Cell Transplantation 25(1) Abstracts

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Cell Transplantation, Vol. 25, pp. 1-15, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688173
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Infusion of Human Bone Marrow-Derived Mesenchymal Stem Cells Alleviates Autoimmune Nephritis in a Lupus Model by Suppressing Follicular Helper T-Cell Development

Eunkyeong Jang,*1 Mini Jeong,*1 Sukhyung Kim,* Kiseok Jang,† Bo-Kyeong Kang,‡ Dong Yun Lee,§ Sang-Cheol Bae,¶ Kyung Suk Kim,# and Jeehee Youn*

*Department of Anatomy and Cell Biology, Hanyang University, Seoul, Korea
†Department of Pathology, Hanyang University, Seoul, Korea
‡Department of Radiology, Hanyang University, Seoul, Korea
§BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Institute for Bioengineering and Biopharmaceutical Research, Department of Bioengineering, Hanyang University, Seoul, Korea
Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
#Corestem Inc., Seoul, Korea

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies to components of the cell nucleus. These autoantibodies are predominantly produced with the help of follicular helper T (Tfh) cells and form immune complexes that trigger widespread inflammatory damage, including nephritis. In recent studies, mesenchymal stem cells (MSCs) elicited diverse, even opposing, effects in experimental and clinical SLE. Here we investigated the effect of human bone marrow-derived MSCs (hBMMSCs) in a murine model of SLE, the F1 hybrid between New Zealand Black and New Zealand White strains (NZB/W). We found that infusion of female NZB/W mice with hBM-MSCs attenuated glomerulonephritis; it also decreased levels of autoantibodies and the incidence of proteinuria and improved survival. These effects coincided with a decrease in Tfh cells and downstream components. Infiltration of long-lived plasma cells into the inflamed kidney was also reduced in the hBM-MSC-treated mice. Importantly, hBM-MSCs directly suppressed the in vitro differentiation of naive CD4+
T cells toward Tfh cells in a contact-dependent manner. These results suggest that MSCs attenuate lupus nephritis by suppressing the development of Tfh cells and the subsequent activation of humoral immune components. They thus reveal a novel mechanism by which MSCs regulate humoral autoimmune diseases such as SLE.

Key words: Mesenchymal stem cells (MSCs); Follicular helper T (Tfh) cells; Systemic lupus erythematosus (SLE); Autoimmunity; Nephritis

Received November 25, 2014; final acceptance April 20, 2015. Online prepub date: May 13, 2015.
1These authors provided equal contribution to this work.
Address correspondence to Dr. Jeehee Youn, Department of Anatomy and Cell Biology, College of Medicine, Hanyang University, 222 Wangsimni-roSungdong-gu, Seoul 133-791, Korea. Tel: +82-2-2220-0604; Fax: +82-2-2281-7841; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 17-33, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687688
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Cryopreserved Ex Vivo-Expanded Allogeneic Myeloid Progenitor Cell Product Protects Neutropenic Mice From a Lethal Fungal Infection

Jos Domen,*1,2 Julie L. Christensen,*1,3 Daphne Gille,*4 Stephanie Smith-Berdan,*6 Timothy Fong,* Janice M. Y. Brown,†6 and Anna K. Sedello*6

*Cellerant Therapeutics, San Carlos, CA, USA
†Stanford University, Stanford, CA, USA

Severe neutropenia induced by chemotherapy or conditioning for hematopoietic cell transplantation often results in morbidity and mortality due to infection by opportunistic pathogens. A system has been developed to generate ex vivo-expanded mouse myeloid progenitor cells (mMPCs) that produce functional neutrophils in vivo upon transplantation in a pathogen challenge model. It has previously been demonstrated that transplantation of large numbers of freshly isolated myeloid progenitors from a single donor provides survival benefit in radiation-induced neutropenic mice. In the present work, an ex vivo-expanded and cryopreserved mMPC product generated from an allogeneic donor pool retains protective activity in vivo in a lethal fungal infection model. Infusion of the allogeneic pooled mMPC product is effective in preventing death from invasive Aspergillus fumigatus in neutropenic animals, and protection is dose dependent. Cell progeny from the mMPC product is detected in the bone marrow, spleen, blood, and liver by flow cytometry 1 week postinfusion but is no longer evident in most animals 4 weeks posttransplant. In this model, the ex vivo-generated pooled allogeneic mMPC product (i) expands and differentiates in vivo; (ii) is functional and prevents death from invasive fungal infection; and (iii) does not permanently engraft or cause allosensitization. These data suggest that an analogous ex vivo-expanded human myeloid progenitor cell product may be an effective off-the-shelf bridging therapy for the infectious complications that develop during hematopoietic recovery following hematopoietic cell transplantation or intensive chemotherapy.

