Cell Transplantation 25(11) Abstracts

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Cell Transplantation, Vol. 25, pp. 1911-1923, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X692087
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Review

Clinical Benefits of Stem Cells for Chronic Symptomatic Systolic Heart Failure: A Systematic Review of the Existing Data and Ongoing Trials

Marie-France Poulin,* Anjan Deka,† Burhan Mohamedali,† and Gary L. Schaer†

*Division of Cardiovascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
†Division of Cardiology, Department of Medicine, Rush University Medical Center, Chicago, IL, USA

The benefits of stem cell therapy for patients with chronic symptomatic systolic heart failure due to ischemic and nonischemic cardiomyopathy (ICM and NICM, respectively) are unclear. We performed a systematic review of major published and ongoing trials of stem cell therapy for systolic heart failure and compared measured clinical outcomes for both types of cardiomyopathy. The majority of the 29 published studies demonstrated clinical benefits of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs). Left ventricular ejection fraction (LVEF) was improved in the majority of trials after therapy. Cell delivery combined with coronary artery bypass grafting was associated with the greatest improvement in LVEF. Left ventricular end-systolic volume (or diameter), New York Heart Association functional classification, quality of life, and exercise capacity were also improved in most studies after cell therapy. Most ICM trials demonstrated a significant improvement in perfusion defects, infarct size, and myocardial viability. Several larger clinical trials that are in progress employ alternative delivery modes, cell types, and longer follow-up periods. Stem cells are a promising therapeutic modality for patients with heart failure due to ICM or NICM. More data are required from larger blinded trials to determine which combination of cell type and delivery mode will yield the most benefit with avoidance of harm in these patient populations.

Key words: Systolic heart failure; Stem cells; Bone marrow-derived stem cells; Cell therapy; Ischemic cardiomyopathy (ICM); Nonischemic cardiomyopathy (NICM)

Received January 8, 2016; final acceptance August 21, 2016. Online prepub date: July 27, 2016.
Address correspondence to Gary L. Schaer, M.D., F.A.C.C., Rush University Medical Center, 1717 West Congress Parkway Suite 305 Kellogg Building, Chicago, IL 60612, USA. Tel: +1-312-942-6569; Fax: +1-312-563-8636; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1925-1943, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691411
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Phase I–II Clinical Trial Assessing Safety and Efficacy of Umbilical Cord Blood Mononuclear Cell Transplant Therapy of Chronic Complete Spinal Cord Injury

Hui Zhu,*† Waisang Poon,‡ Yansheng Liu,*† Gilberto Ka-Kit Leung,§ Yatwa Wong,§ Yaping Feng,* Stephanie C. P. Ng,‡ Kam Sze Tsang,‡ David T. F. Sun,‡ David K. Yeung,‡ Caihong Shen,*† Fang Niu,*† Zhexi Xu,*† Pengju Tan,*† Shaofeng Tang,* Hongkun Gao,*† Yun Cha,* Kwok-Fai So,¶#** Robert Fleischaker,†† Dongming Sun,‡‡ John Chen,** Jan Lai,** Wendy Cheng,** and Wise Young**‡‡

*Kunming General Hospital of Chengdu Military Command, Yunnan, P.R. China
†Kunming Tongren Hospital, Yunnan, P.R. China
‡Prince of Wales Hospital, Division of Neurosurgery, Department of Surgery, Chinese University of Hong Kong, Shatin, Hong Kong, SAR, P.R. China
§Queen Mary Hospital, University of Hong Kong, Hong Kong, SAR, P.R. China
¶Department of Ophthalmology and State Key Laboratory of Brain and Cognitive Science, The University of Hong Kong, SAR, P.R. China
#GHM Institute of CNS Regeneration, and Medical Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, P.R. China
**China Spinal Cord Injury Network, Hong Kong Science Technology Park, Hong Kong, SAR, P.R. China
††Vista Biological Laboratory, Carlsbad, CA, USA
‡‡W. M. Keck Center for Collaborative Neuroscience, Rutgers University, Piscataway, NJ, USA

