In the undifferentiated stage, P-iPSCs expressed pluripotency markers as ES cells did, indicating that protein-based reprogramming was stable and authentic. While both stem cell types were differentiated to the terminally-matured mDA neurons, P-iPSCs showed higher DA neuron-specific markers' expression than ES cells. To investigate the mechanism of the superior induction capacity of DA neurons observed in P-iPSCs compared to ES cells, we analyzed histone modifications by genome-wide ChIP sequencing analysis and their corresponding microarray results between two cell types. We found that Wnt signaling was up-regulated, while SFRP1, a counter-acting molecule of Wnt, was more suppressed in P-iPSCs than in mESCs. In PD rat model, transplantation of neural precursor cells derived from both cell types showed improved function. The present study demonstrates that P-iPSCs could be a suitable cell source to provide patient-specific therapy for PD without ethical problems or rejection issues.
Highlights
Progressive degeneration of midbrain dopaminergic neurons is one of major pathological causes in Parkinson’s disease (PD)
Use of embryonic stem cells (ESCs) faces certain ethical and technical limitations because of their origin from human embryo [3], and possibility of immune incompatibility [4,5]. induced pluripotent stem cells (iPSCs) were able to generate DA neurons as well [6], for iPSCs to be employed in clinical trials, there are still lot of tangled problems to solve such as developing methods to circumvent the use of prooncogene, c-Myc, and viral vector which serves as delivery system for iPS generation [7,8]
The expression of Oct4 and SSEA1 were evenly distributed across mouse embryonic stem cells (mESCs) and protein-based iPS cells (P-iPSCs), confirming that both cells maintained homogeneous pluripotent states in prior to differentiation
Summary
Progressive degeneration of midbrain dopaminergic neurons (mDA) is one of major pathological causes in Parkinson’s disease (PD). Since in the late 1980s, transplantation of human fetal ventral mesencephalic tissues into the striatum of PD patients has been adopted as a successful therapy for patients with advanced disease [1,2]. This fetal brain tissue transplantation has serious hurdles such as ethical issue and the limited supply of fetal tissues. To circumvent these difficulties, several investigators utilized neurons with DA phenotype generated from embryonic stem cells (ESCs), the induced pluripotent stem cells (iPSCs), or neural stem cells (NSCs) as a practical and an effective alternative to the fetal brain tissues. Use of ESCs faces certain ethical and technical limitations because of their origin from human embryo [3], and possibility of immune incompatibility [4,5]. iPSCs were able to generate DA neurons as well [6], for iPSCs to be employed in clinical trials, there are still lot of tangled problems to solve such as developing methods to circumvent the use of prooncogene, c-Myc, and viral vector which serves as delivery system for iPS generation [7,8]
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