Cell Transplantation 20(3) Abstracts

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Cell Transplantation, Vol. 20, pp. 351–370, 2011
0963-6897/11 $90.00 + .00
DOI: 10.3727/096368910X528076
E-ISSN 1555-3892
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Stem Cell Transplantation for Lymphoma Patients With HIV Infection

Mariagrazia Michieli,* Mario Mazzucato,† Umberto Tirelli,‡ and Paolo De Paoli§

*Cell Therapy and High Dose Chemotherapy Unit, Centro di Riferimento Oncologico, CRO IRCCS, Aviano, Italy
†Stem Cell Collection and Processing Unit, Centro di Riferimento Oncologico, CRO IRCCS, Aviano, Italy
‡Medical Oncology A, Centro di Riferimento Oncologico, CRO IRCCS, Aviano, Italy
§Scientific Directorate, Centro di Riferimento Oncologico, CRO IRCCS, Aviano, Italy

The advent of Highly Active Antiretroviral Therapy (HAART) has radically changed incidence characteristics and prognosis of HIV-positive patients affected by lymphomas. At this time there is consensus in the literature that, in first line, HIV-positive patients should always be treated with curative intent preferentially following the same approach used in the HIV-negative counterpart. On the contrary, an approach of salvage therapy in HIV-positive lymphomas is still a matter of debate given that for a wide range of relapsed or resistant HIV-negative Hodgkin’s disease (HD) and non-Hodgkin lymphoma (NHL) patients, autologous peripheral or allogeneic stem cell transplantation are among the established options. In the pre-HAART era, therapeutic options derived from pioneering experiences gave only anecdotal success, either when transplantation was used to cure lymphomas or to improve HIV infection itself. Concerns relating to the entity, quality, and kinetics of early and late immune reconstitutions and the possible worsening of underlying viroimmunological conditions were additional obstacles. Currently, around 100 relapsed or resistant HIVpositive lymphomas have been treated with an autologous peripheral stem cell transplantation (APSCT) in the HAART era. Published data compared favorably with any previous salvage attempt showing a percentage of complete remission ranging from 48% to 90%, and overall survival ranging from 36% to 85% at median follow-up approaching 3 years. However, experiences are still limited and have given somewhat confounding indications, especially concerning timing and patients’ selection for APSCT and feasibility and outcome for allogeneic stem cell transplant. Moreover, little data exist on the kinetics of immunological reconstitution after APSCT or relevant to the outcome of HIV infection. The aim of this review is to discuss current knowledge of the role of allogeneic and autologous stem cell transplantation as a modality in the cure of HIV and hemopoietic cancer patients. Several topics dealing with practical aspects concerning the management of APSCT in HIV-positive patients, including patient selection, timing of transplant, conditioning regimen, and relapse or nonrelapse mortality, are discussed. Data relating to the effects of mobilization and transplantation on virological parameters and pre- and posttransplant immune reconstitution are reviewed. Finally, in this review, we examine several ethical and legal issues relative to banking infected or potentially infected peripheral blood stem cells and we describe our experience and strategies to protect positive and negative donors/recipients and the health of caretakers.

Key words: Stem cell transplantation; HIV; Lymphoma; Clinical aspects; Immunity

Address correspondence to Paolo De Paoli, M.D., Scientific Directorate, Centro di Riferimento Oncologico IRCCS, Via F. Gallini, 2 I-33081 Aviano PN, Italy. Tel: +39 0434 659282; Fax: +39 0434 659527; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 20, pp. 371–379, 2011
0963-6897/11 $90.00 + .00
DOI: 10.3727/096368910X528085
E-ISSN 1555-3892
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Neural Stem Cells Reduce Hippocampal Tau and Reelin Accumulation in Aged Ts65Dn Down Syndrome Mice

D. S. Kern,* K. N. Maclean,* H. Jiang,* E. Y. Synder,† J. R. Sladek, Jr.,*‡ and K. B. Bjugstad*

*Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA
†Program in Stem Cell and Regenerative Biology, Burnham Institute for Medical Research, La Jolla, CA, USA
‡Department of Neurology, University of Colorado Denver, Aurora, CO, USA

