Cell Transplantation 22(4) Abstracts

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Cell Transplantation, Vol. 22, pp. 571-617, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X655208
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Systematic Review of Induced Pluripotent Stem Cell Technology as a Potential Clinical Therapy for Spinal Cord Injury

Anne S. Kramer,* Alan R. Harvey,* Giles W. Plant,† and Stuart I. Hodgetts*

*Spinal Cord Repair Laboratory, School of Anatomy, Physiology and Human Biology, The University of Western Australia, Perth, Western Australia
†Stanford Partnership for Spinal Cord Injury and Repair, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA

Transplantation therapies aimed at repairing neurodegenerative and neuropathological conditions of the central nervous system (CNS) have utilized and tested a variety of cell candidates, each with its own unique set of advantages and disadvantages. The use and popularity of each cell type is guided by a number of factors including the nature of the experimental model, neuroprotection capacity, the ability to promote plasticity and guided axonal growth, and the cells’ myelination capability. The promise of stem cells, with their reported ability to give rise to neuronal lineages to replace lost endogenous cells and myelin, integrate into host tissue, restore functional connectivity, and provide trophic support to enhance and direct intrinsic regenerative ability, has been seen as a most encouraging step forward. The advent of the induced pluripotent stem cell (iPSC), which represents the ability to “reprogram” somatic cells into a pluripotent state, hails the arrival of a new cell transplantation candidate for potential clinical application in therapies designed to promote repair and/or regeneration of the CNS. Since the initial development of iPSC technology, these cells have been extensively characterized in vitro and in a number of pathological conditions and were originally reported to be equivalent to embryonic stem cells (ESCs). This review highlights emerging evidence that suggests iPSCs are not necessarily indistinguishable from ESCs and may occupy a different “state” of pluripotency with differences in gene expression, methylation patterns, and genomic aberrations, which may reflect incomplete reprogramming and may therefore impact on the regenerative potential of these donor cells in therapies. It also highlights the limitations of current technologies used to generate these cells. Moreover, we provide a systematic review of the state of play with regard to the use of iPSCs in the treatment of neurodegenerative and neuropathological conditions. The importance of balancing the promise of this transplantation candidate in the light of these emerging properties is crucial as the potential application in the clinical setting approaches. The first of three sections in this review discusses (A) the pathophysiology of spinal cord injury (SCI) and how stem cell therapies can positively alter the pathology in experimental SCI. Part B summarizes (i) the available technologies to deliver transgenes to generate iPSCs and (ii) recent data comparing iPSCs to ESCs in terms of characteristics and molecular composition. Lastly, in (C) we evaluate iPSC-based therapies as a candidate to treat SCI on the basis of their neurite induction capability compared to embryonic stem cells and provide a summary of available in vivo data of iPSCs used in SCI and other disease models.

Key words: Stem cell therapy; Spinal cord; Induced pluripotency; Trophic support; Replacement; Regeneration

Online prepub date: August 27, 2012.
Address correspondence to Stuart I. Hodgetts, Spinal Cord Repair Laboratory, School of Anatomy, Physiology and Human Biology, The University of Western Australia, 35 Stirling Highway, Perth, 6009, Western Australia. Tel: +61-8-6488-8642; Fax: +61-8-6488-1051; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 619-630, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X655091
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Neural Stem Cells and Stroke

Dah-Ching Ding,*1 Chen-Huan Lin,†1 Woei-Cherng Shyu,†‡ and Shinn-Zong Lin†‡§

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

Acute ischemic stroke causes a disturbance of neuronal circuitry and disruption of the blood–brain barrier that can lead to functional disabilities. At present, thrombolytic therapy inducing recanalization of the occluded vessels in the cerebral infarcted area is a commonly used therapeutic strategy. However, only a minority of patients have timely access to this kind of therapy. Recently, neural stem cells (NSCs) as therapy for stroke have been developed in preclinical studies. NSCs are harbored in the subventricular zone (SVZ) as well as the subgranular zone of the brain. The microenvironment in the SVZ, including intercellular interactions, extracellular matrix proteins, and soluble factors, can promote NSC proliferation, self-renewal, and multipotency. Endogenous neurogenesis responds to insults of ischemic stroke supporting the existence of remarkable plasticity in the mammalian brain. Homing and integration of NSCs to the sites of damaged brain tissue are complex morphological and physiological processes. This review provides an update on current preclinical cell therapies for stroke, focusing on neurogenesis in the SVZ and dentate gyrus and on recruitment cues that promote NSC homing and integration to the site of the damaged brain.

