Cell Transplantation 23(4-5) Abstracts

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Cell Transplantation, Vol. 23, pp. 399-406, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678292
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Improved Human Mesenchymal Stem Cell Isolation

Tzu-Min Chan,*† Horng-Jyh Harn,‡§ Hui-Ping Lin,¶ Pei-Wen Chou,†# Julia Yi-Ru Chen,# Tsung-Jung Ho,**††‡‡ Tzyy-Wen Chiou,§§ Hong-Meng Chuang,†¶¶ Shao-Chih Chiu,*## Yen-Chung Chen,¶ Ssu-Yin Yen,§§ Mao-Hsuan Huang,‡¶¶ Bing-Chiang Liang,***††† and Shinn-Zong Lin*##‡‡‡§§§

*Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
†Everfront Biotech Inc., New Taipei City, Taiwan
‡Department of Medicine, China Medical University, Taichung, Taiwan
§Department of Pathology, China Medical University Hospital, Taichung, Taiwan
¶Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan
#Guang Li Biomedicine, Inc., New Taipei City, Taiwan
**School of Chinese Medicine, China Medical University, Taichung, Taiwan
††Division of Chinese Medicine, China Medical University Beigang Hospital, Yunlin County, Taiwan
‡‡Division of Chinese Medicine, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan
§§Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan
¶¶Department of Life Sciences, National Chung Hsing University Taichung, Taiwan
##Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
***Department of Emergency Medicine, Taipei Veterans General Hospital, Taiwan
†††National Yang-Ming University, School of Medicine, Taiwan
‡‡‡Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan
§§§Department of Neurosurgery, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan

Human mesenchymal stem cells (hMSCs) are currently available for a range of applications and benefits and have become a good material for regenerative medicine, tissue engineering, and disease therapy. Before ex vivo expansion, isolation and characterization of primary hMSCs from peripheral tissues are key steps for obtaining adequate materials for clinical application. The proportion of peripheral stem cells is very low in surrounding tissues and organs; thus the recovery ratio will be a limiting factor. In this review, we summarized current common methods used to isolate peripheral stem cells, as well as the new insights revealed to improve the quantity of stem cells and their stemness. These strategies offer alternative ways to acquire hMSCs in a convenient and/or effective manner, which is important for clinical treatments. Improved isolation and mass amplification of the hMSCs while ensuring their stemness and quantity will be an important step for clinical use. Enlarged suitable hMSCs are more clinically applicable for therapeutic transplants and may help people live longer and better.

Key words: Human mesenchymal stem cells (hMSCs); Improved isolation of hMSCs; Liver progenitors;Mechanical dissociation lipoaspirate; Adipose-derived cell; Novel marrow filter device; Clot spots; Bone marrow-derived mesenchymal stem cells (BMMSCs)

Received October 30, 2013; final acceptance January 28, 2014.
Address correspondence to Professor Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC. Tel: +886-4-22052121, ext. 6034; Fax: +886-4-220806666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 407-415, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678481
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

Plasma-Depleted Versus Red Cell-Reduced Umbilical Cord Blood

Wise Young

Department of Cell Biology and Neuroscience, Rutgers, State University of New Jersey, Piscataway, NJ, USA

Umbilical cord blood banks use two methods to store frozen umbilical cord blood (UCB): red cell reduction (RCR) or plasma depletion (PD). The RCR method centrifuges cord blood in hetastarch or albumin to isolate 21 ml of cord blood containing mostly white blood cells, adds 4 ml of 50% dimethyl sulfoxide (DMSO), and then freezes the resulting 25 ml of cell suspension. The PD method removes plasma, saves all the cells, and freezes the cells in 10% DMSO. PD UCB units are cheaper to process but more expensive to store and somewhat more troublesome to thaw. However, when properly thawed and washed, PD UCB units have as many or more total nucleated cells (TNCs), CD34+ cells, and colony-forming units (CFU) than RCR units. Two studies suggest that PD units have 20–25% more TNCs, MNCs, and CD34+ cells, as well as two to three times more CFU than RCR units. Higher TNC, CD34+, and CFU counts predict engraftment rate with faster neutrophil and platelet recovery. PD units have high engraftment rates with low mortality and high disease-free survival, comparable with clinical results of treatments with RCR units. One recent series of studies suggests that PD units are more effective for treating thalassemia with 2-year survival rates of 88%, disease-free survival rates of 74%, and 100% cure rate for children under age 7, compared to only 61% overall survival and 23% disease-free survival rate in thalassemic children treated with RCR units. These findings suggest that PD units not only have more TNCs, CD34+ cells, and CFU than RCR units but also have high engraftment rates and may be more effective for treating certain conditions such as β-thalassemia.

Key words: Plasma depletion (PD); Red cell reduction (RCR); Cryopreservation; Umbilical cord blood; Transplant centers

Received October 30, 2013; final acceptance February 3, 2014.
Address correspondence to Wise Young, Ph.D., M.D., Richard H. Shindell Chair in Neuroscience, W. M. Keck Center for Collaborative Neuroscience, Department of Cell Biology and Neuroscience, Rutgers, State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854-8082, USA. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 417-433, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678472
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

Genetic and Epigenetic Instability of Stem Cells

Karthyayani Rajamani,* Yuan-Sheng Li,* Dean-Kuo Hsieh,† Shinn-Zong Lin,‡§ Horng-Jyh Harn,¶ and Tzyy-Wen Chiou*

*Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan
†Department of Applied Chemistry, Chaoyang University of Technology, Taichung, Taiwan
‡Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan
§Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan
¶Department of Pathology, China Medical University and Hospital, Taichung, Taiwan

Recently, research on stem cells has been receiving an increasing amount of attention, both for its advantages and disadvantages. Genetic and epigenetic instabilities among stem cells have been a recurring obstacle to progress in regenerative medicine using stem cells. Various reports have stated that these instabilities can transform stem cells when transferred in vivo and thus have the potential to develop tumors. Previous research has shown that various extrinsic and intrinsic factors can contribute to the stability of stem cells. The extrinsic factors include growth supplements, growth factors, oxygen tension, passage technique, and cryopreservation. Controlling these factors based on previous reports may assist researchers in developing strategies for the production and clinical application of “safe” stem cells. On the other hand, the intrinsic factors can be unpredictable and uncontrollable; therefore, to ensure the successful use of stem cells in regenerative medicine, it is imperative to develop and implement appropriate strategies and technique for culturing stem cells and to confirm the genetic and epigenetic safety of these stem cells before employing them in clinical trials.