Umbilical cord blood-derived mononuclear cell (UCB-MNC) transplants improve recovery in animal spinal cord injury (SCI) models. We transplanted UCB-MNCs into 28 patients with chronic complete SCI in Hong Kong (HK) and Kunming (KM). Stemcyte Inc. donated UCB-MNCs isolated from human leukocyte antigen (HLA ≥4:6)-matched UCB units. In HK, four patients received four 4-μl injections (1.6 million cells) into dorsal entry zones above and below the injury site, and another four received 8-μl injections (3.2 million cells). The eight patients were an average of 13 years after C5-T10 SCI. Magnetic resonance diffusion tensor imaging of five patients showed white matter gaps at the injury site before treatment. Two patients had fiber bundles growing across the injury site by 12 months, and the rest had narrower white matter gaps. Motor, walking index of SCI (WISCI), and spinal cord independence measure (SCIM) scores did not change. In KM, five groups of four patients received four 4-μl (1.6 million cells), 8-μl (3.2 million cells), 16-μl injections (6.4 million cells), 6.4 million cells plus 30 mg/kg methylprednisolone (MP), or 6.4 million cells plus MP and a 6-week course of oral lithium carbonate (750 mg/day). KM patients averaged 7 years after C3-T11 SCI and received 3–6 months of intensive locomotor training. Before surgery, only two patients walked 10 m with assistance and did not need assistance for bladder or bowel management before surgery. The rest could not walk or do their bladder and bowel management without assistance. At about a year (41–87 weeks), WISCI and SCIM scores improved: 15/20 patients walked 10 m (p = 0.001) and 12/20 did not need assistance for bladder management (p = 0.001) or bowel management (p = 0.002). Five patients converted from complete to incomplete (two sensory, three motor; p = 0.038) SCI. We conclude that UCB-MNC transplants and locomotor training improved WISCI and SCIM scores. We propose further clinical trials.

Key words: Umbilical cord blood; Spinal cord injury (SCI); Mononuclear cells; Lithium; Central pattern generator

Received August 3, 2015; final acceptance August 24, 2016. Online prepub date: April 5, 2016.
Address correspondence to Wise Young, Ph.D., M.D., Rutgers, State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854-8082, USA. Tel: +1-848-445-2061; Fax: +1-848-445-2063; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1945-1966, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691682
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Neural Stem Cells Derived From Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson’s Disease

Rodolfo Gonzalez,*1 Ibon Garitaonandia,*1 Maxim Poustovoitov,* Tatiana Abramihina,* Caleb McEntire,† Ben Culp,† Jordan Attwood,† Alexander Noskov,* Trudy Christiansen-Weber,* Marwa Khater,‡ Sergio Mora-Castilla,‡ CuongTo,‡ Andrew Crain,§ Glenn Sherman,* Andrey Semechkin,* Louise C. Laurent,‡ John D. Elsworth,¶ John Sladek,# Evan Y. Snyder,§ D. Eugene Redmond Jr.,†¶ and Russell A. Kern*

*International Stem Cell Corporation, Carlsbad, CA, USA
†Axion Research Foundation, Hamden, CT, USA
‡Department of Reproductive Medicine, University of California San Diego, La Jolla, CA, USA
§Stem Cell Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
¶Department of Psychiatry and Neurosurgery, Yale University School of Medicine, New Haven, CT, USA
#Department of Neurology, Pediatrics and Neuroscience, University of Colorado School of Medicine, Aurora, CO, USA

Cell therapy has attracted considerable interest as a promising therapeutic alternative for patients with Parkinson’s disease (PD). Clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD. However, the source of fetal tissue grafts is limited and ethically controversial. Human parthenogenetic stem cells offer a good alternative because they are derived from unfertilized oocytes without destroying potentially viable human embryos and can be used to generate an unlimited supply of neural cells for transplantation. We have previously reported that human parthenogenetic stem cellderived neural stem cells (hpNSCs) successfully engraft, survive long term, and increase brain dopamine (DA) levels in rodent and nonhuman primate models of PD. Here we report the results of a 12-month transplantation study of hpNSCs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned African green monkeys with moderate to severe clinical parkinsonian symptoms. The hpNSCs manufactured under current good manufacturing practice (cGMP) conditions were injected bilaterally into the striatum and substantia nigra of immunosuppressed monkeys. Transplantation of hpNSCs was safe and well tolerated by the animals with no dyskinesia, tumors, ectopic tissue formation, or other test article-related serious adverse events. We observed that hpNSCs promoted behavioral recovery; increased striatal DA concentration, fiber innervation, and number of dopaminergic neurons; and induced the expression of genes and pathways downregulated in PD compared to vehicle control animals. These results provide further evidence for the clinical translation of hpNSCs and support the approval of the world’s first pluripotent stem cell-based phase I/IIa study for the treatment of PD (Clinical Trial Identifier NCT02452723).