Key words: Neutropenia; Infection; Allogeneic myeloid progenitors; Ex vivo expansion

Received September 10, 2014; final acceptance February 23, 2015. Online prepub date: March 25, 2015.
1These authors provided equal contribution to this work.
2Current address: Section of Cardiac Surgery, Children’s Mercy Hospital, Kansas City, MO, USA.
3Current address: Fess Parker Winery, Los Olivos, CA, USA.
4Current address: Graduate Program in Genetics, UC Davis, Davis, CA, USA.
5Current address: Department of Biomolecular Engineering, UC Santa Cruz, Santa Cruz, CA, USA.
6These authors are co-senior authors.
Address correspondence to Anna K. SedelloCellerant Therapeutics, 1561 Industrial Road, San Carlos, CA 94070, USA. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 35-53, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687697
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Preconditioning of Cardiosphere-Derived Cells With Hypoxia or Prolyl-4-Hydroxylase Inhibitors Increases Stemness and Decreases Reliance on Oxidative Metabolism

Suat Cheng Tan,*† Renata S. M. Gomes,* Kar Kheng Yeoh,‡§ Filippo Perbellini,*¶ Sophia Malandraki-Miller,* Lucy Ambrose,* Lisa C. Heather,* Giuseppe Faggian,¶ Christopher J. Schofield,‡ Kay E. Davies,* Kieran Clarke,* and Carolyn A. Carr*

*Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
†School of Health Science, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia
‡Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Oxford, UK
§School of Chemical Science, Universiti Sains Malaysia, Pulau Pinang, Malaysia
¶Department of Cardiac Surgery, University of Verona, Verona, Italy

Cardiosphere-derived cells (CDCs), which can be isolated from heart explants, are a promising candidate cell source for infarcted myocardium regeneration. However, current protocols used to expand CDCs require at least 1 month in vitro to obtain sufficient cells for transplantation. We report that CDC culture can be optimized by preconditioning the cells under hypoxia (2% oxygen), which may reflect the physiological oxygen level of the stem cell niche. Under hypoxia, the CDC proliferation rate increased by 1.4-fold, generating 6 × 106
CDCs with higher expression of cardiac stem cell and pluripotency gene markers compared to normoxia. Furthermore, telomerase (TERT), cytokines/ligands involved in stem cell trafficking (SDF/CXCR-4), erythropoiesis (EPO), and angiogenesis (VEGF) were increased under hypoxia. Hypoxic preconditioning was mimicked by treatment with two types of hypoxia-inducible factor (HIF) prolyl-4-hydroxylase inhibitors (PHDIs): dimethyloxaloylglycine (DMOG) and 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetic acid (BIC). Despite the difference in specificity, both PHDIs significantly increased c-Kit expression and activated HIF, EPO, and CXCR-4. Furthermore, treatment with PHDIs for 24 h increased cell proliferation. Notably, all hypoxic and PHDI-preconditioned CDCs had decreased oxygen consumption and increased glycolytic metabolism. In conclusion, cells cultured under hypoxia could have potentially enhanced therapeutic potential, which can be mimicked, in part, by PHDIs.

Key words: Cardiac progenitor cells; Hypoxia-inducible factor (HIF); Hypoxic preconditioning; Dimethyloxaloylglycine (DMOG); 2-(1-Chloro-4-hydroxyisoquinoline-3-carboxamido) acetic acid (BIC)

Received October 2, 2014; final acceptance February 25, 2015. Online prepub date: March 6, 2015.
Address correspondence to Dr. Suat Cheng Tan, School of Health Science, Health Campus, Universiti Sains Malaysia, 16150 Kubang KerianKelantan, Malaysia. Tel: +609-7677776; Fax: +609-7677515; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 55-69, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688254
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

The Paracrine Effect of Skeletal Myoblasts Is Cardioprotective Against Oxidative Stress and Involves EGFR-ErbB4 Signaling, Cystathionase, and the Unfolded Protein Response