Keywords: Epigenetic stability; Genetic stability; Karyotype; Tumorigenic

Received October 31, 2013; final acceptance February 3, 2014.
Address correspondence to Prof. Tzyy-Wen Chiou, Ph.D., Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, No. 1, Sec. 2, Da Hsueh Rd., Shou-Feng, Hualien, Taiwan, ROC. Tel: +886-3-8633638; Fax: +886-3-8630398; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Dr. Horng-Jyh Harn, Department of Pathology, China Medical University and Hospital, 2 Yuh-Der Road, Taichung, Taiwan, 40447, ROC. Tel: +886-4-22052121, ext. 2661; Fax: +886-4-22052121, ext. 2566; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 435-439, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678274
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

Direct Reprogrammed Neuronal Cells as a Novel Resource for Cell Transplantation Therapy

Toru Yamashita and Koji Abe

Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Cell transplantation/replacement therapy is attractive as a novel strategy for neurological diseases such as Parkinson’s disease, Alzheimer’s disease, and stroke. To realize this therapy, safer and more therapeutic effective cell resources are now required. Since induced pluripotent stem cells (iPSCs) can retain high replication competence and pluripotency when they differentiate into various kinds of cells, they are regarded as a promising cell source for cell transplantation therapy. However, high tumorigenesis of iPSCs has to be overcome for clinical applications. Recent progress includes the combination of novel transcriptional factors that can convert somatic cells to various kinds of mature neuronal cells and neural stem cells without requiring iPSC fate. Some evidence indicates that these directly induced neuronal cells have little tumorigenic potential. In this article, we discuss the advantage, issues, and possibility of clinical application of these cells for cell transplantation therapy.

Key words: Induced pluripotent stem cells (iPSCs); Induced neuronal cells (iNCs); Induced neural stem cells (iNSCs); Direct conversion; Cell transplantation

Received October 30, 2013; final acceptance February 5, 2014.
Address correspondence to Koji Abe, Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Tel: +81-86-235-7365; Fax: +81-86-235-7368; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 441-458, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678454
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

Polyglutamine (PolyQ) Diseases: Genetics to Treatments

Hueng-Chuen Fan,* Li-Ing Ho,† Ching-Shiang Chi,‡ Shyi-Jou Chen,* Giia-Sheun Peng,§ Tzu-Min Chan,¶# Shinn-Zong Lin,¶# and Horng-Jyh Harn**

*Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
†Department of Respiratory Care, Veterans General Hospital, Taipei, Taiwan
‡Tung’s Taichung Metroharbor Hospital, Wuchi, Taichung, Taiwan
§Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
¶Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan
#Center for Neuropsychiatry, China Medical University Beigang Hospital, Yun-Lin, Taiwan
**Department of Pathology, China Medical University and Hospital, Taichung, Taiwan

The polyglutamine (polyQ) diseases are a group of neurodegenerative disorders caused by expanded cytosine–adenine–guanine (CAG) repeats encoding a long polyQ tract in the respective proteins. To date, a total of nine polyQ disorders have been described: six spinocerebellar ataxias (SCA) types 1, 2, 6, 7, 17; Machado–Joseph disease (MJD/SCA3); Huntington’s disease (HD); dentatorubral pallidoluysian atrophy (DRPLA); and spinal and bulbar muscular atrophy, X-linked 1 (SMAX1/SBMA). PolyQ diseases are characterized by the pathological expansion of CAG trinucleotide repeat in the translated region of unrelated genes. The translated polyQ is aggregated in the degenerated neurons leading to the dysfunction and degeneration of specific neuronal subpopulations. Although animal models of polyQ disease for understanding human pathology and accessing disease-modifying therapies in neurodegenerative diseases are available, there is neither a cure nor prevention for these diseases, and only symptomatic treatments for polyQ diseases currently exist. Long-term pharmacological treatment is so far disappointing, probably due to unwanted complications and decreasing drug efficacy. Cellular transplantation of stem cells may provide promising therapeutic avenues for restoration of the functions of degenerative and/or damaged neurons in polyQ diseases.

Key words: Polyglutamine (polyQ); Cytosine–adenine–guanine (CAG) repeats; Huntington’s disease (HD); Spinal and bulbar muscular atrophy, X-linked 1 (SMAX1/SBMA); Spinocerebellar ataxias (SCA); Machado–Joseph disease (MJD/SCA3); Dentatorubral pallidoluysian atrophy (DRPLA); Cellular transplantation

Received October 30, 2013; final acceptance January 31, 2014.
Address correspondence to Horng-Jyh Harn, M.D., Ph.D., Department of Pathology, China Medical University and Hospital, Taichung, Taiwan, ROC. Tel: +886-4-22052121; Fax: +886-4-220806666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 459-469, 2014
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DOI: http://dx.doi.org/10.3727/096368914X678418
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

Therapeutic Potential of MicroRNA Let-7: Tumor Suppression or Impeding Normal Stemness

Shao-Chih Chiu,*† Hao-Yu Chung,‡§¶ Der-Yang Cho,*# Tzu-Min Chan,†** Ming-Chao Liu,*† Hiang-Ming Huang,# Tsyng-You Li,* Jian-Yong Lin,* Pei-Chang Chou,* Ru-Huei Fu,*† Wen-Kuang Yang,†† Horng-Jyh Harn,‡‡§§ and Shinn-Zong Lin*†§¶

*Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
†Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
‡Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
§Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan
¶Department of Neurosurgery, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan
#Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan
**Everfront Biotech Inc., New Taipei City, Taiwan
††Cell/Gene Therapy Research Laboratory, China Medical University Hospital, Taichung, Taiwan
‡‡Department of Pathology, China Medical University Hospital, Taichung, Taiwan
§§Department of Medicine, China Medical University, Taichung, Taiwan

The first microRNA, let-7, and its family were discovered in Caenorhabditis elegans and are functionally conserved from worms to humans in the regulation of embryonic development and stemness. The let-7 family has been shown to have an essential role in stem cell differentiation and tumor-suppressive activity. Deregulating expression of let-7 is commonly reported in many human cancers. Emerging evidence has accumulated and suggests that reestablishment of let-7 in tumor cells is a valuable therapeutic strategy. However, findings reach beyond tumor therapeutics and may impinge on stemness and differentiation of stem cells. In this review, we discuss the role of let-7 in development and differentiation of normal adult stem/progenitor cells and offer a viewpoint of the association between deregulated let-7 expression and tumorigenesis. The regulation of let-7 expression, cancer-relevant let-7 targets, and the application of let-7 are highlighted.

Key words: Lethal-7 (let-7); Stemness; Cancer therapy

Received October 30, 2013; final acceptance February 6, 2014.
Address correspondence to Prof. Shinn-Zong Lin, M.D., Ph.D., Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, ROC. Tel: +886-4-22052121, ext. 6034; Fax: +886-4-220806666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 471-479, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678283
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

Adult Neurogenesis and Dendritic Remodeling in Hippocampal Plasticity: Which One Is More Important?

Suk-Yu Yau*†‡1 and Kwok-Fai So*†‡§¶

*Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong
†State Key Laboratory of Brain and Cognitive Science, The University of Hong Kong, Pokfulam, Hong Kong
‡Research Centre of Heart, Brain, Hormone and Health Aging, The University of Hong Kong, Pokfulam, Hong Kong
§GHM Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou, China
¶Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong

Accumulating knowledge has shown that a decrease in hippocampal neurogenesis is linked to the pathophysiology of mood disorders and some hippocampal-dependent learning and memory tasks. The role of adult neurogenesis has initially been proposed based on correlations between decreases or increases in neurogenesis and impairments or improvements, respectively, in animal behaviors following interventions. Its role has been further elucidated through the ablation of neurogenesis. However, the functional roles of neurogenesis in hippocampal-dependent behaviors have been challenged by inconsistent findings between different studies. Despite the fact that factors affecting neurogenesis also induce dendritic or synaptic changes in newborn or existing neurons, these two aspects of structural changes within the hippocampus have always been examined separately. Thus, it is difficult to interpret the functional role of adult neurogenesis or dendritic remodification in hippocampal-dependent behaviors. This review discusses the relative contribution of adult neurogenesis and dendritic/synaptic remodeling of existing neurons to hippocampal plasticity.