Key words: Parkinson’s disease (PD); Neural stem cells (NSCs); Human parthenogenetic stem cells (hpSCs); Pluripotent stem cells; Cell therapy

Received September 30, 2015; final acceptance August 10, 2016. Online prepub date: May 20, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Dr. Russell A. Kern, International Stem Cell Corporation, 5950 Priestly Drive, Carlsbad, CA 92008, USA. Tel: +1-760-940-6383; Fax: +1-760-476-0600; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1967-1977, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691457
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Reduces Neural Stem Cell Proliferation In Vitro and In Vivo

Jingji Jin,* Bethany Grimmig,† James Izzo,* Lecia A. M. Brown,* Charles Hudson,‡ Adam J. Smith,† Jun Tan,†‡§ Paula C. Bickford,†‡ and Brian Giunta*

*Department of Psychiatry and Behavioral Neurosciences, Neuroimmunology Laboratory, University of South Florida Morsani College of Medicine, Tampa, FL, USA
†Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA
‡Research Service, James A. Haley VA Hospital, Tampa, FL, USA
§Department of Psychiatry and Behavioral Neurosciences, Rashid Laboratory for Developmental Neurobiology, University of South Florida Morsani College of Medicine, Tampa, FL, USA

The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite combination antiretroviral therapy (cART). There is evidence that neural stem cells (NSCs) can migrate to sites of brain injury such as those caused by inflammation and oxidative stress, which are pathological features of HAND. Thus, reductions in NSCs may contribute to HAND pathogenesis. Since the HIV non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) has previously been associated with cognitive deficits and promotion of oxidative stress pathways, we examined its effect on NSCs in vitro as well as in C57BL/6J mice. Here we report that EFV induced a decrease in NSC proliferation in vitro as indicated by MTT assay, as well as BrdU and nestin immunocytochemistry.

In addition, EFV decreased intracellular NSC adenosine triphosphate (ATP) stores and NSC mitochondrial membrane potential (MMP). Further, we found that EFV promoted increased lactate dehydrogenase (LDH) release, activation of p38 mitogen-activated protein kinase (MAPK), and increased Bax expression in cultured NSCs. Moreover, EFV reduced the quantity of proliferating NSCs in the subventricular zone (SVZ) of C57BL/6J mice as suggested by BrdU, and increased apoptosis as measured by active caspase-3 immunohistochemistry. If these in vitro and in vivo models translate to the clinical syndrome, then a pharmacological or cell-based therapy aimed at opposing EFV-mediated reductions in NSC proliferation may be beneficial to prevent or treat HAND in patients receiving EFV.

Key words: Neural stem cells (NSCs); Efavirenz (EFV); Oxidative stress

Received January 11, 2016; final acceptance August 8, 2016. Online prepub date: April 8, 2016.
Address correspondence to Brian Giunta, Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Neurosciences, University of South Florida Morsani College of Medicine, 3515 E. Fletcher Avenue, Tampa, FL 33613, USA. Tel: 813-974-0616; Fax: 813-974-1130; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1979-1986, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X692195
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Voluntary Wheel Running Reverses the Decrease in Subventricular Zone Neurogenesis Caused by Corticosterone

Jada Chia-Di Lee,*†‡ Suk-Yu Yau,§ Tatia M. C. Lee,‡¶# Benson Wui-Man Lau,§ and Kwok-Fai So*†‡**††

*Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, P.R. China
†School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, P.R. China
‡The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong, P.R. China
§Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong, P.R. China
¶Laboratory of Neuropsychology, The University of Hong Kong, Hong Kong, P.R. China
#Laboratory of Cognitive Affective Neuroscience, The University of Hong Kong, Hong Kong, P.R. China
**Guangdong–Hong Kong–Macau Institute of CNS Regeneration (GHMICR) and Guangdong Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, P.R. China
††Joint International Research Laboratory of CNS Regeneration, Ministry of Education of PRC, Jinan University, Guangzhou, P.R. China