Antti Siltanen,* Kristo Nuutila,* Yukiko Imanishi,† Hisazumi Uenaka,† Johanna Mäkelä,‡ Tommi Pätilä,¶ Antti Vento,§ Shigeru Miyagawa,† Yoshiki Sawa,† Ari Harjula,§ and Esko Kankuri*

*Pharmacology, University of Helsinki, Helsinki, Finland
†Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
‡Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland
§Cardiothoracic Surgery, Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
¶Children’s Hospital, Cardiothoracic Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

Therapeutic effects of skeletal myoblast transplantation into the myocardium are mediated via paracrine factors. We investigated the ability of myoblast-derived soluble mediators to protect cardiomyocytes from oxidative stress. Fetal rat cardiac cells were treated with conditioned medium from cultures of myoblasts or cardiac fibroblasts, and oxidative stress was induced with H2O2. Myoblast-derived factors effectively prevented oxidative stress-induced cardiac cell death and loss of mitochondrial membrane potential. This protective effect was mediated via epidermal growth factor (EGF) receptor and c-Met signaling, and mimicked by neuregulin 1 but not EGF. Microarray analysis of cardiac cells treated with myoblast versus cardiac fibroblast-derived mediators revealed differential regulation of genes associated with antioxidative effects: cystathionine-g-lyase (cst), xanthine oxidase, and thioredoxin-interacting protein as well as tribbles homolog 3 (trib3). Cardiac cell pretreatment with tunicamycin, an inducer oftrib3, also protected them against H2O2-induced cell death. Epicardial transplantation of myoblast sheets in a rat model of acute myocardial infarction was used to evaluate the expression of CST and trib3 as markers of myoblasts’ paracrine effect in vivo. Myoblast sheets induced expression of the CST as well as trib3 in infarcted myocardium. CST localized around blood vessels, suggesting smooth muscle cell localization. Our results provide a deeper molecular insight into the therapeutic mechanisms of myoblast-derived paracrine signaling in cardiac cells and suggest that myoblast transplantation therapy may prevent oxidative stress-induced cardiac deterioration and progression of heart failure.

Key words: Myoblast; Heart failure; Oxidative stress; Reactive oxygen species; Cystathionase; Tribbles homolog 3 (trib3)

Received October 24, 2013; final acceptance April 8, 2015. Online prepub date: May 27, 2015.
Address correspondence to Antti Siltanen, Pharmacology, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland. Tel: +358-29-41-25362; Fax: +358-29-41-25364; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 71-81, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687921
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Adipose-Derived Stem Cells Accelerate Diabetic Wound Healing Through the Induction of Autocrine and Paracrine Effects

Yur-Ren Kuo,*† Chun-Ting Wang,*‡ Jiin-Tsuey Cheng,† Gour-Shenq Kao,*‡ Yuan-Cheng Chiang,* and Ching-Jen Wang§

*Department of Plastic and Reconstructive Surgery, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan
†Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
‡Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan
§Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan

Cell-based therapy is an attractive approach for the treatment of chronic nonhealing wounds. This study investigated whether adipose-derived stem cells (ASCs) can accelerate diabetic wound healing and traffic in the engraftment of ASCs. Dorsal full-thickness skin wound defects (6 × 5 cm) were created in a streptozotocin (STZ)-induced diabetes rodent model. Group I served as a nondiabetic normal control, group II served as a diabetic control without ASCs, and group III included rats that were injected subcutaneously in the wound margin twice with nondiabetic ASCs (1 × 107
ASCs/dose). The wound healing was assessed clinically. Histological examination and immunohistochemical analyses of periwound tissue were performed. Green fluorescence protein (GFP)+-ASCs were used to examine the engraftment of these cells after injection. XenoLight DiR-labeled ASCs were implanted to detect migration ability using an IVIS imaging system. Results revealed that complete wound healing time statistically decreased in the ASC-treated group compared to the controls (p < 0.001). Histological examination revealed the ASC-treated group showed a significant reduction in the proinflammatory reaction, with significantly increased levels of EGF, VEGF, rPH, and Ki-67 expression compared to the controls. The populations of GFP+-ASCs in circulating blood significantly increased after ASC injection compared to those of controls. Immunofluorescence staining showed GFP+-ASCs significantly accumulated in the subdermal layer of the wound margin and increased angiogenesis via vWF and VEGF expression after injection. IVIS analysis revealed ASCs could exist and home into the periwound area up to 8 weeks postimplantation. In conclusion, ASCs significantly enhanced diabetic wound healing, engrafted into the local wound tissue, and implanted into circulating blood. ASC treatment stimulated neoangiogenesis and increased tissue regeneration through paracrine and autocrine mechanisms.