Key words: Stroke; Homing; Stem cells; Subventricular zone (SVZ); Dentate gyrus; Regeneration

Online prepub date: November 1, 2012.
1These authors provided equal contribution to this work.
Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University and 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 Woei-Cherng Shyu, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC. Tel: +886-4-22052121 ext. 7811; 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. 22, pp. 631-637, 2013
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DOI: http://dx.doi.org/10.3727/096368912X655145
E-ISSN 1555-3892
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Review

Stem Cell Applications in Regenerative Medicine for Neurological Disorders

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

*Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC
†Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC
‡Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, ROC
§Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan, ROC
¶Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, ROC
#Graduate Institute of Chinese Medical Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan, ROC
**Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan, ROC
††Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan, ROC

Stem cells are capable of self-renewal and differentiation into a wide range of cell types with multiple clinical and therapeutic applications. Stem cells are providing hope for many diseases that currently lack effective therapeutic methods, including stroke, amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease. Embryonic stem (ES) cells were originally targeted for differentiation into functional dopamine neurons for cell therapy. Today, induced pluripotent stem (iPS) cells are being tested for such purposes as generating functional dopamine neurons and treating a rat model of Parkinson’s disease. In addition, neural stem cell and mesenchymal stem cells are also being used in neurodegenerative disorder therapies for stroke and Parkinson’s disease. Although stem cell therapy is still in its infancy, it will likely become a powerful tool for many diseases that currently do not have effective therapeutic approaches. In this article, we discuss current research on the potential application of neural stem cells, mesenchymal stem cells, ES cells, and iPS cells to neurodegenerative disorders.

Key words: Stem cell therapy; Neurodegenerative disorders; Regenerative medicine

Online prepub date: October 31, 2012.
Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University and 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 Woei-Cherng Shyu, M.D., Ph.D., Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan, ROC. Tel: +886-4-22052121 ext. 7811; 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. 22, pp. 639-652, 2013
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DOI: http://dx.doi.org/10.3727/096368912X655082
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Review

Parkinson’s Disease: From Genetics to Treatments

Hueng-Chuen Fan,* Shyi-Jou Chen,* Horng-Jyh Harn,† and Shinn-Zong Lin‡

*Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
†Department of Pathology, China Medical University and Hospital, Taichung, Taiwan, ROC
‡Center for Neuropsychiatry, China Medical University and Hospital and Beigang Hospital, Taichung and Yun-Lin, Taiwan, ROC

Parkinson’s disease (PD) is a common neurodegenerative disease and typically presents with tremor, rigidity, bradykinesia, and postural instability. The hallmark pathological features of PD are loss of dopaminergic neurons in the substantia nigra (SN) and the presence of neuronal intracellular Lewy body (LB) inclusions. In general, PD is sporadic; however, familial PD, while uncommon, can be inherited in an autosomal dominant (AD) or autosomal recessive (AR) manner. The molecular investigations of proteins encoded by PD-linked genes have clarified that ADPD is associated with a-synuclein and LRRK2, while ARPD is linked to Parkin, PINK1, DJ1, and ATP13A2. Understanding these genes can bring insights into this disease and create possible genetic tests for early diagnosis. Long-term pharmacological treatment is so far disappointing, probably due to unwanted complications and decreasing drug efficacy. Several strategies have been proposed and tested as alternatives for PD. Cellular transplantation of dopamine-secreting stem cells opens the door to new therapeutic avenues for restoration of the functions of degenerative and/or damaged neurons in PD.