Adult neurogenesis within the dentate gyrus (DG) of the hippocampus can be increased by voluntary exercise but is suppressed under stress, such as with corticosterone (CORT). However, the effects of exercise and CORT on the cell proliferation of the other traditional neurogenic site, the subventricular zone (SVZ), have been reported with controversial results. In addition, the cotreatment effects of voluntary exercise and CORT have not been investigated. This study aims to determine whether CORT can suppress cell proliferation in the SVZ and whether this can be reversed by voluntary exercise. In the present study, the effect of chronic (4 weeks) CORT treatment and wheel running simultaneously on the SVZ cell proliferation of adult Sprague–Dawley rats was examined. The results showed that cell proliferation indicated by bromodeoxyuridine (BrdU) was increased by voluntary wheel running, whereas it was decreased by CORT treatment within the SVZ of the rats without running. For the rats with both CORT treatment and wheel running, it was found that the number of BrdU-labeled cells was approximately at the same level as the vehicle control group. Furthermore, these proliferating cells expressed doublecortin (DCX), a migrating neuroblast marker. Wheel running increased the percentage of BrdU-labeled cells expressing DCX in the SVZ, whereas CORT treatment decreased this percentage. Thus, chronic injection of CORT can decrease the number of proliferating cells, while wheel running can reverse the decrease in cell proliferation within the SVZ to normal levels. In addition, CORT can suppress the cell differentiation within the SVZ, and this was alleviated by wheel running as indicated by the double labeling of BrdU and DCX.

Key words: Adult neurogenesis; Corticosterone (CORT); Subventricular zone (SVZ); Voluntary exercise; Wheel running

Received April 12, 2016; final acceptance August 23, 2016. Online prepub date: July 7, 2016.
Address correspondence to Professor Kwok-Fai So, Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, P.R. China. Tel: (852) 2831-5366; Fax: (852) 2817-0941; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Dr. Benson Wui-Man Lau, Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hunghom, Hong Kong, P.R. China. Tel: (852) 2766-6712; Fax: (852) 2330-8656; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1987-2001, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691448
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Transplantation of Human Urine-Derived Stem Cells Transfected With Pigment Epithelium-Derived Factor to Protect Erectile Function in a Rat Model of Cavernous Nerve Injury

Qiyun Yang,*1 Xin Chen,*1 Tao Zheng,* Dayu Han,* Heng Zhang,* Yanan Shi,† Jun Bian,‡ Xiangzhou Sun,* Kai Xia,* Xiaoyan Liang,† Guihua Liu,† Yuanyuan Zhang,§ and Chunhua Deng*

*Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
†Reproductive Medicine Research Center, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China
‡Department of Urology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, P.R. China
§Wake Forest Institute of Regenerative Medicine, Wake Forest University, Winston Salem, NC, USA

The aim of this study was to investigate whether intracavernous injection of urine-derived stem cells (USCs) or USCs genetically modified with pigment epithelium-derived factor (PEDF) could protect the erectile function and cavernous structure in a bilateral cavernous nerve injury-induced erectile dysfunction (CNIED) rat model. USCs were cultured from the urine of six healthy male donors. Seventy-five rats were randomly divided into five groups (n = 15 per group): sham, bilateral cavernous nerve (CN) crush injury (BCNI), USC, USCGFP+, and USCGFP/PEDF+ groups. The sham group received only laparotomy without CN crush injury and intracavernous injection with phosphate-buffered saline (PBS). All of the other groups were subjected to BCNI and intracavernous injection with PBS, USCs, USCsGFP+, or USCsGFP/PEDF+, respectively. The total intracavernous pressure (ICP) and the ratio of ICP to mean arterial pressure (ICP/MAP) were recorded. The penile dorsal nerves, the endothelium, and the smooth muscle were assessed within the penile tissue. The USC and USCGFP/PEDF+ groups displayed more significantly enhanced ICP and ICP/MAP ratio (p < 0.05) 28 days after cell transplantation. Immunohistochemistry (IHC) and Western blot analysis demonstrated that the protection of erectile function and the cavernous structure by USCsGFP/PEDF+ was associated with an increased number of nNOS-positive fibers within the penile dorsal nerves, improved expression of endothelial markers (CD31 and eNOS) and a smooth muscle marker (smoothelin), an enhanced smooth muscle to collagen ratio, decreased expression of transforming growth factor-b1 (TGF-b1), and decreased cell apoptosis in the cavernous tissue. The paracrine effect of USCs and USCsGFP/PEDF+ prevented the destruction of erectile function and the cavernous structure in the CNIED rat model by nerve protection, thereby improving endothelial cell function, increasing the smooth muscle content, and decreasing fibrosis and cell apoptosis in the cavernous tissue.

