Cell Transplantation 22(5) Abstracts

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Cell Transplantation, Vol. 22, pp. 767-777, 2013
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DOI: http://dx.doi.org/10.3727/096368912X652968
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Stem Cell Therapy for Craniofacial Bone Regeneration: A Randomized, Controlled Feasibility Trial

Darnell Kaigler,*†‡ Giorgio Pagni,* Chan Ho Park,* Thomas M. Braun,§ Lindsay A. Holman,* Erica Yi,* Susan A. Tarle,* Ronnda L. Bartel,¶ and William V. Giannobile*†‡

*Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI, USA
†University of Michigan Center for Oral Health Research, Ann Arbor, MI, USA
‡Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
§Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
¶Aastrom Biosciences, Inc., Ann Arbor, MI, USA

Stem cell therapy offers potential in the regeneration of craniofacial bone defects; however, it has not been studied clinically. Tissue repair cells (TRCs) isolated from bone marrow represent a mixed stem and progenitor population enriched in CD90- and CD14-positive cells. In this phase I/II, randomized, controlled feasibility trial, we investigated TRC cell therapy to reconstruct localized craniofacial bone defects. Twenty-four patients requiring localized reconstruction of jawbone defects participated in this longitudinal trial. For regenerative therapy, patients were randomized to receive either guided bone regeneration (GBR) or TRC transplantation. At 6 or 12 weeks following treatment, clinical and radiographic assessments of bone repair were performed. Bone biopsies were harvested and underwent quantitative micro-computed tomographic (μCT) and bone histomorphometric analyses. Oral implants were installed, subsequently restored, and functionally loaded with tooth restorations. Reconstructed sites were assessed for 1 year following therapy. No study-related, serious adverse events were reported. Following therapy, clinical, radiographic, tomographic, and histological measures demonstrated that TRC therapy accelerated alveolar bone regeneration compared to GBR therapy. Additionally, TRC treatment significantly reduced the need for secondary bone grafting at the time of oral implant placement with a fivefold decrease in implant bony dehiscence exposure (residual bone defects) as compared to GBR-treated sites (p < 0.01). Transplantation of TRCs for treatment of alveolar bone defects appears safe and accelerates bone regeneration, enabling jawbone reconstruction with oral implants. The results from this trial support expanded studies of TRC therapy in the treatment of craniofacial deformities (ClinicalTrials.gov number CT00755911).

Key words: Bone regeneration; Craniofacial tissue engineering; Stem cells; Cell therapy; Implants

Received October 25, 2011; final acceptance April 25, 2012. Online prepub date: July 5, 2012.
Address correspondence to Darnell Kaigler, D.D.S., M.S., Ph.D., Department of Periodontics and Oral Medicine, University of Michigan, 1011 N. University, Ann Arbor, MI 48109, USA. Tel: +1-734-615-4023; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or William V. Giannobile, D.M.D., D.Med.Sc., Michigan Center for Oral Health Research, University of Michigan, 1011 N. University Ave., Ann Arbor, MI 48109, USA. Tel: +1-734-763-2105; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 779-795, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X639017
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Human Adipose-Derived Stromal Cells for Cell-Based Therapies in the Treatment of Systemic Sclerosis

Nicolò Scuderi,*1 Simona Ceccarelli,†1 Maria Giuseppina Onesti,* Paolo Fioramonti,* Chiara Guidi,‡ Ferdinando Romano,§ Luigi Frati,¶ Antonio Angeloni,† and Cinzia Marchese†

*Department of Surgery “P. Valdoni,” University Sapienza, Rome, Italy
†Department of Experimental Medicine, University Sapienza, Rome, Italy
‡Bioscience Institute, Falciano, Republic of San Marino
§Department of Public Health and Infectious Diseases, University Sapienza, Rome, Italy
¶Department of Molecular Medicine, University Sapienza, Rome, Italy

The present study was designed to evaluate the clinical outcome of cell-based therapy with cultured adipose-derived stromal cells (ASCs) for the treatment of cutaneous manifestations in patients affected by systemic sclerosis (SSc). ASCs have an extraordinary developmental plasticity, including the ability to undergo multilineage differentiation and self-renewal. Moreover, ASCs can be easily harvested from small volumes of liposuction aspirate, showing great in vitro viability and proliferation rate. Here we isolated, characterized, and expanded ASCs, assessing both their mesenchymal origin and their capability to differentiate towards the adipogenic, osteogenic, and chondrogenic lineage. We developed an effective method for ASCs transplantation into sclerodermic patients by means of a hyaluronic acid (HA) solution, which allowed us to achieve precise structural modifications. ASCs were isolated from subcutaneous adipose tissue of six sclerodermic patients and cultured in a chemical-defined medium before autologous transplantation to restore skin sequelae. The results indicated that transplantation of a combination of ASCs in HA solution determined a significant improvement in tightening of the skin without complications such as anechoic areas, fat necrosis, or infections, thus suggesting that ASCs are a potentially valuable source of cells for skin therapy in rare diseases such as SSc and generally in skin disorders.

