ognizant Communication Corporation

CELL TRANSPLANTATION
The Regenerative Medicine Journal

ABSTRACTS
VOLUME 18, NUMBER 9, 2009

Cell Transplantation, Vol. 18, pp. 951-975, 2009
0963-6897/09 $90.00 + 00
DOI: 10.3727/096368909X471251
E-ISSN 1555-3892
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Review of Lithium Effects on Brain and Blood

Wise Young

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

Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3b(GSK3b). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/b-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third of the patients with manic depression, improves the lives of about a third, and is ineffective in about a third. Recent studies suggest that some anticonvulsants (i.e., valproate, carbamapazine, and lamotrigene) may be useful in patients that do not respond to lithium. Lithium has been reported to be beneficial in animal models of brain injury, stroke, Alzheimer's, Huntington's, and Parkinson's diseases, amyotrophic lateral sclerosis (ALS), spinal cord injury, and other conditions. Clinical trials assessing the effects of lithium are under way. A recent clinical trial suggests that lithium stops the progression of ALS.

Key words: Lithium; Mechanisms of effects; Mood disorders; Brain effects; Blood effects

Address correspondence to Wise Young, Ph.D., M.D., W. M. Keck Center for Collaborative Neuroscience, Rutgers, State University of New Jersey, 604 Allison Road, D-251, Piscataway, NJ 08854, USA. E-mail: wisey@mac.com




Cell Transplantation, Vol. 18, pp. 977-983, 2009
0963-6897/09 $90.00 + 00
DOI: 10.3727/096368909X12483162196962
E-ISSN 1555-3892
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Recent Advances of Dendritic Cells (DCs)-Based Immunotherapy for Malignant Gliomas

Der-Yang Cho,1,2 Shinn-Zong Lin,1,2 Wen-Kuang Yang,1 Den-Mei Hsu,1 Han-Chung Lee,1 Wen-Yeun Lee,1 and Shih-Ping Liu1

1Department of Neurosurgery, Center for Neuropsychiatric, Cell/Gene Therapy Research Laboratory, China Medical University & Hospital, Taiwan, Republic of China
2Graduate Institute of Immunology, China Medical University, Taiwan, Republic of China

Immunotherapy is a new light of hope for the treatment of malignant gliomas. The brain is no longer believed to be an immunologically privileged organ. The major advantage of immunotherapy is the tumorspecific cytotoxic effect on the tumor cells with minimal side effects. Autologous dendritic cells (DCs)-based immunotherapy is a promising and feasible method. DCs are the most potent antigen-presenting cells (APCs). DCs prime T lymphocytes by epitopic major histocompatibility (MHC) class I and II for CD8+ cytotoxic T lymphocytes (CTLs) and CD4+ T helper cells, respectively. From the tissue specimen examination after DCs-based immunotherapy, CD8+ CTLs have replaced T regulatory cells (Tregs) as the major dominant tissue infiltrating lymphocytes (TILs). CD8+ CTLs play a key role in the tumor response, which may also be effective against cancer stem cells. DCs themselves also produce many cytokines including interferon-g and interleukin (IL-2) to kill the tumor cells. From the preliminary better outcomes in the literature for malignant gliomas, DC-based immunotherapy may improve tumor response by increasing the survival rate and time. It is recommended that DC-based immunotherapy is applied as soon as possible with conjunctive radiotherapy and chemotherapy. Malignant gliomas have heterogeneity of tissue-associated antigens (TAAs). To find universal common antigens through different kinds of tumor culture may be the essential issue for tumor vaccine development in the future.