Key words: Adipose-derived stem cells (ASCs); Diabetic wound healing; Tissue regeneration

Received November 21, 2014; final acceptance April 3, 2015. Online prepub date: April 7, 2015.
Address correspondence to Yur-Ren Kuo, M.D., Ph.D., at his current affiliation: Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, 100 Tzyou 1st Rd., Kaohsiung 80756, Taiwan. Tel: +886-7-3121101, ext. 7675; Fax: +886-7-7311482; 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. 25, pp. 83-95, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687958
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Quantifying Insulin Therapy Requirements to Preserve Islet Graft Function Following Islet Transplantation

Chris Orr,* Jeannette Stratton,* Irram Rao,* Mohamad Al-Sayed,* Craig Smith,† Mohamed El-Shahawy,* Donald Dafoe,‡ Yoko Mullen,* Ismail Al-Abdullah,* and Fouad Kandeel*

*Southern California Islet Cell Resources Center, Department of Diabetes, Endocrinology, and Metabolism, Beckman Research Institute of the City of Hope, Duarte, CA, USA
†Division of Surgery, Harbor-UCLA Medical Center, Torrance, CA, USA
‡Kidney-Pancreas Transplant Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA

A mathematical nonlinear regression model of several parameters (baseline insulin intake, posttransplant 2-h postprandial blood glucose, and stimulated C-peptide) from type 1 diabetics with HbA1c <6.5% who do not require insulin therapy and have no hypoglycemic instances was developed for accurately predicting supplemental insulin requirements in the posttransplant period. An insulin deficit threshold of 0.018 U/kg/day was defined as the average first-year calculated insulin deficit (CID), above which HbA1c rose to >6.5% during year 2 of the posttransplant period. When insulin-untreated subjects were divided into two groups based on whether the average CID was smaller (group I) or greater (group II) than the insulin deficit threshold, HbA1c was found to be similar in the two groups in year 1, but increased significantly in group II to above 6.5% (with mean glucose of 121.9 mg/dl) but remained below 6.5% in group I subjects (with mean glucose of 108.7 mg/dl) in year 2 of the follow-up period. The greater insulin deficit in group II was also associated with a higher susceptibility to hyperglycemia during periods of low serum Rapamune and Prograf levels (combined levels below 11.2 and 4.7 ng/ml, respectively). Although the differences between predicted insulin requirement (PIR) and actual empirical insulin intake in the insulin-treated subjects were generally small, they were nonetheless sufficient to identify over- and underinsulinization at each follow-up visit for all subjects (n = 14 subjects, 135 observations). The newly developed model can effectively identify underinsulinized islet transplant recipients at risk for graft dysfunction due to inadequate supplemental insulin intake or those potentially susceptible to graft function loss due to inadequate immunosuppression. While less common following islet cell therapy, the model can also identify overinsulinized subjects who may be at risk for hypoglycemia.

Key words: Islet transplantation; Insulin therapy; Glucose toxicity; Graft dysfunction

Received September 5, 2014; final acceptance March 26, 2015. Online prepub date: April 7, 2015.
Address correspondence to Chris Orr, Department of Diabetes, Endocrinology and Metabolism, City of Hope National Medical Center, 1500 Duarte Rd, Duarte, CA 91010, USA. Tel: +1 (626) 359-8111; Fax: +1 (626) 301-8489; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 97-108, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687732
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Islet Endothelial Cells Derived From Mouse Embryonic Stem Cells

Neha Jain and Eun Jung Lee

New Jersey Institute of Technology, Department of Biomedical Engineering, Newark, NJ, USA