Tau accumulation, in the form of neurofibrillary tangles (NFT), is an early neuropathological characteristic of Alzheimer’s disease (AD) and early onset AD frequently seen in Down syndrome (DS). We investigated the presence of tau accumulation in the brains of aging DS mice using the Ts65Dn mouse model. All aged mice appeared to have substantial clusters of extracellular granules that were positive for tau and reelin, but not for amyloid-β or APP. These clusters were found primarily in CA1 of the hippocampus. In addition, the aged trisomic DS mice had a significantly greater accumulation of extracellular tau/reelin granular deposits compared to disomic littermates. These granules were similar to those described by others who also found extracelluar proteinous granules in the brains of non-DS mice engineered to model aging and/or AD. When neural stem cells (NSC) were implanted unilaterally into the hippocampus of the Ts65Dn mice, the tau/reelin-positive granules were significantly reduced in both trisomic and disomic mice. Our findings indicate that changes in tau/reelin-positive granules could be used as an index for neuropathological assessment in aging DS and AD. Furthermore, changes in granule density could be used to test the efficacy of novel treatments, such as NSC implantation. Lastly, it is speculated that the unique abilities of NSC to migrate and express growth factors might be a contributing factor to reducing tau/reelin accumulation in aging DS and AD.

Key words: Tau; Down syndrome; Alzheimer’s disease; Neural stem cells; Ts65Dn mice; Reelin

Address correspondence to Kimberly B. Bjugstad, Ph.D., Department of Pediatrics, University of Colorado at Denver, Anschutz Medical Campus, Mail Stop 8313, 12800 E. 19th Avenue, Aurora, CO 80045, USA. Tel: 303-724-3040; Fax: 303-724-3838; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 20, pp. 381–390, 2011
0963-6897/11 $90.00 + .00
DOI: 10.3727/096368910X524773
E-ISSN 1555-3892
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Combined Application of Neutrophin-3 Gene and Neural Stem Cells Is Ameliorative to Delay of Denervated Skeletal Muscular Atrophy After Tibial Nerve Transection in Rats

Sen Lin,*† Jianguang Xu,† Shaonan Hu,† Lei Xu,† Changqing Zhang,* Yang Wang,‡ and Yudong Gu†

*Department of Orthopaedics, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
†Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai, China
‡Department of Anatomy, Histology and Embryology, Shanghai Medical Center, Fudan University, Shanghai, China

Examination of the therapeutic efficacy of neural stem cells (NSCs) has recently become the focus of much investigation. In this study we present an insight of the effects of combined application with neurotrophin-3 (NT-3) and NSCs that derived from rat embryo spinal cord on delaying denervated skeletal muscular atrophy after tibial nerve was severed. NT-3 gene was amplified by PCR and subcloned into lentiviral vector pWPXL-MOD to construct a lentiviral expression vector pWPXL-MOD-NT-3. A positive clone expressing NT-3 (named NSCs-NT-3) was obtained and used for differentiation in vitro and transplantation. Sixty adult rats, whose tibial nerves were sectioned, were divided into two groups: one grafted with NSCs-NT-3 (experimental group, n = 30) and the other with NSCs transfected by pWPXL-MOD (control group, n = 30). The cell survival and differentiation, NT-3 gene expression, and effect of delaying denervated skeletal muscular atrophy were examined through immunohistostaining, RT-PCR, Western blot, electrophysiological analysis, and mean cross-sectional area (CSA) of gastrocnemius, respectively. The results show that the NT-3 gene, which is comprised of 777 bp, was cloned and significantly different expression were detected between NSCs and NSCs-NT-3 in vitro. Quantitative analysis of the choline acetyltransferase (ChAT) immunopositive cells revealed a significant increase in experimental group compared to the control group 4 weeks after implantation (p < 0.01). Twelve weeks after transplantation, the ChAT immunopositive cells were detected near the engrafted region only in experimental group. Furthermore, the effect in delaying denervated skeletal muscular atrophy is indicated in the EMG examination and mean CSA of gastrocnemius. These findings suggest that the neural stem cells expressing NT-3 endogenously would be a better graft candidate for the delay of denervated skeletal muscular atrophy.