Key words: Cavernous never injury; Erectile dysfunction (ED); Urine-derived stem cells (USCs); Pigment epithelium-derived factor (PEDF)

Received December 3, 2015; final acceptance July 19, 2016. Online prepub date: April 8, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Chunhua Deng, Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou, P.R. China. Tel: +8602087335633; Fax: +8602087332200; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Yuanyuan Zhang, Wake Forest Institute of Regenerative Medicine, Wake Forest University, 1834 Wake Forest Road, Winston-Salem, NC, USA. Tel: +13367131189; Fax: +13367137290; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 2003-2016, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691691
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Generation of Equine-Induced Pluripotent Stem Cells and Analysis of Their Therapeutic Potential for Muscle Injuries

Eun-Mi Lee,*† Ah-Young Kim,*† Eun-Joo Lee,*† Jin-Kyu Park,* Se-Il Park,‡ Ssang-Goo Cho,§ Hong Kyun Kim,¶ Shin-Yoon Kim,# and Kyu-Shik Jeong*†

*College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
†Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Republic of Korea
‡Cardiovascular Product Evaluation Center, College of Medicine, Yonsei University, Seoul, Republic of Korea
§Department of Animal Biotechnology, Animal Resources Research Center, Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Republic of Korea
¶Department of Ophthalmology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
#Skeletal Diseases Genome Research Center, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

Horse health has become a major concern with the expansion of horse-related industries and sports; the importance of healthy muscles for horse performance and daily activities is undisputed. Here we generated equineinduced pluripotent stem cells (E-iPSCs) by reprogramming equine adipose-derived stem cells (E-ADSCs) into iPSCs using a polycistronic lentiviral vector encoding four transcription factors (i.e., Oct4, Sox2, Klf4, and c-Myc) and then examined their pluripotent characteristics. Subsequently, established E-iPSCs were transplanted into muscle-injured Rag/mdx mice. The histopathology results showed that E-iPSC-transplanted mice exhibited enhanced muscle regeneration compared to controls. In addition, E-iPSC-derived myofibers were observed in the injured muscles. In conclusion, we show that E-iPSCs could be successfully generated from equine ADSCs and transplanted into injured muscles and that E-iPSCs have the capacity to induce regeneration of injured muscles.

Key words: Horse; Induced pluripotent stem cells (iPSCs); Muscle regeneration; Transplantation

Received December 20, 2015; final acceptance August 8, 2016. Online prepub date: May 25, 2016.
Address correspondence to Kyu-Shik Jeong, D.V.M., Ph.D., Department of Pathology, College of Veterinary Medicine, Kyungpook National University, 80 Daehakro, Bukgu, Daegu 41566, Republic of Korea. Tel: +82-53-950-5975; Fax: +82-53-950-5955; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 2017-2026, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691015
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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MyoD Overexpressed Equine Adipose-Derived Stem Cells Enhanced Myogenic Differentiation Potential

Soo-Eun Sung,*† Meeyul Hwang,*† Ah-Young Kim,*† Eun-Mi Lee,*† Eun-Joo Lee,*† Su-Kyeong Hwang,‡ Shin-Yoon Kim,§ Hong-Kyun Kim,¶ and Kyu-Shik Jeong*†

*Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
†Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Republic of Korea
‡Department of Pediatrics, Kyungpook National University Hospital, Daegu, Republic of Korea
§Skeletal Diseases Genome Research Center, Kyungpook National University Hospital, Daegu, Republic of Korea
¶Department of Ophthalmology, Kyungpook National University Hospital, Daegu, Republic of Korea

