Cell Transplantation 24(3) Abstracts

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Cell Transplantation, Vol. 24, pp. 313-317, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686823
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

The Potential Roles of EZH2 in Regenerative Medicine

Ruey-Hwang Chou,*†1 Lian Chiu,‡1 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
‡Department of Nursing, College of Medicine and Nursing, Hungkuang 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

Enhancer of zeste homolog 2 (EZH2), a catalytic component of polycomb repressive complex 2, serves as a histone methyltransferase toward histone H3K27 trimethylation and also recruits DNA methyltransferases to regulate gene expression and chromatin structure. Accumulating evidence indicates the critical roles of EZH2 in stem cell maintenance and cell fate decision in differentiation into specific cell lineages. In this article, we review the updated progress in the field and the potential application of EZH2 in regenerative medicine including nervous system, muscle, pancreas, and dental pulp regeneration.

Key words: Enhancer of zeste homolog 2 (EZH2); Stem cells; Cell lineage; Differentiation; Regenerative medicine

Received December 9, 2014; final acceptance January 27, 2015. Online prepub date: February 2, 2015.
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, 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, ROC. 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. 24, pp. 319-338, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686832
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
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Leukemia Inhibitory Factor and Fibroblast Growth Factor 2 Critically and Mutually Sustain Pluripotency of Rabbit Embryonic Stem Cells

Neng-Wen Lo,* Payungsuk Intawicha,†‡ Yung-Tsung Chiu,§ Kun-Hsiung Lee,¶ Hsi-Chi Lu,# Chien-Hong Chen,¶ Yong-Hsuan Chang,* Chun-Da Chen,† and Jyh-Cherng Ju†**††‡‡§§

*Department of Animal Science and Biotechnology, Tunghai University, Taichung, Taiwan
†Department of Animal Science, National Chung Hsing University, Taichung, Taiwan
‡School of Agriculture and Natural Resources, University of Phayao, Phayao, Thailand
§Taichung Veterans General Hospital, Taichung, Taiwan
¶Division of Animal Technology, Animal Technology Laboratories, Agriculture Technology Research Institute, Hsinchu, Taiwan
#Department of Food Science, Tunghai University, Taichung, Taiwan
**Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
††Agricultural Biotechnology Center and Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
‡‡Medical Research Department, China Medical University Hospital, Taichung, Taiwan
§§Department of Biomedical Informatics, College of Computer Science, Asia University, Taichung, Taiwan

Effects of leukemia inhibitory factor (LIF) and fibroblast growth factor 2 (FGF2) on establishment and maintenance of rabbit embryonic stem cell (rESC) lines were assessed. When grown on MEF feeders, rESC lines derived from fertilized embryos were established and maintained in medium containing paracrine factors LIF (via STAT3) and/or FGF2 (via MEK-ERK1/2 and PI3K-AKT). However, high levels of ERK1/2 and AKT activities in rESCs were crucial for maintaining their undifferentiated proliferation. Although rESCs under the influence of either LIF (500, 1,000, and 2,000 U/ml) or FGF2 (5, 10, and 20 ng/ml) alone had enhanced expression of pluripotency markers, peak expression occurred when both LIF (1,000 U/ml) and FGF2 (10 ng/ml) were applied. Induced dephosphorylation of STAT3, ERK1/2, and AKT by specific inhibitors limited growth of rESCs and caused remarkable losses of self-renewal capacity; therefore, we inferred that STAT3, ERK, and AKT had essential roles in maintainingrESC proliferation and self-renewal. We concluded that LIF and FGF2 jointly maintained the undifferentiated state and self-renewal of rESCs through an integrative signaling module.

Key words: Fibroblast growth factor 2 (FGF2); Leukemia inhibitory factor (LIF); Rabbit embryonic stem cells (rESCs); Self-renewal

Received December 9, 2014; final acceptance February 6, 2015. Online prepub date: February 10, 2015.
Address correspondence to Jyh-Cherng Ju, Ph.D., Graduate Institute of Basic Medical Science, China Medical University, 91 Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC. Tel: +886-4-2233-7203; Fax: +886-4-2286-0265; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 339-347, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686841
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
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Review

Human Umbilical Cord Mesenchymal Stem Cells: A New Era for Stem Cell Therapy

Dah-Ching Ding,*† Yu-Hsun Chang,†‡ Woei-Cherng Shyu,§¶ and Shinn-Zong Lin§¶#

*Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan
†Graduate Institute of Medical Science, Tzu Chi University, Hualien, Taiwan
‡Department of Pediatrics, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan
§Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan
¶Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
#China Medical University Beigang Hospital, Yunlin, Taiwan

The human umbilical cord is a promising source of mesenchymal stem cells (HUCMSCs). Unlike bone marrow stem cells, HUCMSCs have a painless collection procedure and faster self-renewal properties. Different derivation protocols may provide different amounts and populations of stem cells. Stem cell populations have also been reported in other compartments of the umbilical cord, such as the cord lining, perivascular tissue, and Wharton’s jelly. HUCMSCs are noncontroversial sources compared to embryonic stem cells. They can differentiate into the three germ layers that promote tissue repair and modulate immune responses and anticancer properties. Thus, they are attractive autologous or allogenic agents for the treatment of malignant and nonmalignant solid and soft cancers. HUCMCs also can be the feeder layer for embryonic stem cells or other pluripotent stem cells. Regarding their therapeutic value, storage banking system and protocols should be established immediately. This review critically evaluates their therapeutic value, challenges, and future directions for their clinical applications.

Key words: Umbilical cord; Wharton’s jelly; Clinical application; Stem cells

Received December 9, 2014; final acceptance January 21, 2015. Online prepub date: January 23, 2015.
Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan, ROC. Tel: +886-3-8561825; Fax: +886-3-8577161; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 349-366, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686850
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
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Review

Extramedullary Hematopoiesis (EMH) in Laboratory Animals: Offering an Insight Into Stem Cell Research

Shao-Chih Chiu,*† Hua-Hsing Liu,‡ Chia-Ling Chen,‡ Pin-Ru Chen,*§ Ming-Chao Liu,¶ Shinn-Zong Lin,*†#** and Ko-Tung Chang‡

*Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
†Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
‡Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung, Taiwan
§Department of Surgery, Division of Thoracic Surgery, China Medical University Hospital, Taichung, Taiwan
¶Graduate Institute of Clinical Medical Science, China Medical 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

Extramedullary hematopoiesis (EMH) is a pathological process secondary to underlying bone marrow (BM) insufficiency in adults. It is characterized by the emergence of multipotent hematopoietic progenitors scattered around the affected tissue, most likely in the spleen, liver, and lymph node, etc. EMH in patients frequently receives less medical attention and is neglected unless a compressive or obstructive hematopoietic mass appears to endanger the patient’s life. However, on a biological basis, EMH reflects the alteration of relationships among hematopoietic stem and progenitor cells (HSPCs) and their original and new microenvironments. The ability of hematopoietic stem cells (HSCs) to mobilize from the bone marrow and to accommodate and function inextramedullary tissues is rather complicated and far from our current understanding. Fortunately, many reports from the studies of drugs and genetics using animals have incidentally found EMH to be involved. Thereby, the molecular basis of EMH could further be elucidated from those animals after cross-comparison. A deeper understanding of the extramedullary hematopoietic niche could help expand stem cells in vitro and establish a better treatment in patients for stem cell transplantation.

Key words: Extramedullary hematopoiesis (EMH); Bone marrow (BM) insufficiency; Hematopoietic stem and progenitor cells (HSPCs); Animal models; Extramedullary hematopoietic niche

Received December 9, 2014; final acceptance January 27, 2015. Online prepub date: February 2, 2015.
Address correspondence to Ko-Tung Chang, Ph.D., Department of Biological Science and Technology, National Pingtung University of Science and Technology, 92101, No.1, Sheufu Road, Neipu, Pingtung, Taiwan, ROC. Tel: +886-8-7703202, ext. 6362; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 367-376, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686869
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
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Time-Dependent Profiles of MicroRNA Expression Induced by Ischemic Preconditioning in the Gerbil Hippocampus

Miao Sun,*† Toru Yamashita,* Jingwei Shang,* Ning Liu,* Kentaro Deguchi,* Juan Feng,† and Koji Abe*

*Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
†Department of Neurology, Shengjing Hospital, China Medical University, Shenyang, China

MicroRNAs (miRNAs) are critically important in both normal neuronal development and neurological diseases. Although cerebral ischemia has been shown to alter the miRNA profiles of rats, the role of miRNA in the cornu ammonis 1 region of the gerbil hippocampus under ischemic tolerance has not been studied. In the present study, Mongolian gerbils were subjected to one or three times the nonlethal dose of 2-min transient common carotid artery occlusion (tCCAO). miRNA microarray technology detected 251 miRNAs and the expression of seven of these in terms of ischemic tolerance. They were compared at different time points: 1 day, 7 days, 1 month, and 6 months. mmu-miR-15a-5p, related to neurogenesis, showed increased expression after one dose of 2-min tCCAO and was much higher after three doses. An increase in sha-miR-24 and oan-let-7b-3p, related to transactivation response DNA-binding protein (TDP43), was observed after one dose of 2-min tCCAO, but the peak was accelerated to an earlier period of reperfusion after three doses. In contrast, mmu-miR-125b-5p and mmu-miR-132-5p, related to fused in sarcoma/translocated in liposarcoma (FUS/TLS), showed similar increases at both doses. mmu-miR-181c-5p and mmu-miR-378a-5p, related to heat shock protein 70 (HSP70), also showed accelerated expression after three doses. This data set provides new insight about miRNA expression during neurogenesis, and related to TDP43, FUS/TLS, and HSP70, which may be useful when pursuing further studies on the possible use of miRNAs as biomarkers in cerebral ischemic tolerance and neuroregeneration.

Key words: MicroRNA (miRNA); Ischemic preconditioning; Cornu ammonis 1 (CA1); Gerbil

Received December 9, 2014; final acceptance January 29, 2015. Online prepub date: February 2, 2015.
Address correspondence to Prof. Koji Abe, Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, 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. 24, pp. 377-390, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686878
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
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Specialized Vasculature in the Rostral Migratory Stream as a Neurogenic Niche and Scaffold for Neuroblast Migration

Ti-Fei Yuan,*†1 Yu-Xiang Liang,†‡§1 David Tay,‡ Kwok-Fai So,†‡§¶ and Rutledge Ellis-Behnke‡#**††

*School of Psychology, Nanjing Normal University, Nanjing, China
†State Key Lab of Brain and Cognitive Sciences, University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong SAR, China
‡Department of Anatomy, The University of Hong Kong, Hong Kong SAR, China
§Department of Ophthalmology, The University of Hong Kong, Hong Kong SAR, China
¶GHM Institute of CNS Regeneration, Jinan University, Guangzhou, China
#Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Mannheim, Germany
**Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
††Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

Neurovascular niches serve as the hosts for adult neural stem cells in both the hippocampus and subventricular zone. The rostral migratory stream (RMS) vasculature has been found to be important for neuroblast migration, while its roles in hosting putative neural stem cells have not been investigated. Here we investigated the organization of RMS vasculature and its contribution to the production of new neurons. A single pulse of bromodeoxyuridine (BrdU) administration revealed locally formed new neurons within RMS were located adjacent to blood vessels. In addition, BrdU label-retaining cells that are putative neural stem cells were also found close to the vasculature. Sodium fluorescein perfusion assay demonstrated that the blood–brain barrier (BBB) organization was especially “leaky” in the neurogenic niches. Immunohistochemical visualization of some BBB component molecules indicated a thinner BBB in the RMS region, compared to that in the frontal cortex of adult rats. Finally, the expression of vascular endothelial growth factor was strong and specialized in the RMS region, implying that the region was active in cell proliferation and migration. Here we show that the RMS vasculature associated with surrounding astrocytes provides a highly organized neurovascular niche for adult neural stem cell proliferation, in addition to the function of neuroblast migration support. This result points to a new vasculature supporting neurogenic region in the brain.

Key words: Rostral migratory stream (RMS); Adult neurogenesis; Vasculature; Stem cell niche; Astrocyte; Blood–brain barrier (BBB)

Received December 9, 2014; final acceptance February 3, 2015. Online prepub date: February 10, 2015.
1These authors provided equal contribution to this work.
Address correspondence to Dr. Rutledge Ellis-Behnke, Ph.D., Director, Nanomedicine Translational Think Tank, Department of Ophthalmology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany 68167. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it , This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Dr. Kwok-Fai So, Ph.D., Director, GHM Institute of CNS Regeneration, Jinan University, Huangpu Avenue W. 601, Guangzhou, China 510632. E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 391-402, 2015
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DOI: http://dx.doi.org/10.3727/096368915X686887
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
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Intranasal Delivery of Bone Marrow Mesenchymal Stem Cells Improved Neurovascular Regeneration and Rescued Neuropsychiatric Deficits After Neonatal Stroke in Rats

Zheng Zachory Wei,*†1 Xiaohuan Gu,*1 Anwar Ferdinand,* Jin Hwan Lee,* Xiaoya Ji,* Xun Ming Ji,‡ Shan Ping Yu,*† and Ling Wei*§

*Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA
†Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA, USA
‡Department of Neurosurgery, Xuanwu Hospital of Capital Medical University, Beijing, China
§Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA

Neonatal stroke is a major cause of mortality and long-term morbidity in infants and children. Currently, very limited therapeutic strategies are available to protect the developing brain against ischemic damage and promote brain repairs for pediatric patients. Moreover, children who experienced neonatal stroke often have developmental social behavior problems. Cellular therapy using bone marrow mesenchymal stem cells (BMSCs) has emerged as a regenerative therapy after stroke. In the present investigation, neonatal stroke of postnatal day 7 (P7) rat pups was treated with noninvasive and brain-specific intranasal delivery of BMSCs at 6 h and 3 days after stroke (1 × 106 cells/animal). Prior to transplantation, BMSCs were subjected to hypoxic preconditioning to enhance their tolerance and regenerative properties. The effects on regenerative activities and stroke-induced sensorimotor and social behavioral deficits were specifically examined at P24 of juvenile age. The BMSC treatment significantly reduced infarct size and blood–brain barrier disruption, promoted angiogenesis, neurogenesis, neurovascular repair, and improved local cerebral blood flow in the ischemic cortex. BMSC-treated rats showed better sensorimotor and olfactory functional recovery than saline-treated animals, measured by the adhesive removal test and buried food finding test. In social behavioral tests, we observed functional and social behavioral deficits in P24 rats subjected to stroke at P7, while the BMSC treatment significantly improved the performance of stroke animals. Overall, intranasal BMSC transplantation after neonatal stroke shows neuroprotection and great potential as a regenerative therapy to enhance neurovascular regeneration and improve functional recovery observed at the juvenile stage of development.

Key words: Intranasal; Bone marrow mesenchymal stem cells (BMSCs); Regeneration; Neonate; Stroke

Received December 9, 2014; final acceptance January 30, 2015. Online prepub date: February 2, 2015.
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 Suite 617, Atlanta, GA 30322, USA. Tel: +1-404-712-8221; Fax: +1-404-712-1351; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 403-417, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686896
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
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Effect of Lycium barbarum (Wolfberry) on Alleviating Axonal Degeneration After Partial Optic Nerve Transection

Hong-Ying Li,*†‡§ Yi-Wen Ruan,*† Phillis Wan-Foon Kau,¶ Kin Chiu,‡ Raymond Chuen-Chung Chang,§¶ Henry H. L. Chan,# and Kwok-Fai So*‡§¶

*GHM Institute of CNS Regeneration and Guangdong Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, China
†Department of Anatomy, Jinan University School of Medicine, Guangzhou, China
‡Department of Ophthamology, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong, China
§The State Key Laboratory of Brain and Cognitive Science and the Research Centre of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong, China
¶Department of Anatomy, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong, China
#Laboratory of Experimental Optometry (Neuroscience), School of Optometry, The Hong Kong Polytechnic University, Hong Kong, China

Our previous results showed that the polysaccharides extracted from Lycium barbarum (LBP) could delay secondary degeneration of retinal ganglion cell bodies and improve the function of the retinas after partial optic nerve transection (PONT). Although the common degeneration mechanisms were believed to be shared by both neuronal bodies and axons, recently published data from slow Wallerian degeneration mutant (Wlds) mice supported the divergence in the mechanisms of them. Therefore, we want to determine if LBP could also delay the degeneration of axons after PONT. Microglia/macrophages were thought to be a source of reactive oxygen species after central nervous system (CNS) injury. After PONT, however, oxidative stress was believed to occur prior to the activation of microglia/macrophages in the areas vulnerable to secondary degeneration both in the optic nerves (ONs) and the retinas. But the results did not take into account the morphological changes of microglia/macrophages after their activation. So we examined the morphology in addition to the response magnitude of microglia/macrophages to determine their time point of activation. In addition, the effects of LBP on the activation of microglia/macrophages were investigated. The results showed that (1) LBP reduced the loss of axons in the central ONs and preserved the g-ratio (axon diameter/fiber diameter) in the ventral ONs although no significant effect was detected in the dorsal ONs; (2) microglia/macrophages were activated in the ONs by 12 h after PONT; (3) LBP decreased the response magnitude of microglia/macrophages 4 weeks after PONT. In conclusion, our results showed that LBP could delay secondary degeneration of the axons, and LBP could also inhibit the activation of microglia/macrophages. Therefore, LBP could be a promising herbal medicine to delay secondary degeneration in the CNS via modulating the function of microglia/macrophages.

Key words: Lycium barbarum; Optic nerve (ON); Partial transection; Secondary degeneration; Macrophage

Received December 9, 2014; final acceptance January 12, 2015. Online prepub date: January 23, 2015.
Address correspondence to Kwok-Fai So, Chair Professor, Ph.D., Department of Ophthamology, The University of Hong Kong, Hong Kong, China. Tel: (+852) 2817 9227; Fax: (+852) 2817 0857; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Dr. Henry H. L. Chan, School of Optometry, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China. Tel: (+852) 2766 7937; Fax: (+852) 27646051; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 419-428, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687453
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
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Lycium barbarum Polysaccharide Improves Bipolar Pulse Current-Induced Microglia Cell Injury Through Modulating Autophagy

Man Bie,* Yi Lv,† Chaoran Ren,* Feiyue Xing,† Qi Cui,* Jia Xiao,†‡ and Kwok Fai So*‡§¶

*GMH Institute of CNS Regeneration, Guangdong Medical Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, China
†Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
‡Department of Anatomy, The University of Hong Kong, Hong Kong SAR, China
§Department of Ophthalmology, The University of Hong Kong, Hong Kong SAR, China
¶State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China

Blindness and visual impairments are heavy loads for modern society. Visual prosthesis is a promising therapy to treat these diseases. However, electric stimulation (ES)-induced damage of the optic nerve and adjacent cells are problems that must not be overlooked. In the current study, we aimed to investigate the effects of ES on cultured microglia cells and the potential protective mechanisms from a natural compound Lycium barbarum polysaccharide (LBP). Cellular injuries were induced by 9 mA bipolar pulse current in BV-2 cells for 15 min. Treatment with LBP alone or in association with either autophagic inhibitor 3-MA or autophagic agonist rapamycin was preadded for 2 h before the ES challenge. After that, morphological and molecular changes of the cells were measured at 2 h or 6 h postchallenges. We found that ES induced evident morphological and pathological changes of BV-2 cells, including oxidative stress, inflammation, and apoptosis. Pretreatment with LBP significantly attenuated these injuries with enhanced endogenous autophagy. When cellular autophagy was inhibited or enhanced by corresponding drug, the protective properties of LBP were partly inhibited or maintained, respectively. In addition, we demonstrated that ERK and p38 MAPK exerted diversified roles in the protection of LBP against ES-induced cellular damages. In conclusion, LBP improves bipolar pulse current-induced microglia cell injury through modulating autophagy and MAPK pathway.

Key words: Lycium barbarum polysaccharide (LBP); Microglia injury; Electric stimulation (ES); Autophagy

Received February 4, 2015; final acceptance February 6, 2015. Online prepub date: January 23, 2015.
Address correspondence to Jia Xiao, Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China. Tel: +86 20 85225180; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Kwok Fai So, GMH Institute of CNS Regeneration, Guangdong Medical Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, China. Tel: +86 20 85228362; E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 429-446, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686904
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
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Review

Electrical Stimulation and Motor Recovery

Wise Young

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

In recent years, several investigators have successfully regenerated axons in animal spinal cords without locomotor recovery. One explanation is that the animals were not trained to use the regenerated connections. Intensive locomotor training improves walking recovery after spinal cord injury (SCI) in people, and >90% of people with incomplete SCI recover walking with training. Although the optimal timing, duration, intensity, and type of locomotor training are still controversial, many investigators have reported beneficial effects of training on locomotor function. The mechanisms by which training improves recovery are not clear, but an attractive theory is available. In 1949, Donald Hebb proposed a famous rule that has been paraphrased as “neurons that fire together, wire together.” This rule provided a theoretical basis for a widely accepted theory that homosynaptic and heterosynaptic activity facilitate synaptic formation and consolidation. In addition, the lumbar spinal cord has a locomotor center, called the central pattern generator (CPG), which can be activated nonspecifically with electrical stimulation or neurotransmitters to produce walking. The CPG is an obvious target to reconnect after SCI. Stimulating motor cortex, spinal cord, or peripheral nerves can modulate lumbar spinal cord excitability. Motor cortex stimulation causes long-term changes in spinal reflexes and synapses, increases sprouting of the corticospinal tract, and restores skilled forelimb function in rats. Long used to treat chronic pain, motor cortex stimuli modify lumbar spinal network excitability and improve lower extremity motor scores in humans. Similarly, epidural spinal cord stimulation has long been used to treat pain and spasticity. Subthreshold epidural stimulation reduces the threshold for locomotor activity. In 2011, Harkema et al. reported lumbosacral epidural stimulation restores motor control in chronic motor complete patients. Peripheral nerve or functional electrical stimulation (FES) has long been used to activate sacral nerves to treat bladder and pelvic dysfunction and to augment motor function. In theory, FES should facilitate synaptic formation and motor recovery after regenerative therapies. Upcoming clinical trials provide unique opportunities to test the theory.


Key words: Functional electrical stimulation (FES); Central pattern generator (CPG); Spinal cord injury (SCI); Synaptic formation; Motor recovery

Received December 9, 2014; final acceptance January 27, 2015. Online prepub date: February 2, 2015.
Address correspondence to Wise Young, Ph.D., M.D., Distinguished Professor of Cell Biology and Neuroscience, The Richard H. Shindell Chair in Neuroscience, and Founding Director of the W. M. Keck Center for Collaborative 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. 24, pp. 447-457, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686913
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
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Review

G-CSF as an Adjunctive Therapy With Umbilical Cord Blood Cell Transplantation for Traumatic Brain Injury

Ike De La Peña,* Paul R. Sanberg,* Sandra Acosta,* Shinn-Zong Lin,†‡§¶ 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
†Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
‡Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan
§Department of Neurosurgery, China Medical University–An Nan Hospital, Tainan, Taiwan
¶Graduate Institute of Immunology, China Medical University, Taichung, Taiwan

Traumatic brain injury (TBI), a major contributor to deaths and permanent disability worldwide, has been recently described as a progressive cell death process rather than an acute event. TBI pathophysiology is complicated and can be distinguished by the initial primary injury and the subsequent secondary injury that ensues days after the trauma. Therapeutic opportunities for TBI remain very limited with patients subjected to surgery or rehabilitation therapy. The efficacy of stem cell-based interventions, as well as neuroprotective agents in other neurological disorders of which pathologies overlap with TBI, indicates their potential as alternative TBI treatments. Furthermore, their therapeutic limitations may be augmented when combination therapy is pursued instead of using a single agent. Indeed, we demonstrated remarkable combined efficacy of human umbilical cord blood (hUCB) cell therapy and granulocyte-colony-stimulating factor (G-CSF) treatment in TBI models, providing essential evidence for the translation of this approach to treat TBI. Further studies are warranted to determine the mechanisms underlying therapeutic benefits exerted by hUCB + G-CSF in order to enhance its safety and efficacy in the clinic.

Key words: Traumatic brain injury (TBI); Stem cells; Granulocyte-colony-stimulating factor (G-CSF); Neuroinflammation

Received December 9, 2014; final acceptance January 27, 2015. Online prepub date: February 2, 2015.
Address correspondence to Prof. Cesar V. Borlongan, 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. 24, pp. 459-470, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686922
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Transplantation of Human Placenta-Derived Multipotent Stem Cells Reduces Ischemic Brain Injury in Adult Rats

Kou-Jen Wu,* Seong-Jin Yu,* Chia-Wen Chiang,† Kuna-Hung Cho,‡ Yu-Wei Lee,§ B. Linju Yen,§ Li-Wei Kuo,† and Yun Wang*

*Center for Neuropsychiatric Research, National Health Research Institutes (NHRI), Miaoli, Taiwan
†Institute of Biomedical Engineering and Nanomedicine, NHRI, Miaoli, Taiwan
‡Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
§Regenerative Medicine Research Group, Institute of Cellular and System Medicine, NHRI, Miaoli, Taiwan

After the onset of stroke, a series of progressive and degenerative reactions, including inflammation, is activated, which leads to cell death. We recently reported that human placenta-derived multipotent stem cells (hPDMCs) process potent anti-inflammatory effects. In this study, we examined the protective effect of hPDMC transplants in a rodent model of stroke. Adult male Sprague–Dawley rats were anesthetized. hPDMCs labeled with a vital dye of fluorescing microparticles, DiI, or vehicle were transplanted into three cortical areas adjacent to the right middle cerebral artery (MCA). Five minutes after grafting, the right MCA was transiently occluded for 60 min. Stroke animals receiving hPDMCs showed a significant behavioral improvement and reduction in lesion volume examined by T2-weighted images 4 days poststroke. Brain tissues were collected 1 day later. Human-specific marker HuNu immunoreactivity and DiI fluorescence were found at the hPDMC graft sites, suggesting the survival of hPDMCs in host brain. Grafting of hPDMCs suppressed IBA1 immunoreactivity and deramification of IBA1+ cells in the perilesioned area, suggesting activation of microglia was attenuated by the transplants. Taken together, our data indicate that hPDMC transplantation reduced cortical lesions and behavioral deficits in adult stroke rats, and these cells could serve as a unique anti-inflammatory reservoir for the treatment of ischemic brain injury.

Key words: Ischemia; Placenta; Stem cells; Transplantation; Inflammation

Received December 9, 2014; final acceptance February 4, 2015. Online prepub date: February 9, 2015.
Address correspondence to Li-Wei Kuo, National Health Research Institutes, Miaoli, Taiwan. Tel: +886-37-246166, ext. 37120; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Yun Wang, National Health Research Institutes, Miaoli, Taiwan. Tel: +886-37-246166, ext. 36700; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 471-485, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686931
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Current Proceedings of Cerebral Palsy

Hueng-Chuen Fan,* Li-Ing Ho,† Ching-Shiang Chi,‡ Shin-Nan Cheng,‡ Chun-Jung Juan,§ Kuo-Liang Chiang,¶ 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
‡Department of Pediatrics, Tung’s Taichung Metroharbor Hospital, Wuchi, Taichung, Taiwan
§Department of Chest Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
¶Department of Pediatric Neurology, Kuang-Tien General Hospital, Shalu, Taichung, Taiwan
#Center for Neuropsychiatry, China Medical University and Hospital and Beigang Hospital, Taichung and Yun-Lin, Taiwan
**Department of Pathology, China Medical University and Hospital, Taichung, Taiwan

Cerebral palsy (CP) is a complicated disease with varying causes and outcomes. It has created significant burden to both affected families and societies, not to mention the quality of life of the patients themselves. There is no cure for the disease; therefore, development of effective therapeutic strategies is in great demand. Recent advances in regenerative medicine suggest that the transplantation of stem cells, including embryonic stem cells, neural stem cells, bone marrow mesenchymal stem cells, induced pluripotent stem cells, umbilical cord blood cells, and human embryonic germ cells, focusing on the root of the problem, may provide the possibility of developing a complete cure in treating CP. However, safety is the first factor to be considered because some stem cells may cause tumorigenesis. Additionally, more preclinical and clinical studies are needed to determine the type of cells, route of delivery, cell dose, timing of transplantation, and combinatorial strategies to achieve an optimal outcome.

Key words: Cerebral palsy (CP); Embryonic stem cells (ESCs); Neural stem cells (NSCs); Mesenchymal stem cells (MSCs); Induced pluripotent stem cells (iPSCs); Umbilical cord blood (UCB) cells; Human embryonic germ (hEG) cells

Received December 9, 2014; final acceptance January 28, 2015. Online prepub date: February 2, 2015.
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. 24, pp. 487-492, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686940
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Adipose Tissue-Derived Stem Cells in Neural Regenerative Medicine

Da-Chuan Yeh,*1 Tzu-Min Chan,†‡1 Horng-Jyh Harn,§¶ Tzyy-Wen Chiou,# Hsin-Shui Chen,**†† Zung-Sheng Lin,‡‡ and Shinn-Zong Lin§§¶¶##***

*Department of Internal Medicine, China Medical University Beigan Hospital, Yunlin, Taiwan
†Department of Medical Education and Research, China Medical University Beigan Hospital, Yunlin, Taiwan
‡Department of Medical Education and Research, China Medical University-An-Nan Hospital, Tainan, Taiwan
§Department of Medicine, China Medical University, Taichung, Taiwan
¶Department of Pathology, China Medical University Hospital, Taichung, Taiwan
#Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan
**School of Medicine, China Medical University, Taichung, Taiwan
††Department of Physical Medicine and Rehabilitation, China Medical University Beigang Hospital, Yunlin, Taiwan
‡‡Department of Surgery, China Medical University Beigan Hospital, Yunlin, Taiwan
§§Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
¶¶Graduate Institute of Immunology, 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

Adipose tissue-derived stem cells (ADSCs) have two essential characteristics with regard to regenerative medicine: the convenient and efficient generation of large numbers of multipotent cells and in vitro proliferation without a loss of stemness. The implementation of clinical trials has prompted widespread concern regarding safety issues and has shifted research toward the therapeutic efficacy of stem cells in dealing with neural degeneration in cases such as stroke, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, cavernous nerve injury, and traumatic brain injury. Most existing studies have reported that cell therapies may be able to replenish lost cells and promote neuronal regeneration, protect neuronal survival, and play a role in overcoming permanent paralysis and loss of sensation and the recovery of neurological function. The mechanisms involved in determining therapeutic capacity remain largely unknown; however, this concept can still be classified in a methodical manner by citing current evidence. Possible mechanisms include the following: 1) the promotion of angiogenesis, 2) the induction of neuronal differentiation and neurogenesis, 3) reductions in reactive gliosis, 4) the inhibition of apoptosis, 5) the expression of neurotrophic factors, 6) immunomodulatory function, and 7) facilitating neuronal integration. In this study, several human clinical trials using ADSCs for neuronal disorders were investigated. It is suggested that ADSCs are one of the choices among various stem cells for translating into clinical application in the near future.

Key words: Adipose tissue-derived stem cells (ADSCs); Stroke; Amyotrophic lateral sclerosis; Parkinson’s disease; Alzheimer’s disease; Huntington’s disease; Cavernous nerve injury

Received December 9, 2014; final acceptance January 27, 2015. Online prepub date: February 2, 2015.
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. 24, pp. 493-507, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686959
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

The Antisenescence Effect of Trans-Cinnamaldehyde on Adipose-Derived Stem Cells

Karthyayani Rajamani,* Yi-Chun Lin,† Tung-Chou Wen,* Jeanne Hsieh,‡ Yi-Maun Subeq,§ Jen-Wei Liu,* Po-Cheng Lin,† Horng-Jyh Harn,¶ Shinn-Zong Lin,#**††‡‡ and Tzyy-Wen Chiou*

*Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan
†Gwoxi Stem Cell Applied Technology Co., Ltd., Hsinchu, Taiwan
‡Molecular Medicine Program, National Taiwan University, Taipei, Taiwan
§Department of Nursing, Tzu Chi University, Hualien, Taiwan
¶Department of Pathology, China Medical University and Hospital, Taichung, Taiwan
#Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
**Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
††Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan
‡‡Department of Neurosurgery, China Medical University-An-Nan Hospital, Tainan, Taiwan

As assuring cell quality is an essential parameter for the success of stem cell therapy, the impact of various senescence-inducing stress signals, and strategies to circumvent them, has been an important area of focus in stem cell research. The aim of this study was to demonstrate the capacity of trans-cinnamaldehyde (TC) in reversing stress-induced senescence and maintaining the quality of stem cells in a chemically (H2O2)-induced cell senescence model. Because of the availability and the promising application potential in regenerative medicine, adipose-derived stem cells (ADSCs) were chosen for the study. We found that H2O2 treatment resulted in the expression of senescence characteristics in the ADSCs, including decreased proliferation rate, increased senescence-associated β-galactosidase (SA-β-gal) activity, decreased silent mating type information regulation 2 homolog (SIRT1) expression, and decreased telomerase activity. However, TC treatment was sufficient to rescue or reduce the effects of H2O2induction, ultimately leading to an increased proliferation rate, a decrease in the percentage of SA-β-gal-positive cells, upregulation of SIRT1 expression, and increased telomerase activity of the senescent ADSCs at the cellular level. Moreover, a chemically induced liver fibrosis animal model was used to evaluate the functionality of these rescued cells in vivo. Liver dysfunction was established by injecting 200 mg/kg thioacetamide (TAA) intraperitoneally into Wistar rats every third day for 60 days. The experimental rats were separated into groups: normal group (rats without TAA induction), sham group (without ADSC transplantation), positive control group (transplanted with normal ADSCs), H2O2 group (transplanted with H2O2-induced senescent ADSCs), and H2O2 + TC group (transplanted with ADSCs pretreated with H2O2 and then further treated with TC). In the transplantation group, 1 × 106 human ADSCs were introduced into each rat via direct liver injection. Based on the biochemical analysis and immunohistochemical staining results, it was determined that the therapeutic effects on liver fibrosis by the induced senescent ADSCs (H2O2 group) were not as significant as those exerted by the normal ADSCs (the positive control group). However, the H2O2 + TC group showed significant reversal of liver damage when compared to the H2O2 group 1 week posttransplantation. These data confirmed that the TC treatment had the potential to reduce the effects of H2O2-induced senescence and to restore in vivo functionality of the induced senescent ADSCs. It is therefore suggested that TC has potential applications in maintaining the quality of stem cells and could aid in treating senescence-related disorders.

Key words: Senescence; Silent mating type information regulation 2 homolog (SIRT1); Adipose-derived stem cells (ADSCs); Liver fibrosis

Received December 9, 2014; final acceptance January 31, 2015. Online prepub date: February 4, 2015.
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 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. 24, pp. 509-520, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686968
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Human Adipose-Derived Stem Cells Accelerate the Restoration of Tensile Strength of Tendon and Alleviate the Progression of Rotator Cuff Injury in a Rat Model

Hsin-Shui Chen,*†‡ Yu-Ting Su,§ Tzu-Min Chan,¶# Yu-Jie Su,§ Wan-Sin Syu,** Horng-Jyh Harn,††‡‡ Shinn-Zong Lin,§§§¶¶## and Shao-Chih Chiu§§§

*School of Medicine, China Medical University, Taichung, Taiwan
†Department of Physical Medicine and Rehabilitation, China Medical University Beigang Hospital, Yunlin, Taiwan
‡Ph.D. Program for Aging, China Medical University, Taichung, Taiwan
§Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
¶Department of Medical Education and Research, China Medical University Beigang Hospital, Yunlin, Taiwan
#Department of Medical Education and Research, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan
**Gwo Xi Stem Cell Applied Technology Co., Ltd, Hsinchu, Taiwan
††Department of Pathology, China Medical University Hospital, Taichung, Taiwan
‡‡Department of Medicine, China Medical University, Taichung, Taiwan
§§Center for Neuropsychiatry, China Medical University Hospital, 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

Adult stem cell therapy for the treatment of tendon injuries is a growing area of research. This study is aimed to investigate the efficacy of human adipose-derived stem cell (hADSC) injection on the tendon during its healing process in a rat model of rotator cuff injury. hADSCs were injected 3 days after collagenase-induced rotator cuff injuries in experimental groups, while the control group received saline as a placebo. Histological and biomechanical analyses were performed 7, 14, 21, and 28 days after collagenase injection. Compared to the control group, it was found that inflammatory cells were significantly decreased in the hADSC-treated group after collagenase injection for 7 and 14 days. In the hADSC-injected group, the fiber arrangement and tendon organization had also been improved. On the seventh day after collagenase injection, the load to failure of the hADSC-injected group (15.87 ± 2.20 N) was notably higher than that of the saline-injected group (11.20 ± 1.35 N). It is suggested that the tensile strength of the supraspinatus tendon was significantly enhanced. Local administration of hADSCs might have the possibility to restore the tensile strength and attenuate the progression of tendinitis. Taken together, these findings demonstrate that the recovery processes in damaged tendons can be facilitated architecturally and functionally after hADSC injection.

Key words: Rotator cuff injury; Tendon; Human adipose-derived stem cells (hADSCs); Biomechanical test

Received December 9, 2014; final acceptance January 31, 2015. Online prepub date: February 4, 2015.
Address correspondence to Shao-Chih Chiu, Ph.D., Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, ROC. Tel: +886-4-22052121, ext. 7829; 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. 24, pp. 521-532, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686977
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Applicability of Adipose-Derived Stem Cells in Type 1 Diabetes Mellitus

Hui-Ping Lin,*†1 Tzu-Min Chan,‡§1 Ru-Huei Fu,¶# Chih-Pin Chuu,* Shao-Chih Chiu,¶# Yu-Hsiung Tseng,** Shih-Ping Liu,¶††‡‡ Kuang-Chi Lai,§§¶¶ Mu-Chin Shih,## Zung-Sheng Lin,§§ Hsin-ShuiChen,¶¶*** Da-Chuan Yeh,††† and Shinn-Zong Lin¶#‡‡‡§§§

*Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan
†National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
‡Department of Medical Education and Research, China Medical University Beigan Hospital, Yunlin, Taiwan
§Department of Medical Education and Research, China Medical University-An-Nan Hospital, Tainan, Taiwan
¶Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
#Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
**Department of Nephrology, China Medical University Beigan Hospital, Yunlin, Taiwan
††Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
‡‡Department of Social Work, Asia University, Taichung, Taiwan
§§Department of Surgery, China Medical University Beigan Hospital, Yunlin, Taiwan
¶¶School of Medicine, China Medical University, Taichung, Taiwan
##Department of Clinical Laboratory, China Medical University-An-Nan Hospital, Tainan, Taiwan
***Department of Physical Medicine and Rehabilitation, China Medical University Beigang Hospital, Yunlin, Taiwan
†††Department of Internal Medicine, China Medical University Beigan Hospital, Yunlin, Taiwan
‡‡‡Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan
§§§Department of Neurosurgery, China Medical University-An-Nan Hospital, Tainan, Taiwan

Type 1 diabetes mellitus (T1DM) is a form of early onset diabetes mellitus characterized by the autoimmune destruction of insulin-producing cells (IPCs), resulting in hyperglycemia and abnormal glucose metabolism. There are currently no treatments available capable of completely curing the symptoms associated with the loss or functional defects of IPCs. Nonetheless, stem cell therapy has demonstrated considerable promise in the replacement of IPCs with immunomodulatory functions to overcome the defects caused by T1DM. Adipose-derived stem cells (ADSCs) are particularly suitable for use in cell transplantation therapy, especially when seeking to avoid the ethical issues and tumorigenic complications commonly associated with embryos or induced pluripotent stem cells. Cell-based treatments have demonstrated therapeutic advantages and clinical applicability of ADSCs in T1DM, ensuring their suitability for transplantation therapy. This manuscript focuses on the benefits and possible mechanisms in a T1DM-relevant model and displays positive results from finished or ongoing human clinical trials. We also discuss and hypothesize potential methods to further enhance the therapeutic efficacy of these efforts, such as a humanized rodent model and gene therapies for IPC clusters, to meet the clinical applicability of the standard.

Key words: Adipose-derived stem cells (ADSCs); Type 1 diabetes; Insulin-producing cells (IPCs); Anti-inflammation; Immunomodulatory; Humanized rodent model; Gene therapies

Received December 9, 2014; final acceptance January 12, 2015. Online prepub date: January 23, 2015.
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  or Da-Chuan Yeh, M.D., Department of Internal Medicine, China Medical University Beigan Hospital, Yunlin, Taiwan, ROC. E-mail:  This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 533-540, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687228
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Proposal

A Proposed Novel Stem Cell Therapy Protocol for Liver Cirrhosis

Po-Cheng Lin,* Tzyy-Wen Chiou,† Zung-Sheng Lin,‡ Ko-Chang Huang,§ Yi-Chun Lin,† Pi-Chun Huang,* Wan-Sin Syu,* Horng-Jyh Harn,¶# and Shinn-Zong Lin**††‡‡

*Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan
†Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan
‡Department of General Surgery, China Medical University Beigan Hospital, Yunlin, Taiwan
§Department of Gastroenterological, China Medical University Beigan Hospital, Yunlin, Taiwan
¶Department of Pathology, China Medical University Hospital, Taichung, Taiwan
#Department of Medicine, China Medical University, Taichung, Taiwan
**Center for Neuropsychiatry and Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan
††Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
‡‡Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan

Currently, there is not an effective therapy for cirrhosis of the liver except for liver transplant. However, finding a compatible liver is difficult due to the low supply and increased demand for healthy livers. Stem cell therapy may be a solution for liver cirrhosis. In our previous report, stem cells from Wharton’s jelly and bone marrow were shown to improve liver function in a chemically induced liver fibrosis animal model. However, the immunological rejection of an allograft is always a risk for clinical application. In this study proposal, we suggest using human adipose-derived stem cells (ADSCs) because they are an immune-privileged cell type; they lack human leukocyte antigen-DR expression, and they also suppress the proliferation of activated allogenic lymphocytes and inhibit the production of inflammatory cytokines. In addition, ADSCs contain a sufficient amount of adult stem cells for autologous transplantation. Based on these benefits, ADSCs are promising candidates for clinical application when compared to other stem cell types. The aim of our study will be to investigate the safety and efficacy of autologous ADSCs for the clinical treatment of liver cirrhosis.

Key words: Stem cell therapy; Adipose-derived stem cells (ADSCs); Liver cirrhosis; Clinical treatment

Received January 28, 2015; final acceptance February 4, 2015. Online prepub date: February 9, 2015.
Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University and Hospital, No. 2, Yude Road, Taichung 40447, Taiwan, ROC. Tel: +886-4-22052121, ext. 6034; 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, China Medical University Hospital, 2 Yuh-Der Road, Taichung 40447, 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. 24, pp. 541-559, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686986
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Enhanced Antioxidant Capacity of Dental Pulp-Derived iPSC-Differentiated Hepatocytes and Liver Regeneration by Injectable HGF-Releasing Hydrogel in Fulminant Hepatic Failure

Chih-Hung Chiang,*†1 Wai-Wah Wu,‡§1 Hsin-Yang Li,‡¶ Yueh Chien,*# Cho-Chin Sun,† Chi-Hsien Peng,‡** Alex Tong-Long Lin,† Chi-Shuan Huang,‡§ Ying-Hsiu Lai,# Shih-Hwa Chiou,*# Shuen-IuHung,* Yuh-Lih Chang,*# Yuan-Tzu Lan,‡# Dean-Mo Liu,†† Chian-Shiu Chien,‡,‡‡Teh-Ia Huo,*‡‡ Shou-Dong Lee,§ and Chien-Ying Wang‡§§¶¶

*Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
†Department of Urology, Taipei Veterans General Hospital and Su-Ao/Yuan-Shan Branch, Taipei, Taiwan
‡School of Medicine, National Yang-Ming University, Taipei, Taiwan
§Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan
¶Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
#Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
**Department of Ophthalmology, Shin Kong Wu Ho-Su Memorial Hospital and Fu-Jen Catholic University, Taipei, Taiwan
††Department of Materials Science and Engineering, National Chiao Tung University, Hsinchu, Taiwan
‡‡Division of Gastroenterology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
§§Division of Trauma, Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
¶¶Department of Pharmacy, Tajen University, Pingtung, Taiwan

Acute hepatic failure (AHF) is a severe liver injury leading to sustained damage and complications. Induced pluripotent stem cells (iPSCs) may be an alternative option for the treatment of AHF. In this study, we reprogrammed human dental pulp-derived fibroblasts into iPSCs, which exhibited pluripotency and the capacity to differentiate into tridermal lineages, including hepatocyte-like cells (iPSC-Heps). These iPSC-Heps resembled human embryonic stem cell-derived hepatocyte-like cells in gene signature and hepatic markers/functions. To improve iPSC-Heps engraftment, we next developed an injectable carboxymethyl-hexanoyl chitosan hydrogel (CHC) with sustained hepatocyte growth factor (HGF) release (HGF–CHC) and investigated the hepatoprotectiveactivity of HGF–CHC-delivered iPSC-Heps in vitro and in an immunocompromised AHF mouse model induced by thioacetamide (TAA). Intrahepatic delivery of HGF–CHC–iPSC-Heps reduced the TAA-induced hepatic necrotic area and rescued liver function and recipient viability. Compared with PBS-delivered iPSC-Heps, the HGF–CHC-delivered iPSC-Heps exhibited higher antioxidant and antiapoptotic activities that reduced hepatic necrotic area. Importantly, these HGF–CHC-mediated responses could be abolished by administering anti-HGF neutralizing antibodies. In conclusion, our findings demonstrated that HGF mediated the enhancement of iPSC-Hep antioxidant/antiapoptotic capacities and hepatoprotection and that HGF–CHC is as an excellent vehicle for iPSC-Hep engraftment in iPSC-based therapy against AHF.

Key words: Hydrogel; Induced pluripotent stem cells (iPSCs); Hepatocyte growth factor (HGF); Acute hepatic failure (AHF)

Received January 25, 2014; final acceptance February 3, 2015. Online prepub date: February 9, 2015.
1These authors provided equal contribution to this work.
Address correspondence to Dr. Chien-Ying Wang, Division of Trauma, Department of Emergency Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei, Taiwan 11217, ROC. Tel: +886-2-77351919; Fax: +886-2-28738013; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 24, pp. 561-571, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X686995
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Differentiation of Embryonic Stem Cells Into Cardiomyocytes Used to Investigate the Cardioprotective Effect of Salvianolic Acid B Through BNIP3 Involved Pathway

Chih-Yang Huang,*†‡ Shao-Yu Chen,* Ru-Huei Fu,§¶ Yu-Chuen Huang,‡# Shih-Yin Chen,‡# Woei-Cherng Shyu,§¶ Shinn-Zong Lin,§¶**†† and Shih-Ping Liu*¶‡‡

*Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
†Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
‡Graduate Institute of Chinese Medical Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan
§Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
¶Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
#Genetics Center, Department of Medical Research, 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
‡‡Department of Social Work, Asia University, Taichung, Taiwan

Cardiovascular diseases are related to many risk factors, such as diabetes, high blood pressure, smoking, and obesity. Myocardial infarction (MI), a cardiovascular disease, is the most common cause of cardiomyocyte death. In MI, hypoxia inducescardiomyocyte apoptosis; in particular, diabetes combined with MI has a synergistic effect that exacerbates cardiomyocyte death. The hypoxia-inducible factor-1α (HIF1α) transcriptional factor and a BH-3 only protein, Bcl-2 adenovirus E1B 19-kDa interacting protein 3 (BNIP3), are known to play fundamental roles in both adaptive and cell death processes in response to hypoxia. In addition, most cardioprotective studies used H9c2 cells that were not beating, so H9c2 cells may not be the best model for testing cardioprotective effects. Embryonic stem cells (ESCs) are pluripotent stem cells that are able to differentiate into several types of cells, including cardiomyocytes. In this study, we reveal a simple method to differentiate ESCs into cardiomyocytes by using poly-D-lysine-coated plates combined with ITS and N2-containing medium and characterized the ESCderived cardiomyocytes by cardiomyocyte marker staining. The ESC-derived cardiomyocytes were used to investigate the protective effect ofsalvianolic acid B (Sal-B) in high glucose combined with hypoxic conditions to mimic diabetes patients with ischemia. The results of MTT and TUNEL assays indicate that Sal-B suppresses the apoptotic effect of treatment with high glucose combined with hypoxia in ESC-derived cardiomyocytes. In particular, Sal-B inhibited HIF1α, BNIP3, and cleavage caspase 3 expression levels, thereby suppressing apoptosis. This is the first study to mention the correlation between BNIP3 and Sal-B for cardioprotectiveeffects. In conclusion, we suggest that Sal-B may be suitable for use as a future cardioprotective medicine.

Key words: Embryonic stem cells; Cardiomyocytes; Salvianolic acid B (Sal-B); B-cell CLL/lymphoma 2 (Bcl-2) adenovirus E1B 19-kDa interacting protein 3 (BNIP3); Hypoxia

Received December 9, 2014; final acceptance January 31, 2015. Online prepub date: February 4, 2015.
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. 24, pp. 573-588, 2015
0963-6897/15 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687002
E-ISSN 1555-3892
Copyright © 2015 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Irisflorentin Modifies Properties of Mouse Bone Marrow-Derived Dendritic Cells and Reduces the Allergic Contact Hypersensitivity Responses

Ru-Huei Fu,*†‡ Chia-Wen Tsai,§ Rong-Tzong Tsai,¶ Shih-Ping Liu,†# Tzu-Min Chan,**†† Yu-Chen Ho,* Hsin-Lien Lin,* Yue-Mi Chen,* Huey-Shan Hung,†# Shao-Chih Chiu,*† Chang-Hai Tsai,‡‡ Yu-Chi Wang,§§ 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
‡Department of Psychology, Asia University, Taichung, Taiwan
§Department of Nutrition, China Medical University, Taichung, Taiwan
¶Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
#Graduate Institute of Basic Medical Science, China Medical 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
‡‡Department of Pediatrics, China Medical University, Taichung, Taiwan
§§Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan

Irisflorentin is an isoflavone component derived from the roots of Belamcanda chinensis (L.) DC. In traditional Chinese medicine, this herb has pharmacological properties to treat inflammatory disorders. Dendritic cells (DCs) are crucial modulators for the development of optimal T-cell immunity and maintenance of tolerance. Aberrant activation of DCs can induce harmful immune responses, and so agents that effectively improve DC properties have great clinical value. We herein investigated the effects ofirisflorentin on lipopolysaccharide (LPS)-stimulated maturation of mouse bone marrow-derived DCs in vitro and in the contact hypersensitivity response (CHSR) in vivo. Our results demonstrated that treatment with up to 40 mM irisflorentin does not cause cellular toxicity. Irisflorentin significantly lessened the proinflammatory cytokine production (tumor necrosis factor-a, interleukin-6, and interleukin-12p70) by LPS-stimulated DCs. Irisflorentin also inhibited the expression of LPS-induced major histocompatibility complex class II and costimulatory molecules (CD40 and CD86) on LPS-stimulated DCs. In addition, irisflorentin diminished LPS-stimulated DC-elicited allogeneic T-cell proliferation. Furthermore, irisflorentin significantly interfered with LPS-induced activation of IκB kinase, c-Jun N-terminal kinase, and p38, as well as the nuclear translocation of NF-κB p65. Subsequently, treatment with irisflorentin obviously weakened 2,4-dinitro-1-fluorobenzene-induced delayed-type hypersensitivity. These findings suggest new insights into the role of irisflorentin as an immunotherapeutic adjuvant through its capability to modulate the properties of DCs.

Key words: Dendritic cells (DCs); Immunosuppression; Irisflorentin; Nuclear factor-κB (NF-κB); Mitogen-activated protein kinase (MAPK); Contact hypersensitivity response (CHSR)

Received December 9, 2014; final acceptance January 31, 2015. Online prepub date: February 4, 2015.
Address correspondence to 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  or 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