Cell Transplantation 26(3) Abstracts

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Cell Transplantation, Vol. 26, pp. 381-394, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693824
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Review

The Regulatory Effects of Transforming Growth Factor-β on Nerve Regeneration

Shiying Li, Xiaosong Gu, and Sheng Yi

Key Laboratory of Neurogeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, P.R. China

Transforming growth factor-β (TGF-β) belongs to a group of pleiotropic cytokines that are involved in a variety of biological processes, such as inflammation and immune reactions, cellular phenotype transition, extracellular matrix (ECM) deposition, and epithelial–mesenchymal transition. TGF-β is widely distributed throughout the body, including the nervous system. Following injury to the nervous system, TGF-β regulates the behavior of neurons and glial cells and thus mediates the regenerative process. In the current article, we reviewed the production, activation, as well as the signaling pathway of TGF-β. We also described altered expression patterns of TGF-β in the nervous system after nerve injury and the regulatory effects of TGF-β on nerve repair and regeneration in many aspects, including inflammation and immune response, phenotypic modulation of neural cells, neurite outgrowth, scar formation, and modulation of neurotrophic factors. The diverse biological actions of TGF-β suggest that it may become a potential therapeutic target for the treatment of nerve injury and regeneration.

Key words: Transforming growth factor-β (TGF-β); TGF-β signaling; Nerve regeneration; Cellular behavior; Scar formation

Received August 6, 2016; final acceptance December 20, 2016. Online prepub date: November 23, 2016.
Address correspondence to Dr. Sheng Yi, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Jiangsu 226001, P.R. China. Tel: +086-513-85051808; Fax: +86-513-85511585; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 395-407, 2017
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DOI: https://doi.org/10.3727/096368916X
694364
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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GSK-3β Inhibition Induced Neuroprotection, Regeneration, and Functional Recovery After Intracerebral Hemorrhagic Stroke

Yingying Zhao,*†1 Zheng Zachory Wei,*†1 James Ya Zhang,†‡ Yongbo Zhang,* Soonmi Won,† Jinmei Sun,*† Shan Ping Yu,*† Jimei Li,* and Ling Wei*†‡

*Department of Neurology and Laboratories of Stem Cell Biology and Regenerative Medicine, Neurological Disease Center and Experimental Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, P.R. China
†Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
‡Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA

Hemorrhagic stroke is a devastating disease that lacks effective therapies. In the present investigation, we tested 6-bromoindirubin-3ʹ-oxime (BIO) as a selective glycogen synthase kinase-3β (GSK-3β) inhibitor in a mouse model of intracerebral hemorrhage (ICH). ICH was induced by injection of collagenase IV into the striatum of 8- to 10-week-old C57BL/6 mice. BIO (8 μg/kg, IP) was administered following either an acute delivery (0–2 h delay) or a prolonged regimen (every 48 h starting at 3 days post-ICH). At 2 days post-ICH, the acute BIO treatment significantly reduced the hematoma volume. In the perihematoma regions, BIO administration blocked GSK-3β phosphorylation/activation, increased Bcl-2 and β-catenin levels, and significantly increased viability of neurons and other cell types. The prolonged BIO regimen maintained a higher level of β-catenin, upregulated VEGF and BDNF, and promoted neurogenesis and angiogenesis in peri-injury zones at 14 days after ICH. The BIO treatment also promoted proliferation of neural stem cells (NSCs) and migration of nascent DCX+ neuroblasts from the subventricular zone (SVZ) to the lesioned cortex. BIO improved functional outcomes on both the neurological severity score and rotarod tests. The findings of this study corroborate the neuroprotective and regenerative effects of BIO and suggest that the Wnt/GSK-3β/β-catenin pathway may be explored for the treatment of acute or chronic ICH.