Key words: Familial Parkinson’s disease (PD); Genetics; a-Synuclein; Leucine-rich repeat kinase (LRRK2); Parkin; PTEN-induced kinase 1 (PINK1); DJ1; ATPase type 13A2 (ATP13A2); Cellular transplantation

Online prepub date: October 31, 2012.
Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, 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. 22, pp. 653-661, 2013
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DOI: http://dx.doi.org/10.3727/096368912X655154
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Review

Aberrant Alternative Splicing Events in Parkinson’s Disease

Ru-Huei Fu,*† Shih-Ping Liu,*‡ Shyh-Jer Huang,§ Hung-Jen Chen,¶ Pin-Ru Chen,† Ya-Hsien Lin,† Yu-Chen Ho,† Wen-Lin Chang,† Chang-Hai Tsai,#** Woei-Cherng Shyu,*† and Shinn-Zong Lin*†‡‡

*Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC
†Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, ROC
‡Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC
§Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan, ROC
¶Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, ROC
#Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan, ROC
**Department of Healthcare Administration, Asia University, Taichung, Taiwan, ROC
‡‡Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan, ROC

Alternative splicing (AS) using a sole gene to express multiple transcripts with diverse protein coding sequences and/or RNA regulatory elements raises genomic complexities. In the nervous system, several thousand AS events play important roles in ion transportation, receptor recognition, neurotransmission, memory, and learning. Not surprisingly, AS influences human physiology, development, and disease. Many research studies have focused on aberrant AS in nervous system diseases, including Parkinson’s disease (PD), the second most common progressive neurodegenerative disorder of the central nervous system. PD affects the lives of several million people globally. It is caused by protein aggregation, such as in Lewy bodies, and the loss of dopamine-containing neurons in the substantia nigra of the midbrain. To our knowledge, six genes, including PARK2, SNCAIP, LRRK2, SNCA, SRRM2, and MAPT, are involved in aberrant AS events in PD patients. In this review, we highlight the relevance of aberrant AS in PD and discuss the use of an aberrant AS profile as a potential diagnostic or prognostic marker for PD and as a possible means of applying therapy.

Key words: Alternative splicing (AS); Cis-regulatory elements; Parkinson’s disease (PD); Trans-acting splicing factors

Online prepub date: October 31, 2012.
Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC. Tel: +886-4-22052121, ext. 6034; Fax: +886-4-22080666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 663-675, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X655109
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Review

Stem Cell-Based Therapy for Ischemic Heart Disease

Lien-Cheng Hsiao,*† Carolyn Carr,* Kuan-Cheng Chang,† Shinn-Zong Lin,‡§¶ and Kieran Clarke*

*Cardiac Metabolism Research Group, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
Division of Cardiology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, ROC
Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC
§Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan, ROC
¶Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, ROC

Despite great advances in therapy over the past decades, ischemic heart disease (IHD) remains the leading cause of death worldwide because the decrease in mortality after acute myocardial infarction (AMI) leads to a longer life span in patients with chronic postinfarct heart failure (HF). There are no existing medical treatments that can cure chronic HF and the only currently available therapeutic option for end-stage HF is heart transplantation. However, transplantation is limited by the shortage of donor organs and patients require lifelong immunosuppression. In the past 10 years, stem cell-based cardiac therapy has been proposed as a promising approach for the treatment of IHD. There is a variety of potential stem cell types for cardiac repair and regeneration, including bone marrow cells (BMCs), resident cardiac stem cells (CSCs) and induced pluripotent stem cells (iPSCs). Stem cell-based therapy may comprise cell transplantation or cardiac tissue engineering (CTE), which might be an attractive alternative to solve the problems of low retention and poor survival of transplanted cells. This review focuses on the characteristics of stem cells from various sources and discusses the strategies of stem cell-based therapy for the treatment of IHD.