Mesenchymal stem cells could potentially be used in the clinical treatment of muscle disorders and muscle regeneration. Adipose-derived stem cells (ADSCs) can be easily isolated from adipose tissue, as opposed to stem cells of other tissues. We believe that cell therapy using ADSCs could be applied to muscle disorders in horses and other species. We sought to improve the myogenic differentiation potential of equine ADSCs (eqADSCs) using a MyoD lentiviral vector. MyoD lentiviruses were transduced into eqADSCs and selected using puromycin. Cells were cultured in differentiation media containing 5% horse serum, and after 5 days the MyoD-transduced cells differentiated into myogenic cells (MyoD-eqADSCs). Using green fluorescent protein (GFP), MyoD-eqADSCs were purified and transplanted into the tibialis anterior muscles of mice after they were injured with the myotoxin notexin. The mice were sacrificed to examine any regeneration in the tibialis anterior muscle 4 weeks after the MyoD-eqADSCs were injected. The MyoD-eqADSCs cultured in growth media expressed murine and equine MyoD; however, they did not express late differentiation markers such as myogenin (MYOG). When cells were grown in differentiation media, the expression of MYOG was clearly observed. According to our reverse transcription polymerase chain reaction and immunocytochemistry results, MyoD-eqADSCs expressed terminal myogenic phase genes, such as those encoding dystrophin, myosin heavy chain, and troponin I. The MyoD-eqADSCs fused to each other, and the formation of myotube-like cells from myoblasts in differentiation media occurred between days 5 and 14 postplating. In mice, we observed GFPpositive myofibers, which had differentiated from the injected MyoD-eqADSCs. Our approaches improved the myogenic differentiation of eqADSCs through the forced expression of murine MyoD. Our findings suggest that limitations in the treatment of equine muscle disorders could be overcome using ADSCs.

Key words: Adipose-derived stem cells (ADSCs); MyoD; Myogenic differentiation; Muscle regeneration therapy

Received September 30, 2015; final acceptance May 24, 2016. Online prepub date: February 17, 2016.
Address correspondence to Kyu-Shik Jeong, D.V.M., Ph.D., 201, Department of Pathology, College of Veterinary Medicine, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, Republic of Korea. Tel: +82-53-950-5975; Fax: +82-53-955-5955; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Hong-Kyun Kim, M.D., Ph.D., Department of Ophthalmology, Kyungpook National University Hospital 130 Dongdeok-ro, Jung-gu, Daegu, Republic of Korea. Tel: +82-53-420-5806; Fax: +82-53-426-6552; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 2027-2040, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X692032
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Xenotransplanted Pig Sertoli Cells Inhibit Both the Alternative and Classical Pathways of Complement-Mediated Cell Lysis While Pig Islets Are Killed

Kandis Wright,1 Rachel Dziuk,1 Payal Mital, Gurvinder Kaur, and Jannette M. Dufour

Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, USA

Xenotransplantation has vast clinical potential but is limited by the potent immune responses generated against xenogeneic tissue. Immune-privileged Sertoli cells (SCs) survive xenotransplantation long term (>90 days) without immunosuppression, making SCs an ideal model to identify xenograft survival mechanisms. Xenograft rejection includes the binding of natural and induced antibodies and the activation of the complement cascade. Using an in vitro cytotoxicity assay, wherein cells were cultured with human serum and complement, we demonstrated that neonatal pig SCs (NPSCs) are resistant to complement-mediated cell lysis and express complement inhibitory factors, membrane cofactor protein (MCP; CD46), and decay-accelerating factor (DAF; CD55) at significantly higher levels than neonatal pig islets (NPIs), which served as non-immune-privileged controls. After xenotransplantation into naive Lewis rats, NPSCs survived throughout the study, while NPIs were rejected within 9 days. Serum antibodies, and antibody and complement deposition within the grafts were analyzed. Compared to preformed circulating anti-pig IgM antibodies, no significant increase in IgM production against NPSCs or NPIs was observed, while IgM deposition was detected from day 6 onward in both sets of grafts. A late serum IgG response was detected in NPSC (days 13 and 20) and NPI (day 20) recipients. Consistently, IgG deposition was first detected at days 9 and 13 in NPSC and NPI grafts, respectively. Interestingly, C3 was deposited at days 1 and 3 in NPI grafts and only at day 1 in NPSC grafts, while membrane attack complex (MAC) deposition was only detected in NPI grafts (at days 1–4). Collectively, these data suggest NPSCs actively inhibit both the alternative and classical pathways of complement-mediated cell lysis, while the alternative pathway plays a role in rejecting NPIs. Ultimately, inhibiting the alternative pathway along with transplanting xenogeneic tissue from transgenic pigs (expressing human complement inhibitory factors) could prolong the survival of xenogeneic cells without immunosuppression.