Key swords: Hippocampal neurogenesis; Dendritic remodeling; Synaptic plasticity; Stress; Learning and memory; Voluntary running

Received October 30, 2013; final acceptance December 23, 2013.
1Present address: Division of Medical Sciences, The University of Victoria, Victoria, British Columbia, Canada.
Address correspondence to Professor Kwok-Fai So, Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China. Tel: +852-2819-9216; Fax: +852-2817-0857; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 481-492, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678490
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Sustained Running in Rats Administered Corticosterone Prevents the Development of Depressive Behaviors and Enhances Hippocampal Neurogenesis and Synaptic Plasticity Without Increasing Neurotrophic Factor Levels

Suk-Yu Yau,*†‡1 Ang Li,*†§ En-Dong Zhang,* Brian R. Christie,¶ Aimin Xu,‡§#** Tatia M. C. Lee,†,††,‡‡ and Kwok-Fai So*†‡§§¶¶

*Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong
†State Key Laboratory of Brain and Cognitive Science, The University of Hong Kong, Pokfulam, Hong Kong
‡Research Centre of Heart, Brain, Hormone and Healthy Ageing, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
§Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR
¶Division of Medical Sciences, The University of Victoria, Victoria, British Columbia, Canada
#Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong
**State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pokfulam, Hong Kong
††Cognitive Affective Neuroscience, The University of Hong Kong, Pokfulam, Hong Kong
‡‡Laboratory of Neuropsychology, The University of Hong Kong, Pokfulam, Hong Kong
§§Department of Ophthalmology, The University of Hong Kong, Pokfulam, Hong Kong
¶¶GHM Institute of CNS Regeneration, Jinan University, Guangzhou, China

We have previously shown that voluntary running acts as an anxiolytic and ameliorates deficits in hippocampal neurogenesis and spatial learning. It also reduces depression-like behaviors that are normally observed in rats that were administered either low (30 mg/kg) or moderate (40 mg/kg) doses of corticosterone (CORT). However, the protective effects of running were absent in rats treated with a high (50 mg/kg) dose of CORT. We examined whether allowing animals to exercise for 2 weeks prior and/or concurrently with the administration of 50 mg/kg CORT treatment could have similar protective effects. We examined hippocampal neurogenesis using immunohistochemical staining of proliferative and survival cells with the thymidine analogs (BrdU, CIdU, and IdU). In addition, we monitored synaptic protein expression and quantified the levels of neurotrophic factors in these animals as well as performing behavioral analyses (forced swim test and sucrose preference test). Our results indicate that the depressive phenotype and reductions in neurogenesis that normally accompany high CORT administration could only be prevented by allowing animals to exercise both prior to and concurrently with the CORT administration period. These animals also showed increases in both synaptophysin and PSD-95 protein levels, but surprisingly, neither brain-derived neurotrophic factor (BDNF) nor insulin-like growth factor 1 (IGF-1) levels were increased in these animals. The results suggest that persistent exercise can strengthen resilience to stress by promoting hippocampal neurogenesis and increasing synaptic protein levels, thereby reducing the deleterious effects of stress.

Key words: Hippocampal neurogenesis; Depression-like behavior; Synaptic plasticity; Physical exercise; Brain-derived neurotrophic factor; Insulin-like growth factor

Received November 6, 2013; final acceptance January 28, 2014.
1Present address: Division of Medical Sciences, The University of Victoria, Victoria, British Columbia, Canada.
Address correspondence to Professor Kwok-Fai So, Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China. Tel: +852-2819-9216; Fax: +852-2817-0857; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Tatia M. C. Lee, Laboratory of Neuropsychology, Room 656, The Jockey Club Tower, The University of Hong Kong, Hong Kong SAR, China. Tel: +852-3917-8394; Fax: +852-2819-0978; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 493-496, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678300
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

Umbilical Cord Blood: A Trustworthy Source of Multipotent Stem Cells for Regenerative Medicine

Tang-Her Jaing

Division of Hematology and Oncology, Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University, Taoyuan, Taiwan

It is conservatively estimated that one in three individuals in the US might benefit from regenerative medicine therapy. However, the relation of embryonic stem cells (ESCs) to human blastocysts always stirs ethical, political, moral, and emotional debate over their use in research. Thus, for the reasonably foreseeable future, the march of regenerative medicine to the clinic will depend upon the development of non-ESC therapies. Current sources of non-ESCs easily available in large numbers can be found in the bone marrow, adipose tissue, and umbilical cord blood (UCB). UCB provides an immune-compatible source of stem cells for regenerative medicine. Owing to inconsistent results, it is certainly an important and clinically relevant question whether UCB will prove to be therapeutically effective. This review will show that UCB contains multiple populations of multipotent stem cells, capable of giving rise to hematopoietic, epithelial, endothelial, and neural tissues both in vitro and in vivo. Here we raise the possibility that due to unique immunological properties of both the stem cell and non-stem cell components of cord blood, it may be possible to utilize allogeneic cells for regenerative applications without needing to influence or compromise the recipient immune system.

Key words: Umbilical cord blood (UCB); Regenerative medicine; Multipotent stem cells; Mesenchymal stem cells (MSCs)

Received October 30, 2013; final acceptance January 28, 2014.
Address correspondence to Tang-Her Jaing, M.D., Division of Hematology and Oncology, Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University, 5 Fu-Shin Street, Kwei-Shan, 333, Taoyuan, Taiwan, ROC. Tel: +886-3328-1200, ext. 8206; Fax: +886-3328-8957; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 497-503, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678346
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

Epithelial and Mesenchymal Stem Cells From the Umbilical Cord Lining Membrane

Ivor J. Lim and Toan Thang Phan

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
CellResearch Corporation Pte Ltd, Singapore