Key words: Neural stem cells (NSCs); Neurotrophin-3 (NT-3); Denervated skeletal muscular atrophy; Transplantation

Address correspondence to Jianguang Xu, Department of Hand Surgery, Huashan Hospital, 12 Middle Urumqi Road, Fudan University, Shanghai 200040, China. Tel: (0086-21) 22121111; Fax: (0086-21) 62896029; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 20, pp. 391–406, 2011
0963-6897/11 $90.00 + .00
DOI: 10.3727/096368910X524764
E-ISSN 1555-3892
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Bone Marrow Mononuclear Cells Increase Retinal Ganglion Cell Survival and Axon Regeneration in the Adult Rat

Camila Zaverucha-do-Valle,* Fernanda Gubert,* Michelle Bargas-Rega,* Juliana L. L. Coronel,* Louise A. Mesentier-Louro,* Andre Mencalha,† Eliana Abdelhay,† Marcelo F. Santiago,* and Rosalia Mendez-Otero*

*Programa de Terapia Celular and Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
†Laboratório de Células-Tronco, Centro Nacional de Transplante de Medula Óssea, Instituto Nacional de Câncer, Rio de Janeiro, Brazil

The central nervous system (CNS) of adult mammals generally does not regenerate, and many studies have attempted to identify factors that could increase neuroprotection and/or axonal outgrowth after CNS lesions. Using the optic nerve crush of rats as a model for CNS injury, we investigated the effect of intravitreal transplantation of syngeneic bone-marrow mononuclear cells (BMMCs) on the survival of retinal ganglion cells (RGC) and on the regeneration of optic axons. Control animals received intravitreal saline injections after lesion. Injections of BMMCs resulted in a 1.6-fold increase in the number of RGCs surviving 14 days after injury. The BMMC-treated animals also had increased numbers of axons, which grew up to 1.5 mm from the crush site, and also had reduced Mu¨ller glia activation. Analysis of mRNAs in all conditions revealed an increase in levels of fibroblast growth factor 2 (FGF-2) mRNA in treated animals 14 days after injury. To investigate whether the regenerated axons could reach the brain, we retrograde labeled the RGCs by injecting a lipophilic tracer into the superior colliculus. We also analyzed the expression of NGFI-A in the superficial layers of the superior colliculus as a possible marker of synaptic input from RGC axons. We found evidence that more RGCs were able to reach the brain after treatment and we showed that NGFI-A expression was higher in the treated animals 60 days after injury. These results demonstrate that transplant of BMMCs can increase neuroprotection and neuroregeneration after injury in a model of optic nerve crush, and these effects could be mediated by FGF-2.

Key words: Optic nerve; Stem cells; Axonal outgrowth; Retina; Neuroprotection; Cell therapy

Address correspondence to Rosalia Mendez-Otero, Instituto de Biofsica Carlos Chagas Filho, Centro de Ciências da Saúde, Sala 62-028, Cidade Universitária, RJ 21941-902, Rio de Janeiro, Brazil. Tel: (+55-21) 2562-6554; Fax: (+55-21) 2280-8193; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 20, pp. 407–419, 2011
0963-6897/11 $90.00 + .00
DOI: 10.3727/096368910X519283
E-ISSN 1555-3892
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Age-Dependent Availability and Functionality of Bone Marrow Stem Cells in an Experimental Model of Acute and Chronic Myocardial Infarction

Ana Ayala-Lugo,*§ Angela M. V. Tavares,†** Ana H. R. Paz,* Ana Alegretti,* Ludmila Miquelito,* Hugo Bock,# Roberto Giugliani,‡§#§§ Nadine Clausell,†¶†† Elizabeth Cirne-Lima,*‡‡ and Luis E. Rohde†¶††

*Embriology and Cell Differentiation Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
†Cardiovascular Research Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
‡Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
§Post-Graduate Program of Genetics and Molecular Biology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
¶Post-Graduate Program of Cardiology and Cardiovascular Sciences, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
#Post-Graduate Program of Biologic Sciences: Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
**Cardiovascular Physiology Laboratory, Physiology Departament, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
††Medical School, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
‡‡Veterinary School, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
§§Biosciences Institute, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