Key words: Xenotransplantation; Sertoli cells (SCs); Complement inhibitors; Humoral immune response

Received December 14, 2015; final acceptance August 31, 2016. Online prepub date: July 14, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Dr. Jannette M. Dufour, Cell Biology and Biochemistry, 3601 4th St. STOP 6540, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. Tel: 806-743-2616; Fax: 806-743-2990; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Dr. Gurvinder Kaur, Cell Biology and Biochemistry, 3601 4th St. STOP 6540, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. Tel: 806-743-4106; Fax: 806-743-2990; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 2041-2050, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691673
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Immunogenicity of Anti-HLA Antibodies in Pancreas and Islet Transplantation

Benjamin Chaigne,* Kirsten Geneugelijk,† Benoit Bedat,‡ Mohamed Alibashe Ahmed,‡ Gideon Honger,§ Sophie de Seigneux,¶ Sandrine Demuylder-Mischler,‡ Thierry Berney,‡ Eric Spierings,† Sylvie Ferrari-Lacraz,* and Jean Villard*

*Transplantation Immunology Unit, Service of Immunology and Allergy and Service of Laboratory Medicine, Geneva University Hospital and Medical School, Geneva, Switzerland
†Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
‡Service of Transplantation and Visceral Surgery, Geneva University Hospital and Medical School, Geneva, Switzerland
§Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
¶Service of Nephrology, Geneva University Hospital and Medical School, Geneva, Switzerland

The aim of the current study was to characterize the anti-HLA antibodies before and after pancreatic islet or pancreas transplantation. We assessed the risk of anti-donor-specific antibody (DSA) sensitization in a single-center, retrospective clinical study at Geneva University Hospital. Data regarding clinical characteristics, graft outcome, HLA mismatch, donor HLA immunogenicity, and anti-HLA antibody characteristics were collected. Between January 2008 and July 2014, 18 patients received islet transplants, and 26 patients received a pancreas transplant. Eleven out of 18 patients (61.1%) in the islet group and 12 out of 26 patients (46.2%) in the pancreas group had anti-HLA antibodies. Six patients (33.3%) developed DSAs against HLA of the islets, and 10 patients (38.4%) developed DSAs against HLA of the pancreas. Most of the DSAs were at a low level. Several parameters such as gender, number of times cells were transplanted, HLA mismatch, eplet mismatch and PIRCHE-II numbers, rejection, and infection were analyzed. Only the number of PIRCHE-II was associated with the development of anti-HLA class II de novo DSAs. Overall, the development of de novo DSAs did not influence graft survival as estimated by insulin independence. Our results indicated that pretransplant DSAs at low levels do not restrict islet or pancreas transplantation [especially islet transplantation (27.8% vs. 15.4%)]. De novo DSAs do occur at a similar rate in both pancreas and islet transplant recipients (mainly of class II), and the immunogenicity of donor HLA is a parameter that should be taken into consideration. When combined with an immunosuppressive regimen and close follow-up, development of low levels of DSAs was not found to result in reduced graft survival or graft function in the current study.

Key words: Islet transplantation; Pancreas transplantation; Anti-HLA antibody; Sensitization; Eplet; PIRCHE

Received January 13, 2016; final acceptance August 19, 2016. Online prepub date: May 18, 2016.
Address correspondence to Jean Villard, Transplantation Immunology Unit, Service of Immunology and Allergy and Service of Laboratory Medicine, Geneva University Hospital and Medical School, 4 rue Gabrielle Perret-Gentil, 1211 Geneva, Switzerland. Tel: 0041 223729394; Fax: 0041 223729390; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 2051-2062, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691646
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Vascular Alterations in a Murine Model of Acute Graft-Versus-Host Disease Are Associated With Decreased Serum Levels of Adiponectin and an Increased Activity and Vascular Expression of Indoleamine 2,3-Dioxygenase

Peter M. Schmid,* Abdellatif Bouazzaoui,† Karin Schmid,† Christoph M. Birner,* Christian Schach,* Lars S. Maier,* Ernst Holler,† and Dierk H. Endemann*

*Department of Internal Medicine 2–Cardiology, University Medical Center Regensburg, Regensburg, Germany
†Department of Internal Medicine 3–Hematology and Oncology, University Medical Center Regensburg, Regensburg, Germany