Intense scientific research over the past two decades has yielded much knowledge about embryonic stem cells, mesenchymal stem cells from bone marrow, as well as epithelial stem cells from the skin and cornea. However, the billions of dollars spent in this research have not overcome the fundamental difficulties intrinsic to these stem cell strains related to ethics (embryonic stem cells), as well as to technical issues such as accessibility, ease of cell selection and cultivation, and expansion/mass production, while maintaining consistency of cell stemness (all of the stem cell strains already mentioned). Overcoming these technical hurdles has made stem cell technology expensive and any potential translational products unaffordable for most patients. Commercialization efforts have been rendered unfeasible by this high cost. Advanced biomedical research is on the rise in Asia, and new innovations have started to overcome these challenges. The Nobel Prize-winning Japanese development of iPSCs has effectively introduced a possible replacement for embryonic stem cells. For non-embryonic stem cells, cord lining stem cells (CLSCs) have overcome the preexisting difficulties inherent to mesenchymal stem cells from the bone marrow as well as epithelial stem cells from the skin and cornea, offering a realistic, practical, and affordable alternative for tissue repair and regeneration. This novel CLSC technology was developed in Singapore in 2004 and has 22 international patents granted to date, including those from the US and UK. CLSCs are derived from the umbilical cord outer lining membrane (usually regarded as medical waste) and is therefore free from ethical dilemmas related to its collection. The large quantity of umbilical cord lining membrane that can be collected translates to billions of stem cells that can be grown in primary stem cell culture and therefore very rapid and inexpensive cell cultivation and expansion for clinical translational therapies. Both mesenchymal and epithelial stem cells can be isolated from the umbilical cord lining membrane, usefully regenerating not only mesenchymal tissue, such as bone, cartilage, and cardiac and striated muscle, but also epithelial tissue, such as skin, cornea, and liver. Both mesenchymal and epithelial CLSCs are immune privileged and resist rejection. Clinically, CLSCs have proved effective in the treatment of difficult-to-heal human wounds, such as diabetic ulcers, recalcitrant chronic wounds, and even persistent epithelial defects of the cornea. Heart and liver regeneration has been shown to be successful in animal studies and await human trials. CLSCs have also been shown to be an effective feeder layer for cord blood hematopoietic stem cells and, more recently, has been recognized as an abundant and high-quality source of cells for iPSC production. Banking of CLSCs by cord blood banks in both private and public settings is now available in many countries, so that individuals may have their personal stores of CLSCs for future translational applications for both themselves and their families. Cord lining stem cells are strongly positioned to be the future of cell therapy and regenerative medicine.

Key words: Cord lining; Stem cells; Regenerative medicine; Tissue repair and regeneration; Antiaging

Received October 30, 2013; final acceptance February 5, 2014.
Address correspondence to Toan Thang Phan, Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Block MD11, 10 Medical Drive, Singapore 117597. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 505-512, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678328
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

Mesenchymal Stem Cells in Regenerative Medicine for Musculoskeletal Diseases: Bench, Bedside, and Industry

Chih-Chang Wei,* Andrew Boyd Lin,† and Shih-Chieh Hung*‡§¶#**

*Stem Cell Laboratory, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
†Department of Biology, Case Western Reserve University, Cleveland, OH, USA
‡Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
§Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
¶Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
#Institute of Pharmacology, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
**Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

Human bone marrow-derived mesenchymal stem cells (MSCs) can self-renew and differentiate into osteoblasts, chondrocytes, and adipocytes. MSCs have effectively emerged as a promising tool for clinical applications, specifically in musculoskeletal diseases. This article reviews the status of preclinical animal studies, clinical trials, and the efforts of the industry in using MSCs to treat musculoskeletal diseases such as bone fractures, bone defects, focal chondral lesions, osteoarthritis, spinal diseases, and tendon injuries. We also discuss the current problems encountered and potential of using MSCs in future clinical studies.

Key words: Mesenchymal stem cells (MSCs); Musculoskeletal diseases (MSDs); Preclinical animal studies; Clinical trials; Industry

Received October 30, 2013; final acceptance January 29, 2014.
Address correspondence to Shih-Chieh Hung, Stem Cell Laboratory, Medical Research and Education, Taipei Veterans General Hospital, 201, Sec 2, Shih-Pai Road, Taipei, Taiwan. Tel: +886-2-28757557; Fax: +886-2-28757657; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 513-529, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678436
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

Mesenchymal Stem Cell Insights: Prospects in Cardiovascular Therapy

Shiu-Huey Chou,* Shinn-Zong Lin,† Wei-Wen Kuo,‡ Peiying Pai,§ Jing-Ying Lin,¶ Chao-Hung Lai,# Chia-Hua Kuo,** Kuan-Ho Lin,††‡‡ Fuu-Jen Tsai,§§ and Chih-Yang Huang§§¶¶##

*Department of Life Science, Fu-Jen Catholic University, Xinzhuang District, New Taipei City, Taiwan
†Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
‡Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
§Division of Cardiology, China Medical University Hospital, Taichung, Taiwan
¶Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan
#Division of Cardiology, Department of Internal Medicine, Armed Force Taichung General Hospital, Taichung, Taiwan
**Department of Sports Sciences, University of Taipei, Taipei, Taiwan
††Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
‡‡Emergency Department, China Medical University Hospital, Taichung, Taiwan
§§School of Chinese Medicine, China Medical University, Taichung, Taiwan
¶¶Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
##Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

Ischemic heart damage usually triggers cardiomyopathological remodeling and fibrosis, thus promoting the development of heart functional failure. Mesenchymal stem cells (MSCs) are a heterogeneous group of cells in culture, with multipotent and hypoimmunogenic characters to aid tissue repair and avoid immune responses, respectively. Numerous experimental findings have proven the feasibility, safety, and efficiency of MSC therapy for cardiac regeneration. Despite that the exact mechanism remains unclear, the therapeutic ability of MSCs to treat ischemia heart diseases has been tested in phase I/II clinical trials. Based on encouraging preliminary findings, MSCs might become a potentially efficacious tool in the therapeutic options available to treat ischemic and nonischemic cardiovascular disorders. The molecular mechanism behind the efficacy of MSCs on promoting engraftment and accelerating the speed of heart functional recovery is still waiting for clarification. It is hypothesized that cardiomyocyte regeneration, paracrine mechanisms for cardiac repair, optimization of the niche for cell survival, and cardiac remodeling by inflammatory control are involved in the interaction between MSCs and the damaged myocardial environment. This review focuses on recent experimental and clinical findings related to cellular cardiomyoplasticity. We focus on MSCs, highlighting their roles in cardiac tissue repair, transdifferentiation, the MSC niche in myocardial tissues, discuss their therapeutic efficacy that has been tested for cardiac therapy, and the current bottleneck of MSC-based cardiac therapies.

Key words: Mesenchymal stem cells (MSCs); Myocardial infarction; Cellular therapy; Differentiation; Regeneration; Niche; Paracrine

Received October 30, 2013; final acceptance February 6, 2014.
Address correspondence to Chih-Yang Huang, Ph.D., Graduate Institute of Basic Medical Science, China Medical University and Hospital, No. 91 Hsueh-Shih Rd., Taichung, Taiwan 40402, ROC. Tel: +886-4-22053366, ext. 3313; Fax: +886-4-22333641; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 531-539, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678337
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Mannitol-Enhanced Delivery of Stem Cells and Their Growth Factors Across the Blood–Brain Barrier

Gabriel S. Gonzales-Portillo,* Paul R. Sanberg,* Max Franzblau,* Chiara Gonzales-Portillo,* Theo Diamandis,* Meaghan Staples,* Cyndy D. Sanberg,† and Cesar V. Borlongan*

*Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA
†Saneron CCEL Therapeutics, Saneron CCEL Therapeutics, Inc., Tampa, FL, USA

Ischemic brain injury in adults and neonates is a significant clinical problem with limited therapeutic interventions. Currently, clinicians have only tPA available for stroke treatment and hypothermia for cerebral palsy. Owing to the lack of treatment options, there is a need for novel treatments such as stem cell therapy. Various stem cells including cells from embryo, fetus, perinatal, and adult tissues have proved effective in preclinical and small clinical trials. However, a limiting factor in the success of these treatments is the delivery of the cells and their by-products (neurotrophic factors) into the injured brain. We have demonstrated that mannitol, a drug with the potential to transiently open the blood–brain barrier and facilitate the entry of stem cells and trophic factors, as a solution to the delivery problem. The combination of stem cell therapy and mannitol may improve therapeutic outcomes in adult stroke and neonatal cerebral palsy.

Key words: Mannitol; Stem cells; Blood–brain barrier permeability; Neurotrophic factors; Cerebral ischemia; Adult; Neonates

Received October 30, 2013; final acceptance November 25, 2013.
Address correspondence to Dr. Cesar V. Borlongan, Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA. Tel: +1-813-974-3988; Fax: +1-813-974-3078; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 541-547, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678409
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

The Use of ADSCs as a Treatment for Chronic Stroke

Tzu-Min Chan,*† Horng-Jyh Harn,‡§ Hui-Ping Lin,¶ Shao-Chih Chiu,*# Po-Cheng Lin,** Hsin-I Wang,** Li-Ing Ho,†† Chih-Pin Chuu,¶ Tzyy-Wen Chiou,‡‡ An-Cheng Hsieh,* Yu-Wen Chen,* Wen-Yu Ho,§§¶¶ and Shinn-Zong Lin*###***

*Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
†Everfront Biotech Inc., New Taipei City, Taiwan
‡Department of Medicine, China Medical University, Taichung, Taiwan
§Department of Pathology, China Medical University Hospital, Taichung, Taiwan
¶Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan
#Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
**GwoXi Stem Cell Applied Technology, Hsinchu, Taiwan
††Department of Respiratory Therapy, Taipei Veterans General Hospital, Taipei, Taiwan
‡‡Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan
§§Department of Laboratory Medicine, China Medical University Beigang Hospital, Yunlin, Taiwan
¶¶Departmentof Medical Technology, Nursing and Management, Jen-Teh Junior College of Medicine, Taiwan
##Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan
***Department of Neurosurgery, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan

Stroke is one of the disorders for which clinically effective therapeutic modalities are most needed, and numerous ways have been explored to attempt to investigate their feasibilities. However, ischemic- or hemorrhagic-induced inflammatory neuron death causes irreversible injuries and infarction regions, and there are currently no truly effective drugs available as therapy. It is therefore urgent to be able to provide a fundamental treatment method to regenerate neuronal brain cells, and therefore, the use of stem cells for curing chronic stroke could be a major breakthrough development. In this review, we describe the features and classification of stroke and focus on the benefits of adipose tissue-derived stem cells and their applications in stroke animal models. The results show that cell-based therapies have resulted in significant improvements in neuronal behaviors and functions through different molecular mechanisms, and no safety problems have so far arisen after transplantation. Further, we propose a clinical possibility to create a homing niche by reducing the degree of invasive intracerebroventricular transplantation and combining it with continuous intravenous administration to achieve a complete cure.

Key words: Cerebrovascular; Chronic stroke; Adipose tissue-derived stem cells (ADSCs); Ischemic; Hemorrhagic; Angiogenesis; Gliosis; Neurotrophic factors

Received October 30, 2013; final acceptance January 29, 2014.
Address correspondence to Professor Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC. Tel: +886-4-22052121, ext. 6034; Fax: +886-4-220806666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 549-557, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678445
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

ADSC Therapy in Neurodegenerative Disorders

Tzu-Min Chan,*† Julia Yi-Ru Chen,‡ Li-Ing Ho,§ Hui-Ping Lin,¶ Kuo-Wei Hsueh,# Demeral David Liu,**†† Yi-Hung Chen,‡‡ An-Cheng Hsieh,* Nu-Man Tsai,§§¶¶ Dueng-Yuan Hueng,## Sheng-Tzeng Tsai,*** Pei-Wen Chou,†‡ Shinn-Zong Lin,*†††‡‡‡§§§1 and Horng-Jyh Harn¶¶¶###1

*Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
†Everfront Biotech Inc., New Taipei City, Taiwan
‡Guang Li Biomedicine, Inc., New Taipei City, Taiwan
§Department of Respiratory Therapy, Taipei Veterans General Hospital, Taipei, Taiwan
¶Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan
#Ph.D. Program for Aging, China Medical University, Taichung, Taiwan
**Department of Dentistry, China Medical University Beigang Hospital, Taiwan
††Department of Dentistry, School of Medicine, China Medical University and Hospital, Taiwan
‡‡Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan
§§School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
¶¶Department of Pathology and Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
##Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taiwan
***Department of Neurosurgery, Tzu Chi General Hospital/Tzu Chi University, Hualien, Taiwan
†††Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan
‡‡‡Department of Neurosurgery, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan
§§§Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
¶¶¶Department of Medicine, China Medical University, Taichung, Taiwan
###Department of Pathology, China Medical University Hospital, Taichung, Taiwan

Neurodegenerative disorders, chronic diseases that can severely affect the patient’s daily life, include amyotrophic lateral sclerosis, Parkinson’s, Alzheimer’s, and Huntington’s diseases. However, these diseases all have the common characteristic that they are due to degenerative irreversibility, and thus no efficient drugs or therapy methods can mitigate symptoms completely. Stem cell therapy, such as adipose tissue-derived stem cells (ADSCs), is a promising treatment for incurable disorders. In this review, we summarized the previous studies using ADSCs to treat neurodegenerative disorders, as well as their therapeutic mechanisms. We also suggested possible expectations for future human clinical trials involving minimized intracerebroventricular combined with intravenous administration, using different cell lineages to finish complementary therapy as well as change the extracellular matrix to create a homing niche. Depending on successful experiments in relevant neurodegenerative disorders models, this could form the theoretical basis for future human clinical trials.

Key words: Neurodegenerative disorders; Adipose tissue-derived stem cells (ADSCs); Amyotrophic lateral sclerosis; Parkinson’s disease; Alzheimer’s disease; Huntington’s disease; Autoimmune encephalomyelitis; Krabbe disease; Niemann-Pick disease; Friedreich’s ataxia

Received October 30, 2013; final acceptance January 29, 2014.
1These authors provided equal contribution to this work.
Address correspondence to Prof. Horng-Jyh Harn, M.D., Ph.D., Department of Pathology, China Medical University Hospital, Taichung, Taiwan, ROC. Tel: +886-4-22052121, ext. 2668; Fax: 886-4-220806666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Prof. Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC. Tel: +886-4-22052121, ext. 6034; Fax: +886-4-220806666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 559-566, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678463
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

The Possible Role of Stem Cells in Acupuncture Treatment for Neurodegenerative Diseases: A Literature Review of Basic Studies

Tsung-Jung Ho,*†‡ Tzu-Min Chan,§¶ Li-Ing Ho,# Ching-Yuan Lai,*,** Chia-Hsien Lin,†† Iona MacDonald,‡‡ Horng-Jyh Harn,§§¶¶ Jaung-Geng Lin,* Shinn-Zong Lin,§##***†††1 and Yi-Hung Chen‡‡1