The islet endothelium comprises a specialized population of islet endothelial cells (IECs) expressing unique markers such as nephrin and α-1 antitrypsin (AAT) that are not found in endothelial cells in surrounding tissues. However, due to difficulties in isolating and maintaining a pure population of these cells, the information on these islet-specific cells is currently very limited. Interestingly, we have identified a large subpopulation of endothelial cells exhibiting IEC phenotype, while deriving insulin-producing cells from mouse embryonic stem cells (mESCs). These cells were identified by the uptake of low-density lipoprotein (LDL) and were successfully isolated and subsequently expanded in endothelial cell culture medium. Further analysis demonstrated that the mouse embryonic stem cell-derived endothelial cells (mESC-ECs) not only express classical endothelial markers, such as platelet endothelial cell adhesion molecule (PECAM1), thrombomodulin, intercellular adhesion molecule-1 (ICAM-1), and endothelial nitric oxide synthase (eNOS) but also IEC-specific markers such as nephrin and AAT. Moreover, mESC-ECs secrete basement membrane proteins such as collagen type IV, laminin, and fibronectin in culture and form tubular networks on a layer of Matrigel, demonstrating angiogenic activity. Further, mESC-ECs not only express eNOS, but also its eNOS expression is glucose dependent, which is another characteristic phenotype of IECs. With the ability to obtain highly purified IECs derived from pluripotent stem cells, it is possible to closely examine the function of these cells and their interaction with pancreatic b-cells during development and maturation in vitro. Further characterization of tissue-specific endothelial cell properties may enhance our ability to formulate new therapeutic angiogenic approaches for diabetes.

Key words: Islet endothelial cells (IECs); Embryonic stem cells (ESCs); Differentiation

Received June 17, 2014; final acceptance March 3, 2015. Online prepub date: March 6, 2015.
Address correspondence to Eun Jung Lee, Ph.D., New Jersey Institute of Technology, Department of Biomedical Engineering, 323 Dr. MLK Blvd, Fenster 615, Newark, NJ 07102, USA. Tel: +1-973-596-8471; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 109-124, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687822
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Comparative Characterization of Human and Equine Mesenchymal Stromal Cells: A Basis for Translational Studies in the Equine Model

Aline Hillmann,* Annette B. Ahrberg,*† Walter Brehm,*‡ Sandra Heller,*§ Christoph Josten,† Felicitas Paebst,‡ and Janina Burk*‡¶

*Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig, Germany
†Department of Orthopedics, Traumatology and Plastic Surgery, University of Leipzig, Leipzig, Germany
‡Large Animal Clinic for Surgery, University of Leipzig, Leipzig, Germany
§Tulane University, Department of Pathology and Laboratory Medicine, New Orleans, LA, USA
¶Institute of Veterinary Physiology, University of Leipzig, Leipzig, Germany

Multipotent mesenchymal stromal cells (MSCs) have gained tremendous attention as potential therapeutic agents for the treatment of orthopedic diseases. Promising results have been obtained after application of MSCs for treatment of tendon and joint disease in the equine model, making it appear favorable to use these results as a basis for the translational process of the therapy. However, while the horse is considered a highly suitable model for orthopedic diseases, knowledge is lacking regarding the level of analogy of equine MSCs and their human counterparts. Therefore, the aim of this study was to assess the properties of human and equine adipose and tendon-derived MSCs in a direct comparison. Basic properties of human and equine MSCs from both tissues were similar. The cells expressed CD29, CD44, CD90, and CD105 and lacked expression of CD73, CD14, CD34, CD45, CD79α, and MCHII/HLA-DR. No significant differences were found between proliferation potential of human and equine MSCs in early passages, but recovery of nucleated cells after tissue digestion as well as proliferation in later passages was higher in equine samples (p < 0.01). All samples showed a good migration capacity and multilineage differentiation potential. However, while osteogenic differentiation was achieved in all equine samples, it was only evident in five out of nine human tendon-derived samples. Human MSCs further showed a higher expression of collagen IIIA1 and tenascin-C, but lower expression of decorin andscleraxis (p < 0.01). Although revealing some potentially relevant differences, the study demonstrates a high level of analogy between human and equine MSCs, providing a basis for translational research in the equine model according to the guidelines issued by the authorities.

Key words: Mesenchymal stromal cells (MSCs); Cell therapy; Animal model; Tendon; Adipose; Horse

Received January 24, 2015; final acceptance March 21, 2015. Online prepub date: April 7, 2015.
Address correspondence to Dr. Janina Burk, University of Leipzig, Large Animal Clinic for Surgery, An den Tierkliniken 21, 04103 Leipzig, Germany. Tel: +49-341-9738264; Fax: +49-341-9738269; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 125-139, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687679
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Limited Functional Effects of Subacute Syngeneic Bone Marrow Stromal Cell Transplantation After Rat Spinal Cord Contusion Injury

Beatrice SandnerMareva Ciatipis, Melanie Motsch, Irina Soljanik, Norbert Weidner, and Armin Blesch

Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany

Cell transplantation might be one means to improve motor, sensory, or autonomic recovery after traumatic spinal cord injury (SCI). Among the different cell types evaluated to date, bone marrow stromal cells (BMSCs) have received considerable interest due to their potential neuroprotective properties. However, uncertainty exists whether the efficacy of BMSCs after intraspinal transplantation justifies an invasive procedure. In the present study, we analyzed the effect of syngeneic BMSC transplantation following a moderate to severe rat spinal cord injury. Adult Fischer 344 rats underwent a T9 contusion injury (200 kDy) followed by grafting of GFP-expressing BMSCs 3 days postinjury. Animals receiving a contusion injury without cellular grafts or an injury followed by grafts of syngeneic GFP-expressing fibroblasts served as control. Eight weeks posttransplantation, BMSC-grafted animals showed only a minor effect in one measure of sensorimotor recovery, no significant differences in tissue sparing, and no changes in the recovery of bladder function compared to both control groups in urodynamic measurements. Both cell types survived in the lesion site with fibroblasts displaying a larger graft volume. Thus, contrary to some reports using allogeneic or xenogeneic transplants, subacute intraparenchymal grafting of syngeneic BMSCs has only a minor effect on functional recovery.

Key words: Neuroprotection; Cell grafting; Spinal cord injury (SCI); Urodynamics; Bladder dysfunction; Bone marrow stromal cells (BMSCs)

Received October 14, 2014; final acceptance February 23, 2015. Online prepub date: March 25, 2015.
Address correspondence to Armin Blesch, Ph.D., Spinal Cord Injury Center, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany. Tel: +49-6221-562 9200; Fax: +49-6221-562 9208; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 141-157, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688065
E-ISSN 1555-3892
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Autologous Olfactory Lamina Propria Transplantation for Chronic Spinal Cord Injury: Three-Year Follow-Up Outcomes From a Prospective Double-Blinded Clinical Trial

Sheng Wang,* Jike Lu,†‡§ Yu-An Li,* Hui Zhou,¶ Wen-Fei Ni,* Xiao-Lei Zhang,† Si-Pin Zhu,* Bo-Bei Chen,# Hui Xu,* Xiang-Yang Wang,* Jian Xiao,** Hongyun, Huang,†† Yong-Long Chi,* and Hua-Zi Xu*

*Department of Spinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
†Orthopedic Research Institute, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
‡Department of Orthopedic Surgery, Taree Hospital, University of Newcastle, NSW, Australia
§Department of Surgery, United Family Hospital, Beijing, China
¶Department of Neurosurgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
#Department of E.N.T. Surgery, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
**Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China
††Department of Neurosurgery, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China

We did a clinical trial to determine whether olfactory mucosa lamina propria (OLP) transplants promote regeneration and functional recovery in chronic human spinal cord injury (SCI). The trial randomized 12 subjects to OLP transplants (n = 8) or control sham surgery (n = 4). The subjects received magnetic resonance imaging (MRI), electromyography (EMG), urodynamic study (UDS), American Spinal Injury Association impairment scale (AIS), and other functional assessments. OLP-transplanted subjects recovered more motor, sensory, and bladder function compared to sham-operated subjects. At 3 years after OLP transplant, one patient improved from AIS A to C and another recovered from AIS A to B, two recovered more than three segmental sensory levels, two had less spasticity, two had altered H-reflexes and SSEP, two regained bladder and anorectal sensation and had improved bladder compliance on UDS. OLP-treated patients had partial or complete tissue bridges at the injury site compared tocavitary gaps in sham-operated patients. The limited recovery suggests that OLP transplants alone do not have significant benefits but may provide a rationale for larger randomized trials or combination therapies.

Key words: Olfactory mucosa; Lamina propria; Autologous transplantation; Spinal cord injury (SCI); Chronic, functional recovery; Double blind; Random clinical trial

Received January 18, 2015; final acceptance April 12, 2015. Online prepub date: April 22, 2015.
Address correspondence to Professor Jike Lu, Department of Spinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, #109 Xue Yuan Xi Lu, Wenzhou, Zhejiang, People’s Republic of China 325027. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Hua-Zi Xu, Department of Spinal Surgery, the Second Affiliated Hospital of Wenzhou Medical University, #109 Xue Yuan Xi Lu, Wenzhou, Zhejiang, People’s Republic of China 325027. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 159-182, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688010
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Peripheral Nerve Regeneration Through Hydrogel-Enriched Chitosan Conduits Containing Engineered Schwann Cells for Drug Delivery