The aim of this study was to investigate the effect of aging and timing of left ventricular ischemic injury on the availability and functionality of stem cells. We studied young and aged male inbred Lewis rats that were used as donors of bone marrow mononuclear cells (BM-MNCs), divided in four experimental groups: controls, sham operated, 48 h post-myocardial infarction (MI), and 28 days post-MI. In vitro studies included flow cytometry analysis, hematopoietic colony-forming capacity, and invasion assays of migration capacity. BM-MNCs from these groups were transplanted in female rats after MI induction. Late engraftment was evaluated by real-time PCR of the SRY chromosome. Percentage of CD34+/CD45+low cells was similar among different experimental groups in young rats, but was significantly higher in aged animals (p < 0.001), particularly 28 days post-MI. KDR+/CD34+ cells were increased 48 h after MI and decreased 28 days post-MI in young animals, while they were profoundly reduced in the aged group (p < 0.001). Triple staining for CD44+/CD29+/CD71+ cells was similar in different groups of aged rats, but we observed an intense increase 48 h post-MI in young animals. Colony-forming units and cytokine-induced migration were significantly attenuated 28 days after the MI. Late engraftment in infarcted transplanted female hearts was present, but considerably heterogeneous. Finally, recovery of left ventricular systolic function in transplanted female recipients was significantly influenced by donors’ BM-MNCs groups (p < 0.01). We have demonstrated that aging and timing of myocardial injury are factors that may act synergistically in determining stem cell availability and function. Such interaction should be considered when planning new cell therapy strategies for acute and chronic ischemic heart disease in the clinical arena.

Key words: Cell therapy; Myocardial infarction (MI); Aging

Address correspondence to Luis E. Rohde, M.D., Heart Failure and Transplant Unit and the Cardiovascular Research Laboratory, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Sala 2061, Porto Alegre, RS, Brazil 90035-003. Phone/Fax: 55 51 21018344; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 20, pp. 421–429, 2011
0963-6897/11 $90.00 + .00
DOI: 10.3727/096368910X522243
E-ISSN 1555-3892
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Targeting Uncoupling Protein-2 Improves Islet Graft Function

Dong Zhang,*†1 Miaoda Shen,*†1 Allison Mikita,† Wensheng Zhang,† Yun Liu,† Quan Liu,† Yifan Dai,† Chenyu Zhang,‡ Shusen Zheng,* and Xin Xiao Zheng†

*Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
†Division of Plastic and Reconstructive Surgery, Thomas E. Starzl Transplantation Institute, Pittsburgh, PA, USA
‡State Key Laboratory of Pharmaceutial Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China

Preserving and enhancing the primary function of transplanted islets is not only crucial for improving the outcome of the islet transplantation, but is also important for reducing the islet mass required to achieve insulin independence. Uncoupling protein 2 (UCP2) is a member of the uncoupling protein family, which is localized to the inner mitochondrial membrane and negatively regulates insulin secretion in the pancreatic β-cells. In this study, we assessed the importance of UCP2 in improving islet graft primary function by using UCP2 gene-knockout (UCP2-KO) mice in a syngeneic islet transplantation model. Islets were isolated from UCP2-KO or wild-type (WT) C57BL/6J mice. The effects of deficiency of UCP2 on islet transplantation and islet function were determined. Two hundred islets from UCP2-KO, but not from WT, donors were capable of completely restoring normoglycemia in 1 week in all syngeneic diabetic recipients. Islets harvested from UCP2-KO mice secreted onefold more insulin in GSIS assay than that from WT mice, and maintained normal GSIS after 72-h exposure to high glucose challenge. In addition, UCP2-KO islets expressed twohold higher Bcl-2 mRNA than that from WT islets, and were resistant to high glucose and proinflammatory cytokine induced death. Our study explored a potential mechanism that may explain the benefit of UCP2-KO islets in islet transplantation. Targeting UCP2 may provide a novel strategy to improve primary function of transplanted islets and reduce the number of islets required in transplantation.

Key words: Uncoupling protein 2 (UCP2); Diabetes; Islets transplant; Primary function

1These authors provided equal contribution to this work.
Address correspondence to Xin Xiao Zheng, M.D., Thomas E. Starzl Transplantation Institute, 200 Lothrop St, BST W1557, Pittsburgh, PA 15261, USA. Tel: 01-1-412-648-0177; Fax: 01-1-412-624-6666; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 20, pp. 167–176, 2011
0963-6897/11 $90.00 + .00
DOI: 10.3727/096368910X522090
E-ISSN 1555-3892
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Establishment of a Brazilian Line of Human Embryonic Stem Cells in Defined Medium: Implications for Cell Therapy in an Ethnically Diverse Population

Ana M. Fraga,*†‡ Marina Sukoyan,§ Prithi Rajan,¶ Daniela Paes de Almeida Ferreira Braga,# Assumpto Iaconelli, Jr.,# José Gonçalves Franco, Jr.,** Edson Borges, Jr.,# and Lygia V. Pereira*†‡