*School of Chinese Medicine, China Medical University, Taichung, Taiwan
†Division of Chinese Medicine, China Medical University Beigang Hospital, Yunlin County, Taiwan
‡Division of Chinese Medicine, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan
§Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
¶Everfront Biotech Inc., New Taipei City, Taiwan
#Department of Respiratory Therapy, Taipei Veterans General Hospital, Taipei, Taiwan
**Department of Emergency Medicine, China Medical University Hospital, Taichung, Taiwan
††Department of Health Industry Management, Kainan University, Taoyuan, Taiwan
‡‡Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan
§§Department of Medicine, China Medical University, Taichung, Taiwan
¶¶Department of Pathology, China Medical University Hospital, Taichung, Taiwan
##Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan
***Department of Neurosurgery, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan
†††Graduate Institute of Immunology, China Medical University, Taichung, Taiwan

This review reports on recent findings concerning the effects of acupuncture and electroacupuncture (EA) on stem cell mobilization and differentiation, in particular with regard to neurogenesis. Traditional Chinese acupuncture has a history of over 2,500 years and is becoming more popular worldwide. Evidence has demonstrated that acupuncture may be of benefit in stroke rehabilitation, parkinsonism, dementia, and depression. This article reviews recent studies concerning the effects of acupuncture/EA on stem cell mobilization and on progenitor cell proliferation in the CNS. The reviewed evidence indicates that acupuncture/EA has beneficial effects in several neurodegenerative diseases, and it may prove to be a nondrug method for mobilizing stem cells in the CNS.

Key words: Neurodegenerative diseases; Neurogenesis; Acupuncture; Electroacupuncture (EA)

Received October 30, 2013; final acceptance February 5, 2014.
1These authors provided equal contribution to this work.
Address correspondence to Yi-Hung Chen, Ph.D., Graduate Institute of Acupuncture Science, China Medical University, 91 Hsuch-Shih Road, Taichung, Taiwan, ROC. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Prof. Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC. Tel: +886-4-22052121, ext. 6034; Fax: +886-4-220806666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 567-571, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678508
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

The Potential Therapeutic Applications of Olfactory Ensheathing Cells in Regenerative Medicine

Ruey-Hwang Chou,*†1 Cheng-You Lu,‡1 Wei-Lee,‡ Jia-Rong Fan,‡ Yung-Luen Yu,*† and Woei-Cherng Shyu‡§

*Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung, Taiwan
†Department of Biotechnology, Asia University, Taichung, Taiwan
‡Center for Neuropsychiatry and Translational Medicine Research Center, China Medical University and Hospital, Taichung, Taiwan
§Graduate Institute of Immunology, China Medical University, Taichung, Taiwan

Olfactory ensheathing cells (OECs) are unique glia cells restricted to the primary olfactory system including the olfactory mucosa, olfactory nerve, and the outer nerve layer of the olfactory bulb. OECs guide growing olfactory axons from the neurons of the nasal cavity olfactory mucosa to the olfactory bulb to connect both the peripheral nervous system (PNS) and central nervous system (CNS). Based on these specialized abilities of OECs, transplantation of OECs to injury sites has been widely investigated for their potential therapeutic applications in neural repair in different injuries. In this article, we reviewed the properties of OECs and their roles in olfactory regeneration and in treatment of different injuries including spinal cord injury, PNS injury, and stroke and neurodegenerative diseases.

Key words: Olfactory ensheathing cells (OECs); Neuronal injury; Regenerative medicine

Received December 2, 2013; final acceptance January 30, 2014.
1These authors provided equal contribution to this work.
Address correspondence to Yung-Luen Yu, Ph.D., Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan, ROC. Tel: +886-4-22052121, ext. 7933; Fax: +886-4-22333496; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Woei-Cherng Shyu, Ph.D., Graduate Institute of Immunology, China Medical University, Taichung, Taiwan. Tel: +886-4-22052121, ext. 7831; Fax: +886-4-22080666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 573-611, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678427
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Spinal Cord Regeneration

Wise Young

W. M. Keck Center for Collaborative Neuroscience, Rutgers, State University of New Jersey, Piscataway, NJ, USA

Three theories of regeneration dominate neuroscience today, all purporting to explain why the adult central nervous system (CNS) cannot regenerate. One theory proposes that Nogo, a molecule expressed by myelin, prevents axonal growth. The second theory emphasizes the role of glial scars. The third theory proposes that chondroitin sulfate proteoglycans (CSPGs) prevent axon growth. Blockade of Nogo, CSPG, and their receptors indeed can stop axon growth in vitro and improve functional recovery in animal spinal cord injury (SCI) models. These therapies also increase sprouting of surviving axons and plasticity. However, many investigators have reported regenerating spinal tracts without eliminating Nogo, glial scar, or CSPG. For example, many motor and sensory axons grow spontaneously in contused spinal cords, crossing gliotic tissue and white matter surrounding the injury site. Sensory axons grow long distances in injured dorsal columns after peripheral nerve lesions. Cell transplants and treatments that increase cAMP and neurotrophins stimulate motor and sensory axons to cross glial scars and to grow long distances in white matter. Genetic studies deleting all members of the Nogo family and even the Nogo receptor do not always improve regeneration in mice. A recent study reported that suppressing the phosphatase and tensin homolog (PTEN) gene promotes prolific corticospinal tract regeneration. These findings cannot be explained by the current theories proposing that Nogo and glial scars prevent regeneration. Spinal axons clearly can and will grow through glial scars and Nogo-expressing tissue under some circumstances. The observation that deleting PTEN allows corticospinal tract regeneration indicates that the PTEN/AKT/mTOR pathway regulates axonal growth. Finally, many other factors stimulate spinal axonal growth, including conditioning lesions, cAMP, glycogen synthetase kinase inhibition, and neurotrophins. To explain these disparate regenerative phenomena, I propose that the spinal cord has evolved regenerative mechanisms that are normally suppressed by multiple extrinsic and intrinsic factors but can be activated by injury, mediated by the PTEN/AKT/mTOR, cAMP, and GSK3b pathways, to stimulate neural growth and proliferation.

Key words: Nogo; Phosphatase and tensin homolog (PTEN); Myelin; Glial scar; Chrondroitin sulfate proteoglycans (CSPGs)

Received October 30, 2013; final acceptance February 13, 2014.
Address correspondence to Wise Young Ph.D., M.D., W. M. Keck Center for Collaborative Neuroscience, Rutgers, State University of New Jersey, Piscataway, NJ 08854-8082, USA. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 613-620, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678355
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Tai Chi Intervention Increases Progenitor CD34+ Cells in Young Adults

Tsung-Jung Ho,*†‡ Li-Ing Ho,§ Kuo-Wei Hsueh,¶ Tzu-Min Chan,#** Shih-Li Huang,* Jaung-Geng Lin,* Wen-Miin Liang,†† Wei-Hung Hsu,‡‡1 Horng-Jyh Harn,§§¶¶1 and Shinn-Zong Lin**##***†††1