Key words: Adipose tissue engineering; Mesenchymal stromal cell (MSC); Hyaluronic acid (HA); Transplantation

Received March 24, 2011; final acceptance December 30, 2011. Online prepub date: April 17, 2012.
1These authors provided equal contribution to this work.
Address correspondence to Cinzia Marchese, Ph.D., Department of Experimental Medicine, University Sapienza, Rome, Viale Regina Elena 324, 00161, Italy. Tel: +39 0649973119-73012; Fax: +39 064454820; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 797-809, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X656126
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Protein Kinase C Activation Stimulates Mesenchymal Stem Cell Adhesion Through Activation of Focal Adhesion Kinase

Byeong-Wook Song,*†1 Woochul Chang,‡1 Bum-Kee Hong,§1 Il-Kwon Kim,*† Min-Ji Cha,*† Soyeon Lim,¶ Eun Ju Choi,*† Onju Ham,*† Se-Yeon Lee,*† Chang Youn Lee,# Jun-Hee Park,# Eunmi Choi,** Heesang Song,†† Yangsoo Jang,*‡‡ and Ki-Chul Hwang*†**

*Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
†Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
‡Institute of Catholic Integrative Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea College of Medicine, Incheon, Republic of Korea
§Heart Center, Gangnam Severance Hospital, Seoul, Republic of Korea
¶Severance Integrative Research Institute for Cerebral and Cardiovascular Disease, Yonsei University Health System, Seoul, Republic of Korea
#Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul, Republic of Korea
**Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
††Department of Biochemistry and Molecular Biology, Chosun University School of Medicine, Gwangju, Republic of Korea

‡‡Cardiology Division, Yonsei University College of Medicine, Seoul, Republic of Korea

Emerging evidence suggests that cell therapy with mesenchymal stem cells (MSCs) has beneficial effects on the injured heart. However, the decreased survival and/or adhesion of MSCs under ischemic conditions limits the application of cell transplantation as a therapeutic modality. We investigated a potential method of increasing the adhesion ability of MSCs to improve their efficacy in the ischemic heart. Treatment of MSCs with PKC activator, phorbol 12-myristate 13-acetate (PMA), increased cell adhesion and spreading in a dose-dependent method and significantly decreased detachment. When MSCs were treated with PKC inhibitor, that is, rottlerin, adhesion of MSCs was slightly diminished, and detachment was also decreased compared to the treatment with PMA. MSCs treated with both PMA and rottlerin behaved similarly to normal controls. In 3D matrix cardiogel, treatment with PMA increased the number of MSCs compared to the control group and MSCs treated with rottlerin. Expressions of focal adhesion kinase, cytoskeleton-associated proteins, and integrin subunits were clearly demonstrated in PMA-treated MSCs by immunoblotting and/or immunocytochemistry. The effect of PKC activator treatment on MSCs was validated in vivo. Following injection into rat hearts, the PMA-treated MSCs exhibited significantly higher retention in infarcted myocardium compared to the MSC group. Infarct size, fibrosis area, and apoptotic cells were reduced, and cardiac function was improved in rat hearts injected with PMA-treated MSCs compared to sham and/or MSC-implanted group. These results indicate that PKC activator is a potential target for niche manipulation to enhance adhesion of MSCs for cardiac regeneration.

Key words: Adhesion; Ischemic heart; Mesenchymal stem cells (MSCs); Protein kinase C (PKC); Transplantation

Received September 6, 2011; final acceptance March 20, 2012. Online prepub date: September 21, 2012.
1These authors provided equal contribution to this work.
Address correspondence to Ki-Chul Hwang, Ph.D., Severence Biomedical Research Institute, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, 120-752, Republic of Korea. Tel: +82-2-2228-8523; Fax: +82-2-365-1878; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 811-819, 2013
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DOI: http://dx.doi.org/10.3727/096368912X636966
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Porous Scaffolds Support Extrahepatic Human Islet Transplantation, Engraftment, and Function in Mice