Cora Meyer,*†1 Sandra Wrobel,*†1 Stefania Raimondo,‡ Shimon Rochkind,§ Claudia Heimann,¶ Abraham Shahar,# Ofra Ziv-Polat,# Stefano Geuna,‡ Claudia Grothe,*† and Kirsten Haastert-Talini*†

*Institute of Neuroanatomy, Hannover Medical School, Hannover, Lower-Saxony, Germany
†Center for Systems Neuroscience (ZSN) Hannover, Lower-Saxony, Germany
‡Department of Clinical and Biological Sciences, Università degli studi di Torino, OrbassanoPiemonte, Italy
§Division of Peripheral Nerve Reconstruction, Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
Medovent GmbH, Mainz, Rhineland-Palatinate, Germany
#N.V.R Research Ltd., Ness-Ziona, Israel

Critical length nerve defects in the rat sciatic nerve model were reconstructed with chitosan nerve guides filled with Schwann cells (SCs) containing hydrogel. The transplanted SCs were naive or had been genetically modified to overexpress neurotrophic factors, thus providing a cellular neurotrophic factor delivery system. Prior to the assessment in vivo, in vitro studies evaluating the properties of engineered SCs overexpressing glial cell line-derived neurotrophic factor (GDNF) or fibroblast growth factor 2 (FGF-218kDa) demonstrated their neurite outgrowth inductive bioactivity for sympathetic PC-12 cells as well as for dissociated dorsal root ganglion cell drop cultures. SCs within NVR-hydrogel, which is mainly composed of hyaluronic acid and laminin, were delivered into the lumen of chitosan hollow conduits with a 5% degree of acetylation. The viability and neurotrophic factor production by engineered SCs within NVR-Gel inside the chitosan nerve guides was further demonstrated in vitro. In vivo we studied the outcome of peripheral nerve regeneration after reconstruction of 15-mm nerve gaps with either chitosan/NVR-Gel/SCs composite nerve guides or autologous nerve grafts (ANGs). While ANGs did guarantee for functional sensory and motor regeneration in 100% of the animals, delivery of NVR-Gel into the chitosan nerve guides obviously impaired sufficient axonal outgrowth. This obstacle was overcome to a remarkable extent when the NVR-Gel was enriched with FGF-218kDa
overexpressing SCs.

Key words: Cellular drug delivery system; Schwann cells (SCs); Sciatic nerve regeneration; Fibroblast growth factor-2; Glial cell line-derived neurotrophic factor (GNDF); Chitosan

Received July 29, 2014; final acceptance April 8, 2015. Online prepub date: April 14, 2015.
1These authors provided equal contribution to this work.
Address correspondence to Kirsten Haastert-Talini, Hannover Medical School, Institute of Neuroanatomy, OE 4140, Carl-Neuberg-Str.1, D-30625 Hannover, Germany. Tel: +49-511-532-2891; Fax: +49-511-532-2880; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 183-193, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688074
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Trophic Effects of Dental Pulp Stem Cells on Schwann Cells in Peripheral Nerve Regeneration

Tsubasa Yamamoto,*† Yohei Osako,* Masataka Ito,‡ Masashi Murakami,* Yuki Hayashi,*§ Hiroshi Horibe,*† Koichiro Iohara,* Norio Takeuchi,*¶ Nobuyuki Okui,# Hitoshi Hirata,** HidenoriNakayama,*† Kenichi Kurita,† and Misako Nakashima*

*Center of Advanced Medicine for Dental and Oral Diseases, National Center for Geriatrics and Gerontology, Research Institute, Morioka, Obu, Japan
†Department of Oral and Maxillofacial Surgery, School of Dentistry, Aichi-Gakuin University, Chikusa-ku, Nagoya, Japan
‡Department of Developmental Anatomy and Regenerative Medicine, National Defense Medical College, Namiki, Tokorozawa, Japan
§Department of Pediatric Dentistry, School of Dentistry, Aichi-Gakuin University, Chikusa-ku, Nagoya, Japan
¶Department of Endodontics, School of Dentistry, Aichi-Gakuin University, Chikusa-ku, Nagoya, Japan
#Department of Orthopedic Surgery and Rheumatology, Nagoya Ekisaikai Hospital, Nakagawa-ku, Nagoya, Japan
**Department of Hand Surgery, Nagoya University, Graduate School of Medicine, Showa-ku, Nagoya, Japan