Key words: Ischemic heart disease (IHD); Heart failure (HF); Stem cell; Cell transplantation; Cardiac tissue engineering (CTE)

Online prepub date: October 4, 2012.
Address correspondence to Carolyn Carr, D.Phil., Department of Physiology, Anatomy and Genetics, Sherrington Building, University of Oxford, Parks Road, Oxford OX1 3PT, UK. Tel: +44-01865 282247; Fax: +44-01865 282272; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Lien-Cheng Hsiao, M.D., Division of Cardiology, Department of Medicine, China Medical University Hospital, 2 Yude Road, Taichung, 40447, Taiwan, ROC. Tel: 886-4-22052121; Fax: 886-4-22053425; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 677-684, 2013
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DOI: http://dx.doi.org/10.3727/096368912X655118
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Review

Stem Cell Therapy for Tendon Injury

Hsin-Shui Chen,*† Yi-Lin Chen,‡ Horng-Jyh Harn,†§¶1 Jung-Sheng Lin,# and Shinn-Zong Lin**††‡‡1

*Department of Physical Medicine and Rehabilitation, China Medical University Beigang Hospital. Yunlin, Taiwan, ROC
†School of Medicine, China Medical University, Taichung, ROC
‡Graduate Institute of Biotechnology and Department of Life Science, National Ilan University, Ilan, Taiwan, ROC
§Department of Pathology, China Medical University Hospital, Taichung, Taiwan, ROC
¶Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan, ROC
#Department of Urology Surgery, Beigang Hospital, Yunlin, Taiwan, ROC
**Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC
††Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan, ROC
‡‡Graduate Institute of Immunology, China Medical University, Taichung, ROC

Tendon injury may occur suddenly or progressively, and can be divided into tendon rupture or tendinopathy based on the severity of injury. It is frequently found in professional or nonprofessional people who are making repetitive movements. In aged people, tendon degeneration becomes obvious; their tendon injuries are then frequently evident. No effective therapies for tendon injury are currently available. In this article, we review the tendon structure, mechanisms of tendon injury, and tendon healing process. More importantly, cell-based therapies for tendon injury are fully addressed, which will play an important role for tendon therapy in the near future.

Key words: Tendon injury; Cell therapy; Stem cell

Online prepub date: October 8, 2012.
1These authors contributed equally to this work.
Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC. Tel: +886-4-22052121 ext. 6034; Fax: +886-4-22080666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 685-700, 2013
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DOI: http://dx.doi.org/10.3727/096368912X655163
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Review

Cells and Materials for Liver Tissue Engineering

Yuan-Sheng Li,*1 Horng-Jyh Harn,†1 Dean-Kuo Hsieh,‡ Tung-Chou Wen,* Yi-Maun Subeq,§ Li-Yi Sun,¶ Shinn-Zong Lin,#**†† and Tzyy-Wen Chiou*

*Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, ROC
†Department of Pathology, China Medical University and Hospital, Taichung, Taiwan, ROC
‡Department of Applied Chemistry, Chaoyang University of Technology, Taichung, Taiwan, ROC
§Department of Nursing, Tzu Chi University, Hualien, Taiwan, ROC
¶Department of Research, Buddhist Tzu Chi General Hospital, Taiwan, ROC
#Center for Neuropsychiatry, China Medical University Hospital Taichung, Taiwan, ROC
**Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan, ROC
††Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, ROC

Liver transplantation is currently the most efficacious treatment for end-stage liver diseases. However, one main problem with liver transplantation is the limited number of donor organs that are available. Therefore, liver tissue engineering based on cell transplantation that combines materials to mimic the liver is under investigation with the goal of restoring normal liver functions. Tissue engineering aims to mimic the interactions among cells with a scaffold. Particular materials or a matrix serve as a scaffold and provide a three-dimensional environment for cell proliferation and interaction. Moreover, the scaffold plays a role in regulating cell maturation and function via these interactions. In cultures of hepatic lineage cells, regulation of cell proliferation and specific function using biocompatible synthetic, biodegradable bioderived matrices, protein-coated materials, surface-modified nanofibers, and decellularized biomatrix has been demonstrated. Furthermore, beneficial effects of addition of growth factor cocktails to a flow bioreactor or coculture system on cell viability and function have been observed. In addition, a system for growing stem cells, liver progenitor cells, and primary hepatocytes for transplantation into animal models was developed, which produces hepatic lineage cells that are functional and that show long-term proliferation following transplantation. The major limitation of cells proliferated with matrix-based transplantation systems is the high initial cell loss and dysfunction, which may be due to the absence of blood flow and the changes in nutrients. Thus, the development of vascular-like scaffold structures, the formation of functional bile ducts, and the maintenance of complex metabolic functions remain as major problems in hepatic tissue engineering and will need to be addressed to enable further advances toward clinical applications.