Romie F. Gibly,*† Xiaomin Zhang,‡ William L. Lowe Jr.,*§¶ and Lonnie D. Shea*#**¶

*Institute of Bionanotechnology in Medicine (IBNAM), Northwestern University, Chicago, IL, USA
†Integrated Graduate Program, Northwestern University, Chicago, IL, USA
‡Department of Surgery, Northwestern University, Chicago, IL, USA
§Department of Medicine, Northwestern University, Chicago, IL, USA
¶Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, USA
#Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA
**The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA

Islet transplantation as a therapy or cure for type 1 diabetes has significant promise but has been limited by islet mass requirements and long-term graft failure. The intrahepatic and intravascular site may be responsible for significant loss of transplanted islets. Nonencapsulating biomaterial scaffolds provide a strategy for architecturally defining and modulating extrahepatic sites beyond the endogenous milieu to enhance islet survival and function. We utilized scaffolds to transplant human islets into the intraperitoneal fat of immunodeficient mice. A smaller human islet mass than previously reported reversed murine diabetes and restored glycemic control at human blood glucose levels. Graft function was highly dependent on the islet number transplanted and directly correlated to islet viability, as determined by the ATP-to-DNA ratio. Islets engrafted and revascularized in host tissue, and glucose tolerance testing indicated performance equivalent to healthy mice. Addition of extracellular matrix, specifically collagen IV, to scaffold surfaces improved graft function compared to serum-supplemented media. Porous scaffolds can facilitate efficient human islet transplantation and provide a platform for modulating the islet microenvironment, in ways not possible with current clinical strategies, to enhance islet engraftment and function.

Key words: Islets; Transplantation; Scaffold; Diabetes; Human

Received August 8, 2011; final acceptance January 5, 2012. Online prepub date: April 10, 2012.
Address Correspondence to Lonnie D. Shea, Department of Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Rd/E136, Evanston, IL 60208, USA. Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 821-830, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X636812
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Transplantation of Human Embryonic Stem Cell-Derived Pancreatic Endoderm Reveals a Site-Specific Survival, Growth, and Differentiation

Lina Sui,* Josué K. Mfopou,* Bing Chen,*Karen Sermon,and Luc Bouwens*

*Cell Differentiation Unit, Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
Department of Embryology and Genetics, Vrije Universiteit Brussel, Brussels, Belgium

Development of β-cells from human embryonic stem cells (hESCs) could compensate for the shortage of islet donors required for diabetes therapy. Although pancreatic progenitors have been derived from hESCs using various protocols, no fully functional β-cells could be generated in vitro. We evaluated the in vivo growth and differentiation of PDX1+ pancreatic endoderm cells obtained from hESCs. Here we show site-specific survival and differentiation when comparing cells grafted in the epididymal fat pad or the subcutaneous space of NOD/SCID mice after 12 weeks follow-up. Subcutaneous grafts persisted and expressed PDX1 at all time points analyzed, showed PDX1 and NKX6.1 coexpression after 6 weeks, and contained NGN3+ cells after 12 weeks. These findings suggest that further specification along the pancreatic lineage occurred at the subcutaneous site. In sharp contrast, in the fat pad grafts only a minority of PDX1+ cells remained after 2 weeks, and no further pancreatic differentiation was observed later on. In addition, contaminating mesenchymal cells present in the implants further developed into cartilage tissue after 6 weeks implantation in the fat pad, but not in the subcutaneous space. These findings indicate that the in vivo microenvironment plays a critical role in the further differentiation of transplanted pancreatic endoderm cells.

Key words: Human embryonic stem cells (hESCs); PDX1-positive pancreatic endoderm (PPP); Transplantation; Pancreatic progenitor; β-Cells

Received February 1, 2011; final acceptance December 22, 2011. Online prepub date: April 2, 2012.
Address correspondence to Prof. Luc Bouwens, Cell Differentiation Unit, Diabetes Research Center Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium. Tel: +32 2477 4457; Fax: +32 2477 4405; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 831-838, 2013
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DOI: http://dx.doi.org/10.3727/096368912X647144
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Intracerebral Transplantation of Differentiated Human Embryonic Stem Cells to Hemiparkinsonian Monkeys

Marina E. Emborg,*† Zhijian Zhang,‡ Valerie Joers,* Kevin Brunner,* Viktorya Bondarenko,* Sachiko Ohshima,* and Su-Chun Zhang‡§¶

*Preclinical Parkinson’s Research Program, Wisconsin National Primate Research Center, Madison, WI, USA
†Department of Medical Physics, University of Wisconsin, Madison, WI, USA
‡Waisman Center, University of Wisconsin, Madison, WI, USA
§Department of Neuroscience, University of Wisconsin, Madison, WI, USA
¶Department of Neurology, University of Wisconsin, Madison, WI, USA

To explore stem cell therapy for Parkinson’s disease (PD), three adult rhesus monkeys were first rendered hemiparkinsonian by unilateral intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) infusion. Five months postinfusion, they were given MRI-guided stereotaxic intrastriatal and intranigral injections of green fluorescent protein (GFP)-labeled cultures of dopaminergic neurons derived from human embryonic stem cells (DA-hES cells). The animals were immunosuppressed using daily oral cyclosporine (CsA). Three months later, viable grafts were observed at the injection sites in one animal, while no obvious grafts were present in the other two monkeys. The surviving grafts contained numerous GFP-positive cells that were positively labeled for nestin and MAP2 but not for glial fibrillary acidic protein (GFAP), NeuN, or tyrosine hydroxylase (TH). The grafted areas in all animals showed dense staining for GFAP, CD68, and CD45. These results indicated that xenografts of human stem cell derivatives in CsA-suppressed rhesus brain were mostly rejected. Our study suggests that immunological issues are obstacles for preclinical evaluation of hES cells and that improved immunosuppression paradigms and/or alternative cell sources that do not elicit immune rejection are needed for long-term preclinical studies.

Key words: Parkinson’s disease (PD); Human embryonic stem (hES) cells; Dopamine (DA); Immune rejection; Cell transplantation; Cell differentiation

Received April 13, 2011; final acceptance March 18, 2012. Online prepub date: June 15, 2012.
Address correspondence to Marina E. Emborg, M.D., Ph.D., Preclinical Parkinson’s Research Program, Wisconsin National Primate Research Center, 1220 Capitol Court, Madison, WI 53715, USA. Tel: +1 (608) 262-9714; Fax: +1 (608) 263-3524; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 839-854, 2013
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DOI: http://dx.doi.org/10.3727/096368912X657404
E-ISSN 1555-3892
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Mesenchymal Stem Cells Expressing Vasoactive Intestinal Peptide Ameliorate Symptoms in a Model of Chronic Multiple Sclerosis

Marién Cobo,*1 Per Anderson,*1 Karim Benabdellah,* Miguel G. Toscano,* Pilar Muñoz,* Angélica García-Pérez,* Iván Gutierrez,† Mario Delgado,‡ and Francisco Martin*

*GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Parque Tecnológico Salud (PTS), Granada, Spain
†Biobanco, Parque Tecnológico Salud (PTS), Armilla, Universidad de Granada, Granada, Spain
‡IPB Lopez Neyra, CSIC, Parque Tecnológico Salud (PTS), Armilla, Granada, Spain

Multiple sclerosis (MS) is a severe debilitating disorder characterized by progressive demyelination and axonal damage of the central nervous system (CNS). Current therapies for MS inhibit the immune response and demonstrate reasonable benefits if applied during the early phase of relapsing–remitting MS (RRMS) while there are no treatments for patients that progress neither to the chronic phase nor for the primary progressive form of the disease. In this manuscript, we have studied the therapeutic efficacy of a cell and gene therapy strategy for the treatment of a mouse model of chronic MS [myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE)]. We used allogenic mesenchymal stem cells (MSCs) as a therapeutic tool and also as vehicle to deliver fully processed 3.3-kDa vasoactive intestinal peptide (VIP) to the peripheral immune organs and to the inflamed CNS. Intraperitoneal administrations of MSCs expressing VIP stopped progression and reduced symptoms when administered at peak of disease. The improvement in clinical score correlated with diminished peripheral T-cell responses against MOG as well as lower inflammation, lower demyelination, and higher neuronal integrity in the CNS. Interestingly, neither lentiviral vectors expressing VIP nor unmodified MSCs were therapeutic when administer at the peak of disease. The increased therapeutic effect of MSCs expressing VIP over unmodified MSCs requires the immunoregulatory and neuroprotective roles of both VIP and MSCs and the ability of the MSCs to migrate to peripheral lymph organs and the inflamed CNS.

Key words: Mesenchymal stem cell (MSC); Cell and gene therapy; Lentiviral vectors; Vasoactive intestinal peptide (VIP); Experimental autoimmune encephalomyelitis (EAE); Multiple sclerosis (MS)

Received October 5, 2011; final acceptance April 27, 2012. Online prepub date: October 2, 2012.
1These authors share first authorship.
Address correspondence to Francisco Martin, GENYO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Avd de la Ilustración 114, Parque Tecnológico Salud (PTS), Granada 18007, Spain. Tel: 34958637103; Fax: 34958637071; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 855-870, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X637019
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Neural Induction With Neurogenin 1 Enhances the Therapeutic Potential of Mesenchymal Stem Cells in an Amyotrophic Lateral Sclerosis Mouse Model

Chan-Il Choi,*†‡ Young-Don Lee,*§¶ Heejaung Kim,# Seung Hyun Kim,# Haeyoung Suh-Kim,*†‡ and Sung-Soo Kim*

*Department of Anatomy, Ajou University School of Medicine, Suwon, South Korea
†Neuroscience Graduate Program, Ajou University School of Medicine, Suwon, South Korea
‡BK21-Division of Cell Transformation and Restoration, Ajou University School of Medicine, Suwon, South Korea
§Center for Cell Death Regulating Biodrug, Ajou University School of Medicine, Suwon, South Korea
¶Department of Molecular Science and Technology, Ajou University School of Medicine, Suwon, South Korea
#Department of Neurology, Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul, South Korea

Amyotrophic lateral sclerosis (ALS) is characterized by progressive dysfunction and degeneration of motor neurons in the central nervous system (CNS). In the absence of effective drug treatments for ALS, stem cell treatment has emerged as a candidate therapy for this disease. To date, however, there is no consensus protocol that stipulates stem cell types, transplantation timing, or frequency. Using an ALS mouse model carrying a high copy number of a mutant human superoxide dismutase-1 (SOD1)G93A transgene, we investigated the effect of neural induction on the innate therapeutic potential of mesenchymal stem cells (MSCs) in relation to preclinical transplantation parameters. In our study, the expression of monocyte chemoattractant protein-1 (MCP-1) was elevated in the ALS mouse spinal cord. Neural induction of MSCs with neurogenin 1 (Ngn1) upregulated the expression level of the MCP-1 receptor, CCR2, and enhanced the migration activity toward MCP-1 in vitro. Ngn1-expressing MSCs (MSCs-Ngn1) showed a corresponding increase in tropism to the CNS after systemic transplantation in ALS mice. Notably, MSCs-Ngn1 delayed disease onset if transplanted during preonset ages, whereas unprocessed MSCs failed to do so. If transplanted near the onset ages, a single treatment with MSCs-Ngn1 was sufficient to enhance motor functions during the symptomatic period (15–17 weeks), whereas unprocessed MSCs required repeated transplantation to achieve similar levels of motor function improvement. Our data indicate that systemically transplanted MSCs-Ngn1 can migrate to the CNS and exert beneficial effects on host neural cells for an extended period of time through paracrine functions, suggesting a potential benefit of neural induction of transplanted MSCs in long-term treatment of ALS.

Key words: Mesenchymal stem cells (MSCs); Amyotrophic lateral sclerosis (ALS); Cu2+/Zn2+ superoxide dismutase; Superoxide dismutase-1 (SOD1); Neurogenin 1 (Ngn1)

Received November 30, 2010; final acceptance December 23, 2011. Online prepub date: April 2, 2012.
Address correspondence to Sung-Soo Kim, Ph.D., Department of Anatomy, Ajou University School of Medicine, Youngtong-gu, Woncheon-dong, San 5, Suwon, 443-749, South Korea. Tel: +82-31-219-5034; Fax: +82-31-219-5039; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Haeyoung Suh-Kim, PhD, Department of Anatomy, Ajou University School of Medicine, Youngtong-gu, Woncheon-dong, San 5, Suwon, 443-749, South Korea. Tel: +82-31-219-5033; Fax: +82-31-219-5039; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 871-879, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X637380
E-ISSN 1555-3892
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Neuroprotective Effect of Human Placenta-Derived Cell Treatment of Stroke in Rats

Jieli Chen,* Amjad Shehadah,* Ajai Pal,† Alex Zacharek,* Xu Cui,* Yisheng Cui,* Cynthia Roberts,* Mei Lu,‡ Andrew Zeitlin,† Robert Hariri,† and Michael Chopp*§

*Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
†Celgene Cellular Therapeutics, Warren, NJ, USA
‡Department of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, MI, USA
§Department of Physics, Oakland University, Rochester, MI, USA

Human placenta-derived adherent (PDA001) cells are mesenchymal-like stem cells isolated from postpartum human placenta. In this study, we tested whether intravenously infused PDA001 improves neurological functional recovery after stroke in rats. In addition, potential mechanisms underlying the PDA001-induced neuroprotective effect were investigated. Young adult male rats (2–3 months) were subjected to 2 h of middle cerebral artery occlusion (MCAo) and treated with PDA001 (4 × 106) or vehicle controls [dextran vehicle or phosphate buffer saline (PBS)] via intravenous (IV) administration initiated at 4 h after MCAo. A battery of functional tests and measurements of lesion volume and apoptotic cells were performed. Immunostaining and ELISA assays for vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) and brain-derived neurotrophic factor (BDNF) were performed in the ischemic brain to test the potential mechanisms underlying the neuroprotective effects of PDA001 cell treatment of stroke. PDA001 cell treatment at 4 h poststroke significantly improved functional outcome and significantly decreased lesion volume, TUNEL, and cleaved caspase 3-positive cell number in the ischemic brain, compared to MCAo-vehicle and MCAo-PBS control. Treatment of stroke with PDA001 cells also significantly increased HGF and VEGF expression in the ischemic border zone (IBZ) compared to controls. Using ELISA assays, treatment of stroke with PDA001 cells significantly increased VEGF, HGF, and BDNF levels in the ischemic brain compared to controls. Conclusion: When administered intravenously at 4 h after MCAo, PDA001 cells promoted neuroprotective effects. These effects induced by PDA001 cell treatment may be related to the increase of VEGF, HGF, and BDNF expression, and a decrease of apoptosis. PDA001 cells may provide a viable cell source to treat stroke.

Key words: Human placenta-derived adherent (PDA001) cell; Stroke; Neuroprotection

Received August 16, 2011; final acceptance December 23, 2011. Online prepub date: March 27, 2012.
Address correspondence to Jieli Chen, M.D., Senior Staff Investigator, Henry Ford Hospital, Neurology Research, Education and Research Building, Room 3091, Detroit, MI 48202, USA. Tel: +1 (313) 916-1991; Fax: +1 (313) 916-1318; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 881-892, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X656144
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Imaging Neural Stem Cell Graft-Induced Structural Repair in Stroke

Marcel M. Daadi,*† Shijun Hu,‡ Jill Klausner,* Zongjin Li,‡ Marc Sofilos,‡ Guohua Sun,* Joseph C. Wu,‡ and Gary K. Steinberg*

*Department of Neurosurgery, Stanford Stroke Center and Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford, CA, USA
†Molecular Medicine Research Institute, Sunnyvale, CA, USA
‡Department of Medicine and Radiology (Molecular Imaging Program at Stanford), Stanford University School of Medicine, Stanford, CA, USA

Stem cell therapy ameliorates motor deficits in experimental stroke model. Multimodal molecular imaging enables real-time longitudinal monitoring of infarct location, size, and transplant survival. In the present study, we used magnetic resonance imaging (MRI) and positron emission tomography (PET) to track the infarct evolution, tissue repair, and the fate of grafted cells. We genetically engineered embryonic stem cell-derived neural stem cells (NSCs) with a triple fusion reporter gene to express monomeric red fluorescence protein and herpes simplex virus-truncated thymidine kinase for multimodal molecular imaging and SPIO labeled for MRI. The infarct size as well as fate and function of grafted cells were tracked in real time for 3 months using MRI and PET. We report that grafted NSCs reduced the infarct size in animals with less than 0.1 cm3 initial infarct in a dose-dependent manner, while larger stroke was not amenable to such beneficial effects. PET imaging revealed increased metabolic activity in grafted animals and visualized functioning grafted cells in vivo. Immunohistopathological analysis demonstrated that, after a 3-month survival period, grafted NSCs dispersed in the stroke-lesioned parenchyma and differentiated into neurons, astrocytes, and oligodendrocytes. Longitudinal multimodal imaging provides insights into time course dose-dependent interactions between NSC grafts and structural changes in infarcted tissue.

Key words: Human neural stem cells (NSCs); Molecular imaging; Position emission tomography (PET); Magnetic resonance imaging (MRI); Cell therapy

Received April 11, 2012; final acceptance May 13, 2012. Online prepub date: October 3, 2012.
Address correspondence to Marcel Daadi, Ph.D., Department of Neurosurgery, Stanford University, MSLS P304, 1201 Welch Rd., Stanford, CA 94305-5487, USA. Tel: +1-650-724-9998; Fax: +1-650-498-4134; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it