Recently, mesenchymal stem cells have demonstrated a potential for neurotrophy and neurodifferentiation. We have recently isolated mobilized dental pulp stem cells (MDPSCs) using granulocyte-colony stimulating factor (G-CSF) gradient, which has high neurotrophic/angiogenic potential. The aim of this study is to investigate the effects of MDPSC transplantation on peripheral nerve regeneration. Effects of MDPSC transplantation were examined in a rat sciatic nerve defect model and compared with autografts and control conduits containing collagen scaffold. Effects of conditioned medium of MDPSCs were also evaluated in vitro. Transplantation of MDPSCs in the defect demonstrated regeneration of myelinated fibers, whose axons were significantly higher in density compared with those in autografts and control conduits only. Enhanced revascularization was also observed in the MDPSC transplants. The MDPSCs did not directly differentiate into Schwann cell phenotype; localization of these cells near Schwann cells induced several neurotrophic factors. Immunofluorescence labeling demonstrated reduced apoptosis and increased proliferation in resident Schwann cells in the MDPSC transplant compared with control conduits. These trophic effects of MDPSCs on proliferation, migration, and antiapoptosis in Schwann cells were further elucidated in vitro. The results demonstrate that MDPSCs promote axon regeneration through trophic functions, acting on Schwann cells, and promoting angiogenesis.

Key words: Mobilized dental pulp stem cells (MDPSCs); Peripheral nerve regeneration; Cell transplantation; Schwann cells; Trophic effect; Sciatic nerve

Received September 03, 2014; final acceptance April 08, 2015. Online prepub date: April 22, 2015.
Address correspondence to Dr. Misako Nakashima, D.D.S, Ph.D., Department of Dental Regenerative Medicine, Center of Advanced Medicine for Dental Oral Diseases, National Center for Geriatrics and Gerontology, Research Institute, 35 Gengo, Morioka, Obu 474-8511, Japan. Tel: +81 562 44 5651, ext. 5065; Fax: +81 562 46 8684; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 195-199, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X689604
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Brief Communication

Biodistribution of Infused Human Umbilical Cord Blood Cells in Alzheimer’s Disease-Like Murine Model

Jared Ehrhart,* Donna Darlington,† Nicole Kuzmin-Nichols,* Cyndy D. Sanberg,* Darrell R. Sawmiller,† Paul R. Sanberg,‡ and Jun Tan†‡

*Saneron CCEL Therapeutics, Inc, Tampa, FL, USA
†Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
‡Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

Human umbilical cord blood cells (HUCBCs), a prolific source of non-embryonic or adult stem cells, have emerged as effective and relatively safe immunomodulators and neuroprotectors, reducing behavioral impairment in animal models of Alzheimer’s disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, and stroke. In this report, we followed the bioavailability of HUCBCs in AD-like transgenic PSAPP mice and nontransgenic Sprague–Dawley rats. HUCBCs were injected into tail veins of mice or rats at a single dose of 1 × 106
or 2.2 × 106 cells, respectively, prior to harvesting of tissues at 24 h, 7 days, and 30 days after injection. For determination of HUCBC distribution, tissues from both species were subjected to total DNA isolation and polymerase chain reaction (PCR) amplification of the gene for human glycerol-3-phosphate dehydrogenase. Our results show a relatively similar biodistribution and retention of HUCBCs in both mouse and rat organs. HUCBCs were broadly detected both in the brain and several peripheral organs, including the liver, kidney, and bone marrow, of both species, starting within 7 days and continuing up to 30 days posttransplantation. No HUCBCs were recovered in the peripheral circulation, even at 24 h posttransplantation. Therefore, HUCBCs reach several tissues including the brain following a single intravenous treatment, suggesting that this route can be a viable method of administration of these cells for the treatment of neurodegenerative diseases.

Key words: Human umbilical cord blood cells (HUCBCs); Biodistribution; Polymerase chain reaction (PCR); Mice; Rats; Neurodegenerative diseases

Received September 3, 2013; final acceptance October 21, 2015. Online prepub date: September 25, 2015.
Address correspondence to Jared Ehrhart, Ph.D., Saneron CCEL Therapeutics Inc13014 N. Dale Mabry Highway, Suite 266, Tampa, FL 33618, USA. Tel: +1-(813) 624-3573; Fax: +1-(813) 969-0206; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it