*Laboratório de Genética Molecular, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil
†Laboratório Nacional de Células-Tronco Embrionárias (LaNCE), Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil
‡Instituto Nacional de Ciência e Tecnologia em Células-Tronco e Terapia Celular, Ribeirão Preto, Brasil
§Russian Academy of Sciences, Novosibirsk, Russia
¶Agni Consulting Services, San Marcos, CA, USA
#Fertility and Associação Instituto Sapientiae, São Paulo, Brasil
**Centro de Reprodução Humana Prof. Franco Júnior, Ribeirão Preto, Brasil

Pluripotent human embryonic stem (hES) cells are an important experimental tool for basic and applied research, and a potential source of different tissues for transplantation. However, one important challenge for the clinical use of these cells is the issue of immunocompatibility, which may be dealt with by the establishment of hES cell banks to attend different populations. Here we describe the derivation and characterization of a line of hES cells from the Brazilian population, named BR-1, in commercial defined medium. In contrast to the other hES cell lines established in defined medium, BR-1 maintained a stable normal karyotype as determined by genomic array analysis after 6 months in continuous culture (passage 29). To our knowledge, this is the first reported line of hES cells derived in South America. We have determined its genomic ancestry and compared the HLA-profile of BR-1 and another 22 hES cell lines established elsewhere with those of the Brazilian population, finding they would match only 0.011% of those individuals. Our results highlight the challenges involved in hES cell banking for populations with a high degree of ethnic admixture.

Key words: Human embryonic stem cells; Brazilian population; Defined medium; Cell banking; Genetic diversity

Address correspondence to Lygia V. Pereira, Laboratório de Genética Molecular and Laboratório Nacional de Células-Tronco Embrionárias (LaNCE), Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, 05508-090, Brasil. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 20, pp. 441–453, 2011
0963-6897/11 $90.00 + .00
DOI: 10.3727/096368910X522252
E-ISSN 1555-3892
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Amniotic Membrane Application Reduces Liver Fibrosis in a Bile Duct Ligation Rat Model

Luciana B. Sant’Anna,* Anna Cargnoni,* Lorenzo Ressel,* Graziella Vanosi,† and Ornella Parolini*

*Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, Brescia, Italy
†Dipartimento di Scienze Cliniche Veterinarie-Sezione di Radiologia Clinica e Sperimentale, Facoltà di Medicina Veterinaria, Università degli Studi di Milano, Milano, Italy

Biliary fibrosis and resultant cirrhosis are among the most common outcomes of chronic liver diseases. Currently, liver transplantation remains the only effective treatment. In seeking alternative therapeutic approaches, we focused on the potential use of the human amniotic membrane (AM). Indeed, AM has gained increasing importance for its antiscarring, anti-inflammatory, and wound-healing properties, as well as for the multipotent differentiation ability and immunomodulatory features of AM-derived cells. Intriguingly, we have recently demonstrated that placenta-derived cells reduce lung fibrosis in bleomycin-treated mice, and that AM patches reduce postischemic cardiac injury in rats. Hence, we have now investigated the effects of human AM on biliary fibrosis induced in rats through the bile duct ligation (BDL) procedure. A fragment of human AM was applied onto the liver surface after BDL and the effects on fibrosis establishment and progression were evaluated at different time points in comparison with fibrosis progression in control BDL rats. The degree of liver fibrosis was first assessed by the semiquantitative Knodell scoring system and, thereafter, by digital image morphometric analysis to quantify the area occupied by ductular reaction, activated myofibroblasts, and collagen deposition. We demonstrated a significant reduction in the severity of BDL-induced fibrosis in AM-treated rats. Indeed, while fibrosis progressed rapidly in control BDL rats, leading to cirrhosis within 6 weeks, AM-treated rats showed confined fibrosis at the portal/periportal area with no signs of cirrhosis, and a reduction in collagen deposition to about 50% of levels observed in control BDL rats. In addition, the AM was able to significantly slow the gradual progression of the ductular reaction and reduce, at all time points, the area occupied by activated myofibroblasts. These findings suggest that human AM, when applied as a patch onto the liver surface, might inhibit fibrosis progression in BDL-injured livers, and could protect against hepatic damage associated with fibrotic degeneration.

Key words: Human amniotic membrane; Placenta cells; Bile duct ligation; Liver fibrosis; Ductular reaction; Myofibroblasts

Address correspondence to Ornella Parolini, Ph.D., Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, Via Bissolati 57, I-25124 Brescia, Italy. Tel: ++390302455754; Fax: ++390302455704; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 20, pp. 455–466, 2011
0963-6897/11 $90.00 + .00
DOI: 10.3727/096368910X522270
E-ISSN 1555-3892
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Transplantation of Insulin-Producing Cells Derived From Umbilical Cord Stromal Mesenchymal Stem Cells to Treat NOD Mice

Hwai-Shi Wang,* Jia-Fwu Shyu,† Wen-Sheng Shen,* Hsin-Chi Hsu,* Torng-Chien Chi,* Chie-Pein Chen,‡ Seng-Wong Huang,§ Yi-Ming Shyr,¶# Kam-Tsun Tang,** and Tien-Hua Chen*¶

*Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming University, Taipei, Taiwan, ROC
†Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, ROC
‡Division of High Risk Pregnancy, Mackay Memorial Hospital, Taipei, Taiwan, ROC
§Department of Surgery, National Yang Ming University, Taipei, Taiwan, ROC
¶Department of Surgery, Veteran General Hospital, Taipei, Taiwan, ROC
#Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan, ROC
**Department of Internal Medicine, Veteran General Hospital, Taipei, Taiwan, ROC

Diabetes mellitus can be treated with islet transplantation, although there is a scarcity of donors. This study investigated whether human mesenchymal stem cells (MSCs) from umbilical cord stroma could be induced to differentiate into insulin-producing cells and the effects of retro-orbital injection of human insulin-producing cells for the treatment of nonobese diabetic (NOD) mice. MSCs were isolated from human umbilical cord stroma and induced to differentiate into insulin-producing cells using differentiation medium. Differentiated cells were evaluated by immunocytochemistry, RT-PCR, and real-time PCR. C-peptide release, both spontaneous and after glucose challenge, was measured by ELISA. Insulin-producing cells were then transplanted into NOD mice. Blood glucose levels and body weights were monitored weekly. Human nuclei and C-peptide were detected in mouse livers by immunohistochemistry. Pancreatic β-cell development-related genes were expressed in the differentiated insulin-producing cells. Differentiated cells’ C-peptide release in vitro increased after glucose challenge. Further, in vivo glucose tolerance tests showed that blood sugar levels decreased after the cells’ transplantation into NOD mice. After transplantation, insulin-producing cells containing human C-peptide and human nuclei were located in the liver. Thus, we demonstrated that differentiated insulin-producing cells from human umbilical cord stromal MSCs transplanted into NOD mice could alleviate hyperglycemia in diabetic mice.

Key words: Insulin-producing cells; Diabetes; Mesenchymal stem cells; Umbilical cord stroma

Address correspondence to Tien-Hua Chen, M.D., Department of Anatomy, School of Medicine, Yang Ming University, Peitou, Taipei, Taiwan, 112, ROC. Tel: +(886)-2-2-28267035; Fax: +(886)-2-28212884; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 20, pp. 467–474, 2011
0963-6897/11 $90.00 + .00
DOI: 10.3727/096368910X528094
E-ISSN 1555-3892
Copyright © 2011 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Selective Depletion of Cross-Presenting Dendritic Cells Enhances Islet Allograft Survival

Robyn M. Sutherland, Yifan Zhan, Emma M. Carrington, Sarah L. Londrigan,1 and Andrew M. Lew

The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia MHC class I presentation of peptides derived from exogenous antigens (not synthesized within the antigenpresenting cell) is called cross-presentation and is mediated by selective subsets of dendritic cells (DC). A proportion of both donor and host DC may cross-present. Although there has been many studies that have investigated the role of donor versus host DC (i.e., direct vs. indirect pathway), what role cross-presenting DC play in allograft rejection has not been determined. We recently identified an agent, cytochrome c (cytc), that selectively depletes cross-presenting DC in vivo. By administering cytc we were able to study the impact of cross-presenting DC on rejection of islets grafted into fully mismatched mice. We found that cytc protected about half of the islet allografts from rejection. Our results indicate that cross-presenting DC can make potent contributions to the immune response to islet allografts, and contend that agents such as cytc that selectively target DC heralds a novel method of immunosuppression.

Key words: Dendritic cell; Cross-presentation; Immunosuppression; Allograft; Islet

1Current address: Department of Microbiology and Immunology, The University of Melbourne, Parkville 3010, Victoria, Australia.
Address correspondence to Dr. Andrew M. Lew, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne 3052, Australia. Tel: 61 3 9345 2555; Fax: 61 3 9347 0852; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it