Key words: Anaplastic astrocytoma; Cancer stem cells; Cytotoxic T lymphocytes (CTLs); Dendritic cells (DCs); Glioblastoma multiforme (GBM); Immunotherapy; Malignant gliomas; Tumor vaccine

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, Republic of China. Tel: 886-42-2052121, ext. 5023; Fax: 886-42-2052121, ext. 5035; E-mail: d5057@mail.cmuh.org.tw




Cell Transplantation, Vol. 18, pp. 985-998, 2009
0963-6897/09 $90.00 + 00
DOI: 10.3727/096368909X471279
E-ISSN 1555-3892
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Human Umbilical Cord Blood Cell Grafts for Brain Ischemia

Dong-Hyuk Park,1,2 Cesar V. Borlongan,1 Alison E. Willing,1 David J. Eve,1 L. Eduardo Cruz,3 Cyndy D. Sanberg,4 Yong-Gu Chung,2 and Paul R. Sanberg1,5

1Center of Excellence for Aging & Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
2Department of Neurosurgery, Korea University Medical Center, Korea University College of Medicine, Seoul, Korea
3ryopraxis and Silvestre Laboratory, Cryopraxis, BioRio, Po´lo de Biotechnologia do Rio de Janeiro, Rio di Janiero, Brazil
4Saneron CCEL Therapeutics, Inc., Tampa, FL, USA
5Office of Research and Innovation, University of South Florida, Tampa, FL, USA

Irreversible and permanent damage develop immediately adjacent to the region of reduced cerebral blood perfusion in stroke patients. Currently, the proven thrombolytic treatment for stroke, tissue plasminogen activator, is only effective when administered within 3 h after stroke. These disease characteristics should be taken under consideration in developing any therapeutic intervention designed to widen the narrow therapeutic range, especially cell-based therapy. Over the past several years, our group and others have characterized the therapeutic potential of human umbilical cord blood cells for stroke and other neurological disorders using in vitro and vivo models focusing on the cells' ability to differentiate into nonhematopoietic cells including neural lineage, as well as their ability to produce several neurotrophic factors and modulate immune and inflammatory reaction. Rather than the conventional cell replacement mechanism, we advance alternative pathways of graft-mediated brain repair involving neurotrophic effects resulting from release of various growth factors that afford cell survival, angiogenesis, and anti-inflammation. Eventually, these multiple protective and restorative effects from umbilical cord blood cell grafts may be interdependent and act in harmony in promoting therapeutic benefits for stroke.

Key words: Angiogenesis; Human umbilical cord blood cells; Inflammation; Middle cerebral artery occlusion; Neurogenesis; Stroke; Transplantation

Address correspondence to Paul R. Sanberg, Center of Excellence for Aging & Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida College of Medicine, MDC 78, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612, USA. Tel: 813-74-3154; Fax: 813-974-3078; E-mail: psanberg@health.usf.edu




Cell Transplantation, Vol. 18, pp. 999-1002, 2009
0963-6897/09 $90.00 + 00
DOI: 10.3727/096368909X471233
E-ISSN 1555-3892
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Gene and Stem Cell Therapy in Ischemic Stroke

Toru Yamashita, Kentaro Deguchi, Shoko Nagotani, Tatsushi Kamiya, and Koji Abe

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

Possible strategies for treating ischemic stroke include neuroprotection (preventing injured neurons from undergoing apoptosis in the acute phase of cerebral ischemia) and stem cell therapy (the repair of disrupted neuronal networks with newly born neurons in the chronic phase of cerebral ischemia). First, we estimated the neuroprotective effect of glial cell line-derived neurotrophic factor (GDNF) by administration of GFNF protein. GDNF protein showed a direct protective effect against ischemic brain damage. Pretreatment of animals with adenoviral vector containing GDNF gene (Ad-GDNF) 24 h before the subsequent transient middle cerebral artery occlusion (MCAO) effectively reduced infarcted volume. Secondly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin. Both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their antioxidative property. Lastly, we developed a restorative stroke therapy with a bioaffinitive scaffold, which is able to provide an appropriate platform for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.