*School of Chinese Medicine, China Medical University, Taichung, Taiwan
†Division of Chinese Medicine, China Medical University Beigang Hospital, Yunlin County, Taiwan
‡Division of Chinese Medicine, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan
§Department of Respiratory Therapy, Taipei Veterans General Hospital, Taipei, Taiwan
¶Ph.D. Program for Aging, China Medical University, Taichung, Taiwan
#Everfront Biotech Inc., New Taipei City, Taiwan
**Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
††Graduate Institute of Biostatistics, China Medical University, Taichung, Taiwan
‡‡Department of Chinese Medicine, Lo-Sheng Sanatorium, Department of Health, Executive Yuan, Taiwan
§§Department of Pathology, China Medical University Hospital, Taichung, Taiwan
¶¶Department of Medicine, China Medical University, Taichung, Taiwan
##Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan
***Department of Neurosurgery, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan
†††Graduate Institute of Immunology, China Medical University, Taichung, Taiwan

Tai Chi has been shown to have many great health benefits. However, few research attempts have been made to explore the effects of practicing TCC on life span. This study provides direct evidence of Tai Chi’s antiaging effects. We conducted a retrospective cross-sectional study to compare the rejuvenating and antiaging effects among Tai Chi group (TCC) and brisk walking group (BW) and no exercise habit group (NEH). Thirty-two participants were selected out of a possible 60 based on a survey, and they were separated into three groups: the TCC group (practicing for more than 1 year), the BW group (practicing for more than 1 year), and the NEH group. The CD34+ cell counts in peripheral blood of the participants was determined, and the Kruskal–Wallis test was used to evaluate and compare the antiaging effects of the three groups. Of the 32 participants in this study, the participants in the TCC group (N = 10) outperformed the NEH group (N = 12) with respect to the number of CD34+ progenitor cells. No significant difference was found between the TCC group and the BW group. TCC practice sustained for more than 1 year may be an intervention against aging as effective as BW in terms of its benefits on the improvement of CD34+ number.

Key words: Tai Chi; CD34+ stem cell; Antiaging; Longevity

Received October 30, 2013; final acceptance February 17, 2014.
1These authors provided equal contribution to this work.
Address correspondence to Prof. Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC. Tel: +886-4-22052121, ext. 6034; Fax: +886-4-220806666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 621-630, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678355
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

Decellularization and Recellularization Technologies in Tissue Engineering

Ru-Huei Fu,*†1 Yu-Chi Wang,‡1 Shih-Ping Liu,†§ Ton-Ru Shih,* Hsin-Lien Lin,* Yue-Mi Chen,* Jiun-Huei Sung,* Chia-Hui Lu,* Jing-Rong Wei,* Zih-Wan Wang,* Shyh-Jer Huang,¶ Chang-Hai Tsai,#** Woei-Cherng Shyu,*† and Shinn-Zong Lin*†††‡‡

*Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
†Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
‡Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
§Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
¶Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
#Department of Pediatrics, China Medical University, Taichung, Taiwan
**Department of Healthcare Administration, Asia University, Taichung, Taiwan
††Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan
‡‡Department of Neurosurgery, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan

Decellularization is the process by which cells are discharged from tissues/organs, but all of the essential cues for cell preservation and homeostasis are retained in a three-dimensional structure of the organ and its extracellular matrix components. During tissue decellularization, maintenance of the native ultrastructure and composition of the extracellular matrix (ECM) is extremely acceptable. For recellularization, the scaffold/matrix is seeded with cells, the final goal being to form a practical organ. In this review, we focus on the biological properties of the ECM that remains when a variety of decellularization methods are used, comparing recellularization technologies, including bioreactor expansion for perfusion-based bioartificial organs, and we discuss cell sources. In the future, decellularization–recellularization procedures may solve the problem of organ assembly on demand.

Key words: Biomaterial; Decellularization; Extracellular matrix (ECM); Organ bioengineering and regeneration; Recellularization

Received October 30, 2013; final acceptance January 31, 2014.
1These authors provided equal contribution to this work.
Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, No. 2, Yude Road, Taichung 40447, Taiwan, ROC. Tel: +886-4-22052121, ext. 6034; Fax: +886-4-22080666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Ru-Huei Fu, Ph.D., Graduate Institute of Immunology, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan, ROC. Tel: +886-4-22052121, ext. 7826; Fax: +886-4-22052121, ext. 7810; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 631-639, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678319
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Review

The Therapeutic Potential of Anti-Interleukin-20 Monoclonal Antibody

Yu-Hsiang Hsu and Ming-Shi Chang

Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Interleukin (IL)-20, a member of the IL-10 family of cytokines, was discovered in 2001. IL-20 acts on multiple cell types by activating on a heterodimer receptor complex of either IL-20R1–IL-20R2 or IL-22R1–IL-20R2. Recent evidence indicates that IL-20’s interaction with its receptors might have proinflammatory effects on chronic inflammatory diseases, particularly rheumatoid arthritis (RA), osteoporosis, and breast cancer. Updated information about IL-20, such as its identification, expression, receptors, signaling, and biological activities, is illustrated in this review based on our research and the data available in the literature. IL-20 is a pleiotropic cytokine, which promotes inflammation, angiogenesis, and chemotaxis. IL-20 also regulates osteoclast differentiation by altering the receptor activator of NF-kB (RANK) and RANK ligand (RANKL) axis. Inflammation, angiogenesis, and osteoclastogenesis are critical for the pathogenesis of RA, osteoporosis, and breast cancerinduced osteolysis. Based on the in vitro and in vivo data and clinical samples, we demonstrated that IL-20 plays pivotal roles in these three diseases. In experimental models, anti-IL-20 monoclonal antibody ameliorates arthritis severity, protects against ovariectomized-induced bone loss, and inhibits breast tumor-induced osteolysis. This review presents the clinical implications of IL-20, which will lead to a better understanding of the biological functions of IL-20 in these diseases and provide new therapeutic options in the future.

Key words: Interleukin (IL)-20; Rheumatoid arthritis (RA); Osteoporosis; Breast cancer

Received October 30, 2013; final acceptance January 30, 2014.
Address correspondence to Ming-Shi Chang, Professor, Department of Biochemistry and Molecular Biology, National Cheng Kung University, College of Medicine, Tainan 70428, Taiwan, ROC. Tel: +886-6-235-3535, ext. 5677; Fax: +886-6-274-1694; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 641-656, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678373
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Dryocrassin Suppresses Immunostimulatory Function of Dendritic Cells and Prolongs Skin Allograft Survival

Ru-Huei Fu,*† Yu-Chi Wang,‡ Shih-Ping Liu,†§ Ton-Ru Shih,* Hsin-Lien Lin,* Yue-Mi Chen,* Rong-Tzong Tsai,¶ Chang-Hai Tsai,#** Woei-Cherng Shyu,*† and Shinn-Zong Lin*†,††‡‡

*Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
†Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
‡Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan
§Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
¶Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
#Department of Pediatrics, China Medical University, Taichung, Taiwan
**Department of Healthcare Administration, Asia University, Taichung, Taiwan
††Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan
‡‡Department of Neurosurgery, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan

Dendritic cells (DCs) are the major specialized antigen-presenting cells for the development of optimal T-cell immunity. DCs can be used as pharmacological targets to monitor novel biological modifiers for the cure of harmful immune responses, such as transplantation rejection. Dryopteris crassirhizoma Nakai (Aspiadaceae) is used for traditional herbal medicine in the region of East Asia. The root of this fern plant has been listed for treating inflammatory diseases. Dryocrassin is the tetrameric phlorophenone component derived from Dryopteris. Here we tested the immunomodulatory potential of dryocrassin on lipopolysaccharide (LPS)-stimulated activation of mouse bone marrow-derived DCs in vitro and in skin allograft transplantation in vivo. Results demonstrated that dryocrassin reduced the emission of tumor necrosis factor-a, interleukin-6, and interleukin-12p70 by LPS-stimulated DCs. The expression of LPS-induced major histocompatibility complex class II, CD40, and CD86 on DCs was also blocked by dryocrassin. Moreover, LPS-stimulated DC-elicited allogeneic T-cell proliferation was alleviated by dryocrassin. In addition, dryocrassin inhibited LPS-induced activation of IκB kinase, JNK/p38 mitogen-activated protein kinase, and the translocation of NF-κB. Treatment with dryocrassin noticeably diminished 2,4-dinitro-1-fluorobenzene-reduced delayed-type hypersensitivity and extended skin allograft survival. Dryocrassin may be one of the potent immunosuppressive agents for transplant rejection via the destruction of DC maturation and function.

Key words: Dryocrassin; Dendritic cells (DCs); Immunosuppression; Nuclear factor-κB; Mitogen-activated protein kinase; Skin allograft

Received October 30, 2014; final acceptance February 5, 2014.
Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, No. 2, Yude Road, Taichung 40447, Taiwan, ROC. Tel: +886-4-22052121, ext. 6034; Fax: +886-4-22080666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Ru-Huei Fu, Ph. D., Graduate Institute of Immunology, China Medical University, No. 91, Hsueh-shih Road, Taichung 40402, Taiwan, ROC. Tel: +886-4-22052121, ext. 7826; Fax: +886-4-22052121, ext. 7810; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 657-668, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678373
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Salvianolic Acid B Maintained Stem Cell Pluripotency and Increased Proliferation Rate by Activating Jak2–Stat3 Combined With EGFR–Erk1/2 Pathways

Chia Hui Liu,* Woei-Cherng Shyu,*† Ru-Huei Fu,*† Shyh-Jer Huang,‡§ Cheng-Hsuan Chang,¶ Yu-Chuen Huang,#** Shih-Yin Chen,#** Shinn-Zong Lin,*†††‡‡ and Shih-Ping Liu†¶§§

*Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
†Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
‡School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan
§Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
¶Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
#Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
**Graduate Institute of Chinese Medical Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan
††Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan
‡‡Department of Neurosurgery, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan
§§Department of Social Work, Asia University, Taichung, Taiwan

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are considered the most powerful in terms of differentiating into three-germ-layer cells. However, maintaining self-renewing ESCs and iPSCs in vitro requires leukemia-induced factor (LIF), an expensive reagent. Here we describe a less expensive compound that may serve as a LIF substitute—salvianolic acid B (Sal B), a Salvia miltiorrhiza extract. We found that Sal B is capable of upregulating Oct4 and Sox2, two genes considered important for the maintenance of ESC pluripotency. Our MTT data indicate that instead of triggering cell death, Sal B induced cell proliferation, especially at optimum concentrations of 0.01 nM and 0.1 nM. Other results indicate that compared to non-LIF controls, Sal B-treated ESCs expressed higher levels of several stem cell markers while still maintaining differentiation into three-germlayer cells after six passages. Further, we found that Sal B triggers the Jak2–Stat3 and EGFR–ERK1/2 signaling pathways. Following Sal B treatment, (a) levels of phosphorylated (p)-Jak2, p-Stat3, p-EGFR, and p-ERK proteins all increased; (b) these increases were suppressed by AG490 (a Jak2 inhibitor) and ZD1839 (an EGFR inhibitor); and (c) cytokines associated with the Jak2–Stat3 signaling pathway were upregulated. Our findings suggest that Sal B can be used as a LIF replacement for maintaining ESC pluripotency while increasing cell proliferation.

Key words: Embryonic stem cells (ESCs); Induced pluripotent stem cells (iPSCs); Salvia miltiorrhiza; Salvianolic acid B (Sal B)

Received October 30, 2013; final acceptance February 6, 2014.
Address correspondence to Shih-Ping Liu, Ph.D., No. 2, Yuh-Der Road, Taichung, Taiwan 40447, ROC. Tel: +886-4-2205-2121, ext. 7828; Fax: +886-4-2205-2121, ext. 7810; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 669-690, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368914X678364
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

MicroRNA142-3p Promotes Tumor-Initiating and Radioresistant Properties in Malignant Pediatric Brain Tumors

Yi-Yen Lee,*†1 Yi-Ping Yang,*‡1 Ming-Chao Huang,†§2 Mong-Lien Wang,§2 Sang-Hue Yen,§¶ Pin-I Huang,*¶ Yi-Wei Chen,*¶ Shih-Hwa Chiou,*‡§ Yuan-Tzu Lan,*‡ Hsin-I Ma,# Yang-Hsin Shih,§** and Ming-Teh Chen§**

*Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
†Division of Pediatric Neurosurgery, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
‡Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
§School of Medicine, National Yang-Ming University, Taipei, Taiwan
¶Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan
#Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan
**Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan

Primary central nervous system (CNS) atypical teratoid/rhabdoid tumor (ATRT) is an extremely malignant pediatric brain tumor observed in infancy and childhood. It has been reported that a subpopulation of CD133+ cells isolated from ATRT tumors present with cancer stem-like and radioresistant properties. However, the exact biomolecular mechanisms of ATRT or CD133-positive ATRT (ATRT-CD133+) cells are still unclear. We have previously shown that ATRT-CD133+ cells have pluripotent differentiation ability and the capability of malignant cells to be highly resistant to ionizing radiation (IR). By using microRNA array and quantitative RT-PCR in this study, we showed that expression of miR142-3p was lower in ATRT-CD133+ cells than in ATRT-CD133− cells. miR142-3p overexpression significantly inhibited the self-renewal and tumorigenicity of ATRT-CD133+ cells. On the contrary, silencing of endogenous miR142-3p dramatically increased the tumor-initiating and stem-like cell capacities in ATRT cells or ATRT-CD133 cells and further promoted the mesenchymal transitional and radioresistant properties of ATRT cells. Most importantly, therapeutic delivery of miR142-3p in ATRT cells effectively reduced its lethality by blocking tumor growth, repressing invasiveness, increasing radiosensitivity, and prolonging survival time in orthotropic-transplanted immunocompromised mice. These results demonstrate the prospect of developing novel miRNA-based strategies to block the stem-like and radioresistant properties of malignant pediatric brain cancer stem cells.

Key words: Pediatric brain tumor; Atypical teratoid/rhabdoid tumor (ATRT); Cluster of differentiation 133 (CD133); Radiosensitivity; Cancer stem cells (CSCs)

Received October 30, 2013; final acceptance February 14, 2014.
1These authors provided equal contribution to this work.
2These authors provided equal contribution to this work.
Address correspondence to Ming-Teh Chen, M.D., Ph.D., Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan, ROC. Tel: +886-2-28757424; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it