Key words: Biomaterials; Liver diseases; Liver regeneration; Stem cells; Hepatocytes

Online prepub date: November 1, 2012.
1These authors provided equal contribution to this work.
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


Cell Transplantation, Vol. 22, pp. 701-709, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X655127
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Review

Adipose-Derived Stem Cells: Isolation, Characterization, and Differentiation Potential

Shyh-Jer Huang,*† Ru-Huei Fu,‡§1 Woei-Cherng Shyu,‡§1 Shih-Ping Liu,§¶1 Gwo-Ping Jong,#1 Yung-Wei Chiu,**†† Hsiao-Su Wu,‡‡ Yung-An Tsou,§§ Chao-Wen Cheng,¶¶ and Shinn-Zong Lin‡§##

*Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan, ROC
†China Medical University, Taichung, Taiwan, ROC
‡Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, ROC
§Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, ROC
¶Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC
#Division of Cardiology, Armed Forces Taichung General Hospital, Taichung, Taiwan, ROC
**Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
††Emergency Department and Center of Hyperbaric Oxygen Therapy, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan, ROC
‡‡Department of Plastic Surgery, China Medical University Hospital, Taichung, Taiwan, ROC
§§Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung, Taiwan, ROC
¶¶Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan, ROC
##Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan, ROC

In mammals, the two main types of adipose tissues, white and brown adipose tissues, exert different physiological functions. White adipose tissue (WAT) is for storing energy, while brown adipose tissue (BAT) is for energy consumption. Adipose-derived stem cells (ADSCs) are abundant in WAT and BAT, have multipotent characteristics, and are easily extracted. ADSCs can be differentiated into several cell lineages, including adipocytes, osteoblasts, chondrocytes (cartilage cells), myocytes, and neuronal cells. Therefore, ADSC could be considered as a strategy for future regenerative medicine and tissue engineering.

Key words: Adipose-derived stem cells (ADSCs); Bone marrow-derived mesenchymal stem cells (BMSCs); Stromal vascular fraction (SVF); CD marker

Online prepub date: October 12, 2012.
1These authors provided equal contribution to this work.
Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, Taichung, 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


Cell Transplantation, Vol. 22, pp. 711-721, 2013
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DOI: http://dx.doi.org/10.3727/096368912X655172
E-ISSN 1555-3892
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Review

Mesenchymal Stem Cell Insights: Prospects in Hematological Transplantation

Shiu-Huey Chou,* Shinn-Zong Lin,† Cecilia Hsuan Day,‡ Wei-Wen Kuo,§ Chia-Yao Shen,‡ Dennis Jine-Yuan Hsieh,¶ Jing-Ying Lin,# Fuu-Jen Tsai,** Chang-Hai Tsai,†† and Chih-Yang Huang**‡‡§§

*Department of Life Science, Fu-Jen Catholic University, New Taipei City, Taiwan, ROC
†Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, ROC
‡Department of Nursing, MeiHo University, Pingtung, Taiwan, ROC
§Department of Biological Science and Technology, China Medical College, Taichung, Taiwan, ROC
¶School of Medical Technology, Chung Shan Medical University, Taichung, Taiwan, ROC
#Department of Nursing, Central Taiwan University of Science and Technology, Taichung, Taiwan, ROC
**Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan, ROC
††Department of Healthcare Administration, Asia University, Taichung, Taiwan, ROC
‡‡Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC
§§Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, ROC

Adult stem cells have been proven to possess tremendous potential in the treatment of hematological disorders, possibly in transplantation. Mesenchymal stem cells (MSCs) are a heterogeneous group of cells in culture, with hypoimmunogenic character to avoid alloreactive T-cell recognition as well as inhibition of T-cell proliferation. Numerous experimental findings have shown that MSCs also possess the ability to promote engraftment of donor cells and to accelerate the speed of hematological recovery. Despite that the exact mechanism remains unclear, the therapeutic ability of MSCs on hematologic transplantation have been tested in preclinical trials. Based on encouraging preliminary findings, MSCs might become a potentially efficacious tool in the therapeutic options available to treat and cure hematological malignancies and nonmalignant disorders. The molecular mechanisms behind the real efficacy of MSCs on promoting engraftment and accelerating hematological recovery are awaiting clarification. It is hypothesized that direct cell-to-cell contact, paracrine factors, extracellular matrix scaffold, BM homing capability, and endogenous metabolites of immunologic and nonimmunologic elements are involved in the interactions between MSCs and HSCs. This review focuses on recent experimental and clinical findings related to MSCs, highlighting their roles in promoting engraftment, hematopoietic recovery, and GvHD/graft rejection prevention after HSCT, discussing the potential clinical applications of MSC-based treatment strategies in the context of hematological transplantation.