Graft-versus-host disease (GVHD) is the limiting complication after bone marrow transplantation (BMT), and its pathophysiology seems to be highly influenced by vascular factors. Our study aimed at elucidating possible mechanisms involved in vascular GVHD. For this purpose, we used a fully MHC-mismatched model of BALB/c mice conditioned according to two different intensity protocols with total body irradiation and transplantation of allogeneic (C57BL/6) or syngeneic bone marrow cells and splenocytes. Mesenteric resistance arteries were studied in a pressurized myograph. We also quantified the expression of indoleamine 2,3-dioxygenase (IDO), endothelial (eNOS), and inducible NO synthase (iNOS), as well as several pro- and anti-inflammatory cytokines. We measured the serum levels of tryptophan (trp) and kynurenine (kyn), the kyn/trp ratio (KTR) as a marker of IDO activity, and adiponectin (APN). The myographic study showed a correlation of GVHD severity after allogeneic BMT with functional vessel alterations that started with increased vessel stress and ended in eccentric vessel remodeling, increased vessel strain, and endothelial dysfunction. These alterations were accompanied by increasing IDO activity and decreasing APN levels in the serum of allogeneic animals. The mRNA expression showed significantly elevated IDO, decreased eNOS, and elevation of most studied pro- and anti-inflammatory cytokines. Our study provides further data supporting the importance of vessel alterations in GVHD and is the first to show an association of vascular GVHD with hypoadiponectinemia and an increased activity and vascular expression of IDO. Whether there is also a causative involvement of these two factors in the development of GVHD needs to be further investigated.

Key words: Vascular graft-versus-host disease (GVHD); Indoleamine 2,3-dioxygenase (IDO); Adiponectin (APN); Cytokines

Received January 10, 2016; final acceptance August 4, 2016. Online prepub date: May 12, 2016.
Address correspondence to Peter M. Schmid, M.D., Department of Internal Medicine 2, University Medical Center Regensburg, 93042 Regensburg, Germany. Tel: +49 941 9447211; Fax: +49 941 9447213; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 2063-2069, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691998
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Autologous Adipose-Derived Mesenchymal Stromal Cells for the Treatment of Psoriasis Vulgaris and Psoriatic Arthritis: A Case Report

Miguel M. De Jesus, Jayson S. Santiago, Camille V. Trinidad, Melvin E. See, Kimberly R. Semon, Manuel O. Fernandez Jr., and Francisco S. Chung

Cellular Therapeutics Center, Makati Medical Center, Makati City, Metro Manila, Philippines

Psoriasis is a dermatologic disease of immune origins with no definitive cure. We report the Makati Medical Center experience of utilizing autologous mesenchymal stromal cells (MSCs) for one patient with psoriasis vulgaris (PV) and another with psoriatic arthritis (PA). Patients were educated and gave informed consent, according to the principles of the Declaration of Helsinki. The protocol was approved by the Cellular Transplantation Ethics Committee of the Makati Medical Center. Autologous MSCs were cultured from lipoaspirate and expanded in a clean room class 100 facility (Cellular Therapeutics Center, Makati Medical Center). MSCs were infused intravenously at a dose of 0.5–3.1 million cells/kg after complying with quality control parameters. Psoriasis area and severity index (PASI) evaluations were conducted by third-party dermatologists. The PA patient, who was previously unresponsive to standard treatment modalities, demonstrated a decrease in PASI (from 21.6 to 9.0, mild state after two infusions). No improvements were noted in joint pain until further treatment with etanercept and infliximab. The PV patient, who was previously dependent on methotrexate, showed a decrease in PASI from 24.0 to 8.3 after three infusions; this clinical improvement was sustained for 292 days (9.7 months) without methotrexate. The PV patient illustrated a marginal reduction in serum tumor necrosis factor-a (TNF-a), while significant (3.5- to 5-fold) decreases in reactive oxygen species (ROS) activity were noted. The ROS levels correlated with the clinical improvement of the PV patient. No serious adverse events were noted for either patient as a result of MSC infusions. This report demonstrates safe and tolerable transplantation of autologous MSCs for the treatment of psoriasis and warrants large clinical studies to investigate the long-term safety and efficacy of this approach.

Key words: Arthritis; Autoimmune; Mesenchymal stromal cells (MSCs); Psoriasis; Reactive oxygen species (ROS)

Received December 17, 2015; final acceptance August 8, 2016. Online prepub date: June 9, 2016.
Address correspondence to Francisco S. Chung, Ph.D., 2 Amorsolo Street, Makati City, Metro Manila 1229, Philippines. Tel: +632-8888-999 loc 3614; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 2071-2081, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691989
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Expansion of Hair Follicle Stem Cells Sticking to Isolated Sebaceous Glands to Generate In Vivo Epidermal Structures

Huishan Zhang,*1 Huashan Zhao,*1 Jingqiao Qiao,*1 Shoubing Zhang,† Shuang Liu,* Na Li,*‡ Xiaohua Lei,* Lