Ectopic pregnancy-derived human trophoblastic stem cells regenerate dopaminergic nigrostriatal pathway to treat parkinsonian rats
Authors: Jia-Jin Jason Chen
Jau-Nan Lee
Tony Tung-Yin Lee
Tsung-Hsun Hsieh
Eing-Mei Tsai
Mi-Chun Kao
Sher Singh
Ruey-Meei Wu
Cheng-Fang Tsai
Yu-Chih Wang
Journal: PLoS ONE (2012)
Discipline: Multidisciplinary
Keywords: Stem cell therapy; Parkinson's disease; hTS cells; trophoblast neural stem cells; Nanog
Affiliations: Department of Obstetrics and Gynecology and Center of Excellence for Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Abstract:  Background: Stem cell therapy is a potential strategy to treat patients with Parkinson's disease (PD); however, several practical limitations remain. As such, finding the appropriate stem cell remains the primary issue in regenerative medicine today. We isolated a pre-placental pluripotent stem cell from the chorionic villi of women with early tubal ectopic pregnancies. Our objectives in this study were (i) to identify the characteristics of hTS cells as a potential cell source for therapy; and (ii) to test if hTS cells can be used as a potential therapeutic strategy for PD. Methods and findings: hTS cells expressed gene markers of both the trophectoderm (TE) and the inner cell mass (ICM). hTS cells exhibited genetic and biological characteristics similar to that of hES cells, yet genetically distinct from placenta-derived mesenchymal stem cells. All-trans retinoic acid (RA) efficiently induced hTS cells into trophoblast neural stem cells (tNSCs) in 1-day. Overexpression of transcription factor Nanog was possibly achieved through a RA-induced non-genomic c-Src/Stat3/Nanog signaling pathway mediated by the subcellular c-Src mRNA localization for the maintenance of pluripotency in tNSCs. tNSC transplantation into the lesioned striatum of acute and chronic PD rats not only improved behavioral deficits but also regenerated dopaminergic neurons in the nigrostriatal pathway, evidenced by immunofluorescent and immunohistological analyses at 18-weeks. Furthermore, tNSCs showed immunological advantages for the application in regenerative medicine. Conclusions: We successfully isolated and characterized the unique ectopic pregnancy-derived hTS cells. hTS cells are pluripotent stem cells that can be efficiently induced to tNSCs with positive results in PD rat models. Our data suggest that the hTS cell is a dynamic stem cell platform that is potentially suitable for use in disease models, drug discovery, and cell therapy such as PD. 

Retracted: Yes

PubPeer comments:
 2021 retraction. https: journals.plos.org plosone article?id=10.1371 journal.pone.0247151 After this article [1] was published, the authors notified the journal that data were duplicated in Fig 4G and 4J; the aspect ratio differs for the corresponding blot images in the two panels. The authors offered an updated figure with replacement data in Fig 4J but commented that the raw data underlying Fig 4 are no longer available. In following up on this issue, it came to light that the handling Academic Editor and two of the articleu2019s authors are affiliated with the same institution (National Cheng Kung University). We sincerely regret that this potential competing interest was not identified and addressed prior to the articleu2019s publication. In light of this issue, PLOS ONE reassessed the article with support from a different member of PLOS ONEu2019s Editorial Board and an external reviewer. The following additional concerns were raised in the reassessment: The immunolabeling results reported in Fig 3C are of poor quality and do not provide clear evidence to support the claims made. The authors provided the original image and a revised figure but these did not resolve the concerns. The control and experimental panels in Fig 5C appear substantially different. The authors clarified that these data were obtained in different experiments conducted in different laboratories. As such, the findings reported in this figure and the related results statements are in question. The authors provided an alternative image but even considering this replacement data, the corresponding results statement in the article was not supported. The statistical methods used in the study were not appropriate and or adequate in some cases, some of the statistical tests needed to support the findings were not conducted or were not reported, and the sample size was too low in some experiments to rigorously address the indicated questions. The authors offered to address the concerns about the reported statistics by providing results of reanalyses, but some of the original data are no longer available, and in light of the sample size issue, statistical reanalyses would not fully resolve these data concerns. The article did not include adequate controls for the immunohistochemistry experiments, many of the histological results were wrongly interpreted, and overall, the article did not report experimental evidence to support several of the articleu2019s claims. For example, the following claims were not supported by the reported results: u25cb. u201cabundant newly generated TH-positive neurons appeared in the lesioned substantia nigra pars compacta (SNC) with multiple outgrowths to form neural circuitries with the surrounding host tissuesu201d; and u25cb. the central conclusion that transplantation of trophoblastic stem cells regenerated the dopaminergic nigrostriatal pathway in a chronic Parkinsonu2019s Disease rat model. There are multiple instances in which experiments and or findings were not clearly or accurately reported in the article. The authors offered replacement figures and text revisions to address the above issues. However, the PLOS ONE Editors determined that the concerns call into question the overall reliability of the results and conclusions reported in the published article, and so we retract this article. TTYL, CFT, THH, JJJC, YCW, MCK, SS, EMT, and JNL did not agree with retraction and stand by the articleu2019s findings. RMW either could not be reached or did not respond directly. Note, the following information was omitted from the articleu2019s [1] Competing Interests statement: Authors TT-YL, E-MT, and J-NL are listed as inventors on patent application titled u201cGeneration of neural stem cells from human trophoblast stem cellsu201d (International Publication Number WO 2012 068170 A2, Application Number PCT US201 1 060868; filed November 2011). Reference 1.Lee TT-Y, Tsai C-F, Hsieh T-H, Chen J-JJ, Wang Y-C, Kao M-C, et al. (2012) Ectopic Pregnancy-Derived Human Trophoblastic Stem Cells Regenerate Dopaminergic Nigrostriatal Pathway to Treat Parkinsonian Rats. PLoS ONE 7(12): e52491. https: doi.org 10.1371 journal.pone.0052491 pmid:23285066 ,