Key words: 6-Bromoindirubin-3ʹ-oxime (BIO); Wnt signaling; Neural stem cells (NSCs); Neurogenesis; Intracerebral hemorrhage (ICH)

Received February 25, 2016; final acceptance December 7, 2016. Online prepub date: February 14, 2017.
1These authors provided equal contribution to this work.
Address correspondence to Ling Wei, M.D., Departments of Anesthesiology and Neurology, Emory University School of Medicine, 101 Woodruff Circle WMRB 617, Atlanta, GA 30322, USA. Tel: 404-712-8661; Fax: 404-727-6300; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Jimei Li, M.D., Department of Neurology, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Xi-Cheng District, Beijing 100050, P.R. China. Tel: 010-63014411; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  


Cell Transplantation, Vol. 26, pp. 409-416, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
694247
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Neuroprotection of Granulocyte Colony-Stimulating Factor for Early Stage Parkinson’s Disease

Sheng-Tzung Tsai,* Sung-Chao Chu,† Shu-Hsin Liu,‡ Cheng-Yoong Pang,§ Ting-Wen Hou,* Shinn-Zong Lin,* and Shin-Yuan Chen*

*Department of Neurosurgery, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan
†Department of Oncology/Hematology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan
‡Department of Nuclear Medicine, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan
§Department of Medical Research, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan

Parkinson’s disease (PD) is a slowly progressive neurodegenerative disease. Both medical and surgical choices provide symptomatic treatment. Granulocyte colony-stimulating factor (G-CSF), a conventional treatment for hematological diseases, has demonstrated its effectiveness in acute and chronic neurological diseases through its anti-inflammatory and antiapoptosis mechanisms. Based on previous in vitro and in vivo studies, we administered a lower dose (3.3 μg/kg) G-CSF injection for 5 days and six courses for 1 year in early-stage PD patients as a phase I trial. The four PD patient’s mean unified PD rating scale motor scores in medication off status remained stable from 23 before the first G-CSF injection to 22 during the 2-year follow-up. 3,4-Dihydroxy-6-18F-fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) studies also revealed an annual 3.5% decrease in radiotracer uptake over the caudate nucleus and 7% in the putamen, both slower than those of previous reports of PD. Adverse effects included transient muscular–skeletal pain, nausea, vomiting, and elevated liver enzymes. Based on this preliminary report, G-CSF seems to alleviate disease deterioration for early stage PD patients. The effectiveness of G-CSF was possibly due to its amelioration of progressive dopaminergic neuron degeneration.

Key words: Parkinson’s disease (PD); Granulocyte colony-stimulating factor (G-CSF); Neuroprotection

Received October 12, 2016; final acceptance January 31, 2017. Online prepub date: December 7, 2016.
Address correspondence to Dr. Shin-Yuan Chen, Department of Neurosurgery, Tzu Chi General Hospital, 707, Sec. 3, Chung-Yang Road, Hualien 970, Taiwan. Tel: +886-3-8561825, ext. 2151; Fax: +886-3-8463164; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 417-427, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693464
E-ISSN 1555-3892
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Chondrogenic Differentiation of Mesenchymal Stem Cells in Three-Dimensional Chitosan Film Culture

Tsai-Jung Lu,*1 Fang-Yao Chiu,†1 Hsiao-Ying Chiu,‡ Ming-Chau Chang,*† and Shih-Chieh Hung†‡§¶#

*Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan
†Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
‡Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
§Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
¶Department of Orthopaedics, and Integrative Stem Cell Center, China Medical University Hospital, Taichung, Taiwan
#Graduate Institute of Biomedical Sciences, New Drug Development, China Medical University, Taichung, Taiwan

Articular cartilage has a very limited capacity for self-repair, and mesenchymal stem cells (MSCs) have the potential to treat cartilage defects and osteoarthritis. However, in-depth mechanistic studies regarding their applications are required. Here we demonstrated the use of chitosan film culture for promoting chondrogenic differentiation of MSCs. We found that MSCs formed spheres 2 days after seeding on dishes coated with chitosan. When MSCs were induced in a chondrogenic induction medium on chitosan films, the size of the spheres continuously increased for up to 21 days. Alcian blue staining and immunohistochemistry demonstrated the expression of chondrogenic proteins, including aggrecan, type II collagen, and type X collagen at 14 and 21 days of differentiation. Importantly, chitosan, with a medium molecular weight (size: 190–310 kDa), was more suitable than other sizes for inducing chondrogenic differentiation of MSCs in terms of sphere size and expression of chondrogenic proteins and endochondral markers. We identified that the mechanistic target of rapamycin (mTOR) signaling and its downstream S6 kinase (S6K)/S6 were activated in chitosan film culture compared to that of monolayer culture. The activation of mTOR/S6K was continuously upregulated from days2 to 7 of differentiation. Furthermore, we found that mTOR/S6K signaling was required for chondrogenic differentiation of MSCs in chitosan film culture through rapamycin treatment and mTOR knockdown. In conclusion, we showed the suitability of chitosan film culture for promoting chondrogenic differentiation of MSCs and its potential in the development of new strategies in cartilage tissue engineering.

Key words: Mesenchymal stem cells (MSCs); Chondrogenesis; Chitosan film culture; Spheroid; Mechanistic target of rapamycin (mTOR)

Received August 19, 2016; final acceptance November 18, 2016. Online prepub date: October 12, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Shih-Chieh Hung, M.D., Ph.D., Integrative Stem Cell Center, China Medical University Hospital, 7F, No. 6 Xueshi Road, North District, Taichung 404, Taiwan. Tel: +886-4-22052121, #7728; Fax: +886-4-422333922; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Ming-Chau Chang, M.D., Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei 11217, Taiwan. Tel: +886-2-8757557, #121; Fax: +886-2-28757567; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 429-438, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
694382
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Review

Pre-S2 Mutant-Induced Mammalian Target of Rapamycin Signal Pathways as Potential Therapeutic Targets for Hepatitis B Virus-Associated Hepatocellular Carcinoma

Chiao-Fang Teng,* Han-Chieh Wu,† Woei-Cherng Shyu,‡§ Long-Bin Jeng,* and Ih-Jen Su†¶#

*Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan
†National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan
‡Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
§Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
¶Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
#Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan

Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Pre-S2 mutant represents an HBV oncoprotein that is accumulated in the endoplasmic reticulum (ER) and manifests as type II ground glass hepatocytes (GGHs). Pre-S2 mutant can induce ER stress and initiate multiple ER stress-dependent or -independent cellular signal pathways, leading to growth advantage of type II GGH. Importantly, the mammalian target of rapamycin (mTOR) signal pathways are consistently activated throughout the liver tumorigenesis in pre-S2 mutant transgenic mice and in human HCC tissues, leading to hepatocyte proliferation, metabolic disorders, and HCC tumorigenesis. In this review, we summarize the pre-S2 mutant-induced mTOR signal pathways and its implications in HBV-related HCC tumorigenesis. Clinically, the presence of pre-S2 mutant exhibits a high resistance to antiviral treatment and carries a high risk of HCC development in patients with chronic HBV infection. Targeting at pre-S2 mutant-induced mTOR signal pathways may thus provide potential strategies for the prevention or therapy of HBV-associated HCC.

Key words: Hepatitis B virus (HBV); Hepatocellular carcinoma (HCC); Ground glass hepatocytes (GGHs); Pre-S2 mutant; Mammalian target of rapamycin (mTOR)

Received August 31, 2016; final acceptance January 6, 2017. Online prepub date: February 14, 2017.
Address correspondence to Ih-Jen Su, M.D., Ph.D., Department of Biotechnology, Southern Taiwan University of Science and Technology, No. 1 Nantai Street, Yongkang District, Tainan City 710, Taiwan (R.O.C.). Tel: 886-6-253-3131; Fax: 886-6-242-5747; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Long-Bin Jeng, M.D., Ph.D., Organ Transplantation Center, China Medical University Hospital, No. 2 Yude Road, North District, Taichung City 404, Taiwan (R.O.C.). Tel: 886-4-2205-2121; Fax: 886-4-2202-9083; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 439-448, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
694193
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Review

Mesenchymal Stem Cells: The Magic Cure for Intraventricular Hemorrhage?

Won Soon Park,*†‡1 So Yoon Ahn,*†1 Se In Sung,* Jee-Yin Ahn,§ and Yun Sil Chang*†‡

*Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
†Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, South Korea
‡Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
§Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, South Korea

Severe intraventricular hemorrhage (IVH) remains a major cause of mortality and long-term neurologic morbidities in premature infants, despite recent advances in neonatal intensive care medicine. Several preclinical studies have demonstrated the beneficial effects of mesenchymal stem cell (MSC) transplantation in attenuating brain injuries resulting from severe IVH. Because there currently exists no effective intervention for severe IVH, the therapeutic potential of MSC transplantation in this intractable and devastating disease is creating excitement in this field. This review summarizes recent progress in stem cell research for treating neonatal brain injury due to severe IVH, with a particular focus on preclinical data concerning important issues, such as mechanism of protective action and determining optimal source, route, timing, and dose of MSC transplantation, and on the translation of these preclinical study results to a clinical trial.

Key words: Intraventricular hemorrhage (IVH); Premature infant; Hydrocephalus; Mesenchymal stem cells (MSCs); Cell transplantation

Received September 24, 2016; final acceptance December 20, 2016. Online prepub date: November 30, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Yun Sil Chang, M.D., Ph.D., Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-guSeoul 06351, South Korea. Tel: +82.2-3410-3528; Fax: +82.2-3410-0043; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Jee-Yin Ahn, Ph.D., Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 2066 SebùroJangangu, Suwon, Gyeonggido 16419, South Korea. Tel: +82-31-299-6134; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 449-460, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693310
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Commercial Production of Autologous Stem Cells and Their Therapeutic Potential for Liver Cirrhosis

Yi-Chun Lin,* Horng-Jyh Harn,† Po-Cheng Lin,* Ming-Hsi Chuang,*‡ Chun-Hung Chen,* Shinn-Zong Lin,§ and Tzyy-Wen Chiou

*Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan
Bioinnovation Center, Tzu Chi Foundation, Department of Pathology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan
‡Department of Bioinformatics, Chung Hua University, Hsinchu, Taiwan
§Bioinnovation Center, Tzu Chi Foundation, Department of Neurosurgery, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan
¶Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan

Human adipose-derived stem cells (hADSCs) are a promising source of autologous stem cells for personalized cell-based therapies. Culture expansion of ADSCs provides an attractive opportunity for liver cirrhosis patients. However, safety and stability issues can pose big challenges for personalized autologous stem cell products. In the present study, we addressed whether the commercial production program could provide a consistent product for liver cirrhosis therapy. We collected adipose tissue from three human donors by lipoaspirate and isolated ADSCs, which were expanded in culture to reach 1 × 108 cells (an approximately 1,000-fold expansion) within four passages. We then examined their morphology, chromosome stability, surface markers, and differentiation ability after culture. Next, we explored their therapeutic potential using a rat model of thioacetamide-induced liver cirrhosis. Culture-expanded ADSCs were injected intrahepatically, and their biodistribution was tracked by immunohistochemistry using an antibody against human mitochondria. Finally, we tested for tumor development by subcutaneously injecting a 100-fold dose range of cultured ADSCs into immunocompromised mice. Taken together, we find that culture expansion of autologous ADSCs is a potentially suitable stem cell product for personalized cell-based therapy for patients with liver cirrhosis.

Key words: Adipose-derived stem cells (ADSCs); Autologous; Liver cirrhosis; Personalized

Received September 2, 2016; final acceptance November 16, 2016. Online prepub date: October 6, 2016.
Address correspondence to Dr. Tzyy-Wen Chiou, Ph.D., Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, No. 1, Sec. 2, Da Hsueh Road, Shoufeng, Hualien 97401, Taiwan. Tel: +886-3-8630398; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Horng-Jyh Harn, M.D., Ph.D., Department of Pathology, School of Medicine, China Medical University. No. 707, Sec. 3, Chung Yang Rd., Hualien 970, Taiwan. Tel: +886-4-22053366, ext. 2260; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 461-467, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
692988
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Novel Therapeutic Transplantation of Induced Neural Stem Cells for Stroke

Toru Yamashita,* Wentao Liu,* Yoshiaki Matsumura,* Ryosuke Miyagi,* Yun Zhai,* Momoko Kusaki,* Nozomi Hishikawa,* Yasuyuki Ohta,* Sung Min Kim,† Tae Hwan Kwak,† Dong Wook Han,†‡ and Koji Abe*

*Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
†Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, South Korea
‡Department of Advanced Translational Medicine, KU Open-Innovation Center, School of Medicine, Konkuk University, Seoul, South Korea

Somatic cells can be directly converted into induced neural stem cells (iNSCs) by defined transcription factors. However, the therapeutic effect of undifferentiated iNSCs on ischemic stroke has not been demonstrated. In this study, we used a mouse model of transient middle cerebral artery occlusion (tMCAO). iNSCs (5 × 105) were injected directly into the ipsilateral striatum and cortex 24 h after tMCAO. Histological analysis was performed at 7 days, 28 days, and 8 months after tMCAO. We found that iNSC transplantation successfully improved the survival rate of stroke model mice with significant functional recovery from the stroke. The fate of engrafted iNSCswas that the majority of iNSCs had differentiated into astroglial cells but not into neural cells in both the sham-operated brain and the poststroke brain without forming a tumor up to 8 months after tMCAO. Our data suggest that the directly converted iNSCs can be regarded as a candidate of safe cell resource for transplantation therapy in patients suffering from ischemic stroke.

Key words: Induced neural stem cells (iNSCs); Cerebral ischemia; Cell transplantation; Inflammatory response

Received August 28, 2016; final acceptance October 11, 2016. Online prepub date: September 20, 2016.
Address correspondence to Koji Abe, M.D., Ph.D., Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 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. 26, pp. 469-482, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693473
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Neural Stem Cell-Conditioned Medium Suppresses Inflammation and Promotes Spinal Cord Injury Recovery

Zhijian Cheng,*†1 Dale B. Bosco,†1 Li Sun,† Xiaoming Chen,‡ Yunsheng Xu,‡ Wenjiao Tai,† Ruth Didier,† Jinhua Li,§ Jianqing Fan,¶ Xijing He,* and Yi Ren†‡

*Department of Orthopedics, The Second Affiliated Hospital of Xian Jiaotong University, Xian, P.R. China
†Department of Biomedical Sciences, Florida State University, College of Medicine, Tallahassee, FL, USA
‡Institute of Inflammation and Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, P.R. China
§Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
¶Statistical Laboratory, Princeton University, Princeton, NJ, USA

Spinal cord injury (SCI) causes functional impairment as a result of the initial injury followed by secondary injury mechanism. SCI provokes an inflammatory response that causes secondary tissue damage and neurodegeneration. While the use of neural stem cell (NSC) engraftment to mitigate secondary injury has been of interest to many researchers, it still faces several limitations. As such, we investigated if NSC-conditioned medium (NSC-M) possesses therapeutic potential for the treatment of SCI. It has been proposed that many of the beneficial effects attributed to stem cell therapies are due to secreted factors. Utilizing primary cell culture and murine models of SCI, we determined that systemic treatment with NSC-M was able to significantly improve motor function and lesion healing. In addition, NSC-M demonstrated significant anti-inflammatory potential in vitro and in vivo, reducing inflammatory cytokine expression in both activated macrophages and injured spinal cord tissues. NSC-M was also able to reduce the expression of inducible nitric oxide synthase (iNOS) within the spleen of injured animals, indicating an ability to reduce systemic inflammation. Thus, we believe that NSC-M offers a possible alternative to direct stem cell engraftment for the treatment of SCI.

Key words: Spinal cord injury (SCI); Neural stem cell-conditioned medium (NSC-M); Inflammation; Macrophages

Received September 6, 2016; final acceptance November 18, 2016. Online prepub date: October 12, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Dr. Yi Ren, Department of Biomedical Sciences, Florida State University College of Medicine, 1115 West Street, Tallahassee, FL 32306, USA. Tel: 850-645-2013; Fax: 850-644-5781; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Dr. Xijing He, Department of Orthopedics Surgery, The Second Affiliated Hospital of Xian Jiaotong University, Xian 710004, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 483-492, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693293
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Review

Cell Therapy Regulation in Taiwan

Yuan-Chuan Chen,* Hwei-Fang Cheng,* and Ming-Kung Yeh†‡

*Food and Drug Administration, Ministry of Health and Welfare, Taipei, Taiwan
†School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
‡Department of Public Health, Fu Jen Catholic University, New Taipei, Taiwan

Cell therapy is not only a novel medical practice but also a medicinal product [cell therapy product (CTP)]. More and more CTPs are being approved for marketing globally because of the rapid development of biomedicine in cell culture, preservation, and preparation. However, regulation is the most important criterion for the development of CTPs. Regulations must be flexible to expedite the process of marketing for new CTPs. Recently, the Taiwan Food and Drug Administration (TFDA) updated the related regulations such as regulation of development, current regulatory framework and process, and the application and evaluation processes. When the quality of CTPs has been improved significantly, their safety and efficacy are further ensured. The treatment protocol, a new design for adaptive licensing to current clinical practice, is a rapid process for patients with life-threatening diseases or serious conditions for which there are no suitable drugs, medical devices, or other therapeutic methods available. The hospital can submit the treatment protocol to apply for cell therapy as a medical practice, which may result in easier and faster cell therapy development, and personalized treatment for individual patients will evolve quickly.

Key words: Cell therapy; Clinical application; Investigational new drug (IND); New drug application (NDA); Treatment protocol

Received September 20, 2016; final acceptance January 5, 2017. Online prepub date: September 30, 2016.
Address correspondence to Ming-Kung Yeh, Food and Drug Administration, Ministry of Health and Welfare, No. 161-2 Kunyang Street, Nangang District, Taipei City 11561, Taiwan (R.O.C.). Tel: 886-02-27877700; Fax: 886-02-27877799; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 493-501, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
694238
E-ISSN 1555-3892
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Adiponectin Potentially Contributes to the Antidepressive Effects of Baduanjin Qigong Exercise in Women With Chronic Fatigue Syndrome-Like Illness

Jessie S. M. Chan,*†1 Ang Li,‡§¶1 Siu-man Ng,† Rainbow T. H. Ho,*† Aimin Xu,#**†† Tzy-jyun Yao,‡‡ Xiao-Min Wang,* Kwok-Fai So,‡§¶ and Cecilia L. W. Chan*†

*Department of Social Work and Social Administration, Faculty of Social Science, The University of Hong Kong, Hong Kong Special Administration Region (Hong Kong SAR), P.R. China
†Centre on Behavioral Health, Faculty of Social Science, The University of Hong Kong, Hong Kong SAR, P.R. China
‡Guangdong–Hong Kong–Macau Institute of CNS Regeneration, Guangdong Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, P.R. China
§Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China
¶State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China
#Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China
**Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China
††State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China
‡‡Department of Biostatistics, Harvard C.H. Chan School of Public Health, Cambridge, MA, USA

Our recent study demonstrates that adiponectin signaling plays a significant role in mediating physical exercise-exerted effects on hippocampal neurogenesis and antidepression in mice. Whether the findings can be translated to humans remains unknown. This study aimed to investigate the effects of Baduanjin Qigong exercise on adiponectin and to evaluate whether adiponectin is involved in the antidepressive effects of Qigong exercise on chronic fatigue syndrome (CFS)-like illness. This is a randomized, waitlist-controlled trial. One hundred eight female participants were randomly assigned to either Qigong exercise or waitlist groups. Sixteen 1.5-h Qigong lessons were conducted. Outcome measures were taken at three time points. Baseline adiponectin levels were negatively associated with body weight, body mass index, waist circumference, hip circumference, and waist/hip ratio in women with CFS-like illness. Compared with the waitlist control, Qigong exercise significantly reduced anxiety and depression symptoms and significantly raised plasma adiponectin levels (median = 0.8 vs. −0.1, p < 0.05). More interestingly, increases in adiponectin levels following Qigong exercise were associated with decreases in depression scores for the Qigong group (r = −0.38, p = 0.04). Moreover, adjusted linear regression analysis further identified Qigong exercise and change in adiponectin levels as the significant factors accounting for reduction of depression symptoms. Baduanjin Qigong significantly increased adiponectin levels in females with CFS-like illness. Decreases in depression symptoms were associated with increases in adiponectin levels following Qigong exercise, indicating that the potential contribution of adiponectin to Qigong exercise elicited antidepressiveeffects in human subjects.

Key words: Adiponectin; Baduanjin Qigong exercise; Chronic fatigue syndrome (CFS); Depression; Female

Received October 14, 2016; final acceptance December 20, 2016. Online prepub date: December 7, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Professor Cecilia L. W. Chan, Department of Social Work and Social Administration, The University of Hong Kong, 5/F Jockey Club Tower, The Centennial Campus, Pokfulam, Hong Kong SAR, P.R. China. Tel: 852-3917-2093; Fax: 852-2858-7604; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Kwok-Fai So, Department of Ophthalmology, Room 410, 5 Sassoon Rd, Pokfulam, Hong Kong SAR, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 503-512, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
694373
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Treatment of Spinocerebellar Ataxia With Mesenchymal Stem Cells: A Phase I/IIa Clinical Study

Yun-An Tsai,* Ren-Shyan Liu,†‡ Jiing-Feng Lirng,§ Bang-Hung Yang,†‡ Chin-Hao Chang, Yi-Chen Wang,# Yu-Shan Wu,# Jennifer Hui-Chun Ho,# Oscar K. Lee,**††‡‡ and Bing-Wen Soong§§¶¶

*Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
†Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
‡Faculty of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
§Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
¶Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
#Steminent Biotherapeutics Inc., Taipei, Taiwan
**Taipei City Hospital, Taipei, Taiwan
††Stem Cell Research Center, National Yang-Ming University, Taipei, Taiwan
‡‡Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
§§Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan
¶¶Department of Neurology, National Yang-Ming University, Taipei, Taiwan

Ataxia is one of the most devastating symptoms of many neurodegenerative disorders. As of today, there is not any effective treatment to retard its progression. Mesenchymal stem cells (MSCs) have shown promise in treating neurodegenerative diseases. We hereby report the results of a phase I/IIa clinical study conducted in Taiwan to primarily evaluate the safety, tolerability, and, secondarily, the possible efficacy of intravenous administration of allogeneic adipose tissue-derived MSCs from healthy donors. Six patients with spinocerebellar ataxia type 3 and one with multiple system atrophy-cerebellar type were included in this open-label study with intravenous administration of 106 cells/kg body weight. The subjects were closely monitored for 1 year for safety (vital signs, complete blood counts, serum biochemical profiles, and urinalysis) and possible efficacy (scale for assessment and rating of ataxia and sensory organization testing scores, metabolite ratios on the brain magnetic resonance spectroscopy, and brain glucose metabolism of 18-fluorodeoxyglucose using positron emission tomography). No adverse events related to the injection of MSCs during the 1-year follow-up were observed. The intravenous administration of allogeneic MSCs seemed well tolerated. Upon study completion, all patients wished to continue treatment with the allogeneic MSCs. We conclude that allogeneic MSCs given by intravenous injection seems to be safe and tolerable in patients with spinocerebellar ataxia type 3, thus supporting advancement of the clinical development of allogeneic MSCs for the treatment of spinocerebellar ataxias (SCAs) in a randomized, double-blind, placebo-controlled phase II trials.