Key words: Mesenchymal stem cells (MSCs); Hematopoietic niche; Hematopoiesis; Hematopoietic stem cells (HSCs); Bone marrow (BM)

Online prepub date: November 27, 2012.
Address correspondence to Chih-Yang Huang, Ph.D., Graduate Institute of Basic Medical Science, China Medical University and Hospital, No. 91 Hsueh-Shih Rd., Taichung, Taiwan 40402, ROC. Tel: +886-4-22053366 ext 3313; Fax: +886-4-22333641; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 723-729, 2013
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DOI: http://dx.doi.org/10.3727/096368912X655217
E-ISSN 1555-3892
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Review

The Role of Mesenchymal Stem Cells in Hematopoietic Stem Cell Transplantation: From Bench to Bedsides

Kang-Hsi Wu,*† Han-Ping Wu,‡ Chin-Kan Chan,§¶ Shiaw-Min Hwang,# Ching-Tien Peng,*†** and Yu-Hua Chao††‡‡

*Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan, ROC
†School of Chinese Medicine, China Medical University, Taichung, Taiwan, ROC
‡Department of Pediatrics, Buddhist Tzu-Chi General Hospital, Taichung Branch, Taichung, Taiwan, ROC
§Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan, ROC
¶Department of Pediatrics, Taoyuan General Hospital, Taoyuan, Taiwan, ROC
#Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, Taiwan, ROC
**Department of Biotechnology and Bioinformatics, Asia University, Taichung, Taiwan, ROC
††Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC
‡‡School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC

Mesenchymal stem cells (MSCs) have been shown to be effective in the management of graft-versus-host disease (GVHD) due to their immunomodulatory effects. In addition to prevention and treatment of GVHD, many studies have demonstrated that MSCs can promote hematopoietic engraftment, accelerate lymphocyte recovery, reduce the risk of graft failure, and repair tissue damage in patients receiving hematopoietic stem cell transplantation (HSCT). Bone marrow (BM) has been considered as the traditional source of MSCs, and most of the knowledge concerning MSCs comes from BM studies. However, BM-derived MSCs have several limitations for their clinical application. Fetal-type MSCs can be isolated easier and proliferate faster in vitro as well as possessing a lower immunogenicity. Therefore, fetal-type MSCs, such as umbilical cord-derived MSCs, represent an excellent alternative source of MSCs. MSCs play multiple important roles in HSCT. Nevertheless, several issues regarding their clinical application remain to be discussed, including the safety of use in humans, the available sources and the convenience of obtaining MSCs, the quality control of in vitro-cultured MSCs and the appropriate cell passages, the optimum cell dose, and the optimum number of infusions. Furthermore, it is important to evaluate whether the rates of cancer relapse and infections increase when using MSCs for GVHD. There are still many questions regarding the clinical application of MSCs to HSCT that need to be answered, and further studies are warranted.

Key words: Mesenchymal stem cells (MSCs); Hematopoietic stem cell transplantation (HSCT); Graft-versus-host disease (GVHD); Cell-based therapy

Online prepub date: October 12, 2012.
Address correspondence to Yu-Hua Chao, M.D., Department of Pediatrics, Chung Shan Medical University Hospital, No. 110, Sec. 1, Chien-Kuo N. Road, Taichung 402, Taiwan, ROC. Tel.: +886-4-24739595 ext. 21728; Fax: +886-4-24710934; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 731-739, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X655136
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Targeting Cancer Stem Cells for Treatment of Glioblastoma Multiforme

Der-Yang Cho,*† Shinn-Zong Lin,*†‡ Wen-Kuang Yang,§¶ Han-Chung Lee,*¶ Den-Mei Hsu,§ Hung-Lin Lin,* Chun-Chung Chen,*¶ Chun-Lin Liu,* Wen-Yuan Lee,*¶ and Li-Hui Ho*

*Department of Neurosurgery, Neuropsychiatry Center, China Medical University Hospital, Taichung, Taiwan, ROC
†Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, ROC
‡Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan, ROC
§Cell/Gene Therapy Research Laboratory, China Medical University Hospital, Taichung, Taiwan, ROC
¶Department of Medicine, China Medical University, Taichung, Taiwan, ROC

Cancer stem cells (CSCs) in glioblastoma multiforme (GBM) are radioresistant and chemoresistant, which eventually results in tumor recurrence. Targeting CSCs for treatment is the most crucial issue. There are five methods for targeting the CSCs of GBM. One is to develop a new chemotherapeutic agent specific to CSCs. A second is to use a radiosensitizer to enhance the radiotherapy effect on CSCs. A third is to use immune cells to attack the CSCs. In a fourth method, an agent is used to promote CSCs to differentiate into normal cells. Finally, ongoing gene therapy may be helpful. New therapeutic agents for targeting a signal pathway, such as epidermal growth factor (EGF) and vascular epidermal growth factor (VEGF) or protein kinase inhibitors, have been used for GBM but for CSCs the effects still require further evaluation. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as cyclooxygenase-2 (Cox-2) inhibitors have proven to be effective for increasing radiation sensitivity of CSCs in culture. Autologous dendritic cells (DCs) are one of the promising immunotherapeutic agents in clinical trials and may provide another innovative method for eradication of CSCs. Bone-morphogenetic protein 4 (BMP4) is an agent used to induce CSCs to differentiate into normal glial cells. Research on gene therapy by viral vector is also being carried out in clinical trials. Targeting CSCs by eliminating the GBM tumor may provide an innovative way to reduce tumor recurrence by providing a synergistic effect with conventional treatment. The combination of conventional surgery, chemotherapy, and radiotherapy with stem cell-orientated therapy may provide a new promising treatment for reducing GBM recurrence and improving the survival rate.

Key words: Bone-morphogenetic protein 4 (BMP4); Cancer stem cells (CSCs); Dendritic cells (DCs); Gene therapy; Glioblastoma multiforme (GBM); Immunotherapy; Nonsteroidal anti-inflammatory drugs (NSAIDs); Radiosensitizers

Online prepub date: February 7, 2013.
Address correspondence to Wen-Kuang Yang, M.D., Ph.D., Professor, Cell/Gene Therapy Research Laboratory, China Medical University Hospital, No. 2 Yu-Der Road, Taichung, Taiwan, ROC. Tel: +886-42-2052121 ext. 6077; Fax: +886-42-2064888; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 741-753, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X655190
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Deregulated MicroRNAs Identified in Isolated Glioblastoma Stem Cells: An Overview

Pei-Ming Chu,*†1 Hsin-I Ma,‡1 Li-Hsin Chen,§1 Ming-Teh Chen,¶# Pin-I Huang,¶** Shinn-Zong Lin,† and Shih-Hwa Chiou§¶**

*Department of Anatomy and Cell Biology, College of Medicine, China Medical University, Taichung, Taiwan, ROC
Center for Neuropsychiatry and Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan, ROC
Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan, ROC
§Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC
School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
#Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
**Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC

Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, is extremely resistant to current treatment paradigms and has a high rate of tumor recurrence. Recent progress in the field of tumor-initiating cells suggests that GBM stem cells (GBMSCs) may be responsible for tumor progression, resistance to treatment, and tumor relapse. Therefore, understanding the biologically significant pathways involved in modulating GBMSC-specific characteristics offers great promise for development of novel therapeutics, which may improve therapeutic efficacy and overcome present drug resistance. In addition, targeting deregulated microRNA (miRNA) has arisen as a new therapeutic strategy in treating malignant gliomas. In GBMSCs, miRNAs regulate a wide variety of tumorigenic processes including cellular proliferation, stemness maintenance, migration/invasion, apoptosis, and tumorigenicity. Nevertheless, the latest progress with GBMSCs and subsequent miRNA profiling is limited by the identification and isolation of GBMSCs. In this review, we thus summarize current markers and known features for isolation as well as the aberrant miRNAs that have been identified in GBM and GBMSCs.

Key words: Glioblastoma; GBM stem cells (GBMSCs); microRNA (miRNA); Therapeutic strategy

Online prepub date: November 1, 2012.
1These authors contributed equally to this study.
Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry and Department of Neurosurgery, China Medical University Hospital, Yuh-Der Road, Taichung 40447, Taiwan, ROC. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Shi-Hwa Chiou, M.D., Ph.D., Institute of Pharmacology, School of Medicine, National Yang-Ming University, 155, Sec 2, Linong Street, Taipei, 112, Taiwan, ROC. Tel: +886-2-28757394; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 755-765, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X661436
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Rejuvenation of Aged Pig Facial Skin by Transplanting Allogeneic Granulocyte Colony-Stimulating Factor-Induced Peripheral Blood Stem Cells From a Young Pig

Horng-Jyh Harn,*† Mao-Hsuan Huang,‡ Chi-Ting Huang,§ Po-Cheng Lin,¶ Ssu-Yin Yen,§ Yi-Wen Chou,# Tsung-Jung Ho,**†† Hen-Yi Chu,‡‡ Tzyy-Wen Chiou,§1 and Shinn-Zong Lin†§§¶¶1

*Department of Pathology, China Medical University Hospital, Taichung, Taiwan, ROC
†Department of Medicine, China Medical University, Taichung, Taiwan, ROC
‡Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, ROC
§Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, ROC
¶Department of Research and Development, Gwo Xi Stem Cell Applied Technology Co., Ltd., Hsinchu, Taiwan, ROC
#PhD Program for Aging, China Medical University, Taichung, Taiwan, ROC
**Division of Chinese Medicine, China Medical University Beigan Hospital, Yunlin, Taiwan, ROC
††Department of Chinese Medicine, China Medical University, Taichung, Taiwan, ROC
‡‡Enhance Biomedical Ltd. Taipei, Taiwan, ROC
§§Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan, ROC
¶¶Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan, ROC

Following a stroke, the administration of stem cells that have been treated with granulocyte colony-stimulating factor (GCSF) can ameliorate functional deficits in both rats and humans. It is not known, however, whether the application of GCSF-mobilized peripheral blood stem cells (PBSCs) to human skin can function as an antiaging treatment. We used a Lanyu pig (Sus scrofa) model, since compared with rodents, the structure of a pig’s skin is very similar to human skin, to provide preliminary data on whether these cells can exert antiaging effects over a short time frame. GCSF-mobilized PBSCs from a young male Lanyu pig (5 months) were injected intradermally into the cheek skin of aged female Lanyu pigs, and tissues before and after the cell injections were compared to determine whether this treatment caused skin rejuvenation. Increased levels of collagen, elastin, hyaluronic acid, and the hyaluronic acid receptor CD44 were observed in both dermal and subcutaneous layers following the injection of PBSCs. In addition, the treated skin tissue was tighter and more elastic than adjacent control regions of aged skin tissue. In the epidermal layer, PBSC injection altered the levels of both involucrin and integrin, indicating an increased rate of epidermal cell renewal as evidenced by reductions in both cornified cells and cells of the spinous layers and increases in the number of dividing cells within the basal layer. We found that the exogenous PBSCs, visualized using fluorescence in situ hybridization, were located primarily in hair follicles and adjacent tissues. In summary, PBSC injection restored young skin properties in the skin of aged (90 months) pigs. On the basis of our preliminary data, we conclude that intradermal injection of GCSF-mobilized PBSCs from a young pig can rejuvenate the skin in aged pigs.

Key words: Skin rejuvenation; Granulocyte colony-stimulating factor (GCSF); Peripheral blood stem cells (PBSCs); Lanyu pigs; Hyaluronic acid (HA)

Online prepub date: February 26, 2013.

1These authors provided equal contribution to this work.

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 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, 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