Key words: Cerebral ischemia; Adenoviral vector; Free radical; Neural stem cells; Scaffold

Address correspondence to Koji Abe, Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University2-5-1 Shikata-cho, Okayama, 700-8558 Japan. Tel: +81-86-235-7365; Fax: +81-86-235-7368; E-mail: abekabek@cc.okayama-u.ac.jp




Cell Transplantation, Vol. 18, pp. 1003-1012, 2009
0963-6897/09 $90.00 + 00
DOI: 10.3727/096368909X12483162196683
E-ISSN 1555-3892
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Transplantation of Endothelial Progenitor Cells as Therapeutics for Cardiovascular Diseases

Huey-Shan Hung,1* Woei-Cherng Shyu,1,2* Chang-Hai Tsai,3,4 Shan-hui Hsu,5 and Shinn-Zong Lin1,2,6

1Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan
2Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
3Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan
4Department of Healthcare Administration, Asia University, Taichung, Taiwan
5Department of Chemical Engineering and Institute of Biomedical Engineering, National Chung Hsing University, Taichung, Taiwan
6China Medical University Beigang Hospital, Yunlin, Taiwan

With better understanding of endothelial progenitor cells (EPCs), many therapeutic approaches to cardiovascular diseases have been developed. This article will review novel research of EPCs in promoting angiogenesis, vasculogenesis, and endothelialization, as a design for future clinical treatment. Cell therapy has the potential to supply stem/progenitor cells and multiple angiogenic factors to the region of ischemia. The efficacy of EPC transplantation may be impaired by low survival rate, insufficient cell number, and impaired function in aging and diseases. Combination of EPCs or cells primed with growth factors or genetic modification may improve the therapeutic efficacy. The molecular mechanism involved in EPC repairing processes is essential. Thus, we have also addressed the molecular mechanism of mobilization, homing, and differentiation of EPCs. The potential of therapeutic neovascularization, angiogenic factor therapy, and cell transplantation have been elucidated. Based on past experience and actual knowledge, future strategies for EPC therapy will be proposed in order to fully exploit the potential of EPC transplantation with clinical relevance for cardiovascular disease applications.

Key words: Endothelial progenitor cells (EPCs); Cardiovascular diseases; Angiogenesis; Cell therapy

Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan. Tel: 886-4-22052121; Fax: 886-4-220806666; E-mail: shinnzong@yahoo.com.tw or Shan-hui Hsu, Ph.D., Department of Chemical Engineering, National Chung Hsing University, Taichung, Taiwan. Tel: 886-4-22852317; Fax: 886-4-22864734; E-mail: shhsu@nchu.edu.tw

*These two authors contributed equally to this article.




Cell Transplantation, Vol. 18, pp. 1013-1028, 2009
0963-6897/09 $90.00 + 00
DOI: 10.3727/096368909X471206
E-ISSN 1555-3892
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Mesenchymal Stem Cell Therapy for Nonmusculoskeletal Diseases: Emerging Applications

Tom K. Kuo,1 Jennifer H. Ho,2,3 and Oscar K. Lee1,4,5

1Stem Cell Research Center, National Yang-Ming University, Taiwan
2Graduate Institute of Clinical Medicine, Taipei Medical University, Taiwan
3Department of Ophthalmology, Taipei Medical University-Wan Fang Hospital, Taiwan
4Institute of Clinical Medicine, National Yang-Ming University, Taiwan
55Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan

Mesenchymal stem cells are stem/progenitor cells originated from the mesoderm and can different into multiple cell types of the musculoskeletal system. The vast differentiation potential and the relative ease for culture expansion have established mesenchymal stem cells as the building blocks in cell therapy and tissue engineering applications for a variety of musculoskeletal diseases, including repair of fractures and bone defects, cartilage regeneration, treatment of osteonecrosis of the femoral head, and correction of genetic diseases such as osteogenesis imperfect. However, research in the past decade has revealed differentiation potentials of mesenchymal stem cells beyond lineages of the mesoderm, suggesting broader applications than originally perceived. In this article, we review the recent developments in mesenchymal stem cell research with respect to their emerging properties and applications in nonmusculoskeletal diseases.

Key words: Mesenchymal stem cells; Stem cell therapy; Immunoregulation; Myocardial infarction; Hepatic failure; Ocular disease

Address correspondence to Dr. Oscar Kuang-Sheng Lee, M.D., Ph.D., Institute of Clinical Medicine, National Yang-Ming University and Taipei Veterans General Hospital, 201, Sec 2, Shi-Pai Road, Beitou District, Taipei 11221, Taiwan. Tel: +886-2-28757557; Fax: +886-2-28757657; E-mail: kslee@vghtpe.gov.tw or Dr. Jennifer Hui-Chun Ho, Graduate Institute of Clinical Medicine, Taipei Medical University, Taiwan 111, Sec. 3, Singlong Rd. Wenshan District, Taipei 116, Taiwan. Tel: +886-2-29307930; Fax: +886-2-29342285; E-mail: wh9801@yahoo.com.tw




Cell Transplantation, Vol. 18, pp. 1029-1038, 2009
0963-6897/09 $90.00 + 00
DOI: 10.3727/096368909X471260
E-ISSN 1555-3892
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Alternative Splicing Modulates Stem Cell Differentiation

Ru-Huei Fu,1,2 Shih-Ping Liu,1,3 Chen-Wei Ou,2 Hsiu-Hui Yu,1 Kuo-Wei Li,1 Chang-Hai Tsai,4,5 Woei-Cherng Shyu,1,2* and Shinn-Zong Lin1,2,6*

1Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan
2Graduate Institute of Immunology, China Medical University, Taichung, Taiwan
3Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
4Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan
5Department of Healthcare Administration, Asia University, Taichung, Taiwan
6China Medical University Beigang Hospital, Yunlin, Taiwan

Stem cells have the surprising potential to develop into many different cell types. Therefore, major research efforts have focused on transplantation of stem cells and/or derived progenitors for restoring depleted diseased cells in degenerative disorders. Understanding the molecular controls, including alternative splicing, that arise during lineage differentiation of stem cells is crucial for developing stem cell therapeutic approaches in regeneration medicine. Alternative splicing to allow a single gene to encode multiple transcripts with different protein coding sequences and RNA regulatory elements increases genomic complexities. Utilizing differences in alternative splicing as a molecular marker may be more sensitive than simply gene expression in various degrees of stem cell differentiation. Moreover, alternative splicing maybe provide a new concept to acquire induced pluripotent stem cells or promote cell-cell transdifferentiation for restorative therapies and basic medicine researches. In this review, we highlight the recent advances of alternative splicing regulation in stem cells and their progenitors. It will hopefully provide much needed knowledge into realizing stem cell biology and related applications.

Key words: Alternative splicing; Stem cell; mRNA; Posttranscriptional regulation; Induced pluripotent stem cell

Address correspondence to Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan. Tel: 886-4-22052121, ext. 6034; Fax: 886-4-22080666; E-mail: shinnzong@yahoo.com.tw or Woei-Cherng Shyu, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan. Tel: 886-4-22052121, ext. 7811; Fax: 886-4-22052121, ext. 7810; E-mail: shyu9423@gmail.com

*These two authors contributed equally to this article.




Cell Transplantation, Vol. 18, pp. 1039-1045, 2009
0963-6897/09 $90.00 + 00
DOI: 10.3727/096368909X471224
E-ISSN 1555-3892
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

MicroRNAs Regulation Modulated Self-Renewal and Lineage Differentiation of Stem Cells

Shih-Ping Liu,1,2 Ru-Huei Fu,1,3 Hsiu-Hui Yu,1 Kuo-Wei Li,1 Chang-Hai Tsai,4,5 Woei-Cherng Shyu,1,3 and Shinn-Zong Lin1,3,6

1Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan
2Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
3Department of Immunology, China Medical University, Taichung, Taiwan
4Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan
5Department of Healthcare Administration, Asia University, Taichung, Taiwan
6China Medical University Beigang Hospital, Yunlin, Taiwan

Stem cells are unique cells in the ability that can self-renew and differentiate into a wide variety of cell types, suggesting that a specific molecular control network underlies these features. To date, stem cells have been applied to many clinical therapeutic approaches. For example, hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are the cells responding to ischemia or injury and engage in effective revascularization to repair within impairment regions. Transplantation of MSCs after stroke and hindlimb ischemia results in remarkable recovery through enhancing angiogenesis. MicroRNAs are a novel class of endogenous, small, noncoding RNAs that work via translational inhibition or degradation of their target mRNAs to downregulate gene expression. MicroRNAs have been strongly linked to stem cells, which have a remarkable role in development. In this study, we focused on the microRNA regulation in multiple stem cells. For example, miR-520h was upregulated and miR-129 was downregulated in HSC. MiR-103, 107, 140, 143, 638, and 663 were associated with MSCs while miR-302s and miR-136 were associated with ESCs. In NSCs, miR-92b, let-7, and miR-125 were the critical regulators. This overview of the recent advances in the aspects of molecular control of stem cell biology reveals the importance of microRNAs, which may be helpful for future work.

Key words: Posttranscriptional regulation; MicroRNAs; Stem cells

Address correspondence to Shinn-Zong Lin, M.D., Ph. D., Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan. Tel: 886-4-22052121, ext. 6034; Fax: 886-4-22080666; E-mail: shinnzong@yahoo.com.tw or Woei-Cherng Shyu, M.D., Ph. D., Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan. Tel: 886-4-22052121 ext. 7811; Fax: 886-4-22052121 ext. 7810; E-mail: shyu9423@gmail.com




Cell Transplantation, Vol. 18, pp. 1047-1058, 2009
0963-6897/09 $90.00 + 00
DOI: 10.3727/096368909X471242
E-ISSN 1555-3892
Copyright © 2009 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Forever Young: How to Control the Elongation, Differentiation, and Proliferation of Cells Using Nanotechnology

R. G. Ellis-Behnke,1,2,3,5 Y. X. Liang,1 J. Guo,1 D. K. C. Tay,1 G. E. Schneider,5 L. A. Teather,5 W. Wu,1,2,3,4 and K. F. So1,2,3

1Department of Anatomy, The University of Hong Kong Li Ka Shing Faculty of Medicine, Pokfulam, Hong Kong SAR, China
2State Key Lab for Brain & Cognitive Sciences, The University of Hong Kong Li Ka Shing Faculty of Medicine, Pokfulam, Hong Kong SAR, China
3Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong Li Ka Shing Faculty of Medicine, Pokfulam, Hong Kong SAR, China
4Research Center of Reproduction, Development and Growth, The University of Hong Kong Li Ka Shing Faculty of Medicine, Pokfulam, Hong Kong SAR, China
5Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

Within the emerging field of stem cells there is a need for an environment that can regulate cell activity, to slow down differentiation or proliferation, in vitro or in vivo while remaining invisible to the immune system. By creating a nanoenvironment surrounding PC12 cells, Schwann cells, and neural precursor cells (NPCs), we were able to control the proliferation, elongation, differentiation, and maturation in vitro. We extended the method, using self-assembling nanofiber scaffold (SAPNS), to living animals with implants in the brain and spinal cord. Here we show that when cells are placed in a defined system we can delay their proliferation, differentiation, and maturation depending on the density of the cell population, density of the matrix, and the local environment. A combination of SAPNS and young cells can be implanted into the central nervous system (CNS), eliminating the need for immunosuppressants.

Key words: Nanotechnology; Stem cells; PC12; Schwann cells; Neural precursors; Brain; Spinal cord; Regeneration; Tissue engineering; Growth control; Self-assembling nanofiber scaffold (SAPNS)

Address correspondence to Rutledge Ellis-Behnke, Department of Anatomy, The University of Hong Kong Li Ka Shing Faculty of Medicine, 1/F, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China. Tel: (852) 2819-9205; Fax: (852) 2817-0857; E-mail: rutledge@hkucc.hku.hk or Kwok-Fai So, Department of Anatomy, The University of Hong Kong Li Ka Shing Faculty of Medicine, 1/F, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China. Tel: (852) 2819-9220; Fax: (852) 2817-0857; E-mail: hrmaskf@hkucc.hku.hk