Key words: Clinical trials; Allogeneic mesenchymal stem cells (MSCs); Trinucleotide repeat diseases; Gait disorders/ataxia; Spinocerebellar ataxias (SCAs)

Received January 13, 2016; final acceptance January 5, 2017. Online prepub date: February 14, 2017.
Address correspondence to Bing-Wen Soong, Department of Neurology, National Yang-Ming University, #155, Sec 2, Linong Street, Peitou District, Taipei, Taiwan 11217 (R.O.C.). Tel: +886-2-28712121, ext. 3178; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Oscar K. Lee, Taipei City Hospital, No. 145, Zhengzhou Rd., Datong Dist., Taipei City 10341, Taiwan (R.O.C.). E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  


Cell Transplantation, Vol. 26, pp. 513-527, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
694265
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Imbalanced Production of Reactive Oxygen Species and Mitochondrial Antioxidant SOD2 in Fabry Disease-Specific Human Induced Pluripotent Stem Cell-Differentiated Vascular Endothelial Cells

Wei-Lien Tseng,*†1 Shih-Jie Chou,*1 Huai-Chih Chiang,†‡ Mong-Lien Wang,§ Chian-Shiu Chien,†§ Kuan-Hsuan Chen,‡¶ Hsin-Bang Leu,§#** Chien-Ying Wang,§†† Yuh-Lih Chang,*¶ Yung-Yang Liu,‡†† Yuh-JyhJong,‡‡§§¶¶ Shinn-Zong Lin,## Shih-Hwa Chiou,*†‡§ Shing-Jong Lin,†‡§** and Wen-Chung Yu§**

*Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
†Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
‡Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
§School of Medicine, National Yang-Ming University, Taipei, Taiwan
¶Department of Pharmacology, Taipei Veterans General Hospital, Taipei, Taiwan
#Heath Care and Management Center, Taipei Veterans General Hospital, Taipei, Taiwan
**Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
††Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
‡‡Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
§§Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
¶¶Departments of Pediatrics and Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
##Buddhist Tzu Chi General Hospital, Hualien, Taiwan

Fabry disease (FD) is an X-linked inherited lysosomal storage disease caused by a-galactosidase A (GLA) deficiency. Progressive intracellular accumulation of globotriaosylceramide (Gb3) is considered to be pathogenically responsible for the phenotype variability of FD that causes cardiovascular dysfunction; however, molecular mechanisms underlying the impairment of FD-associated cardiovascular tissues remain unclear. In this study, we reprogrammed human induced pluripotent stem cells (hiPSCs) from peripheral blood cells of patients with FD (FD-iPSCs); subsequently differentiated them into vascular endothelial-like cells (FD-ECs) expressing CD31, VE-cadherin, and vWF; and investigated their ability to form vascular tube-like structures. FD-ECs recapitulated the FD pathophysiological phenotype exhibiting intracellular Gb3 accumulation under a transmission electron microscope. Moreover, compared with healthy control iPSC-derived endothelial cells (NC-ECs), reactive oxygen species (ROS) production considerably increased in FD-ECs. Microarray analysis was performed to explore the possible mechanism underlying Gb3 accumulation-induced ROS production in FD-ECs. Our results revealed that superoxide dismutase 2 (SOD2), a mitochondrial antioxidant, was significantly downregulated in FD-ECs. Compared with NC-ECs, AMPK activity was significantly enhanced in FD-ECs. Furthermore, to investigate the role of Gb3 in these effects, human umbilical vein endothelial cells (HUVECs) were treated with Gb3. After Gb3 treatment, we observed that SOD2 expression was suppressed and AMPK activity was enhanced in a dose-dependent manner. Collectively, our results indicate that excess accumulation of Gb3 suppressed SOD2 expression, increased ROS production, enhanced AMPK activation, and finally caused vascular endothelial dysfunction. Our findings suggest that dysregulated mitochondrial ROS may be a potential target for treating FD.

Key words: Fabry disease (FD); Vascular endothelial dysfunction; Superoxide dismutase 2 (SOD2); Gb3 accumulation; Induced pluripotent stem cells (iPSCs)

Received June 30, 2016; final acceptance December 21, 2016. Online prepub date: December 6, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Wen-Chung Yu, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2 Shih-Pai Road, Taipei 11217, Taiwan. Tel: 886-2-28757394; Fax: 886-2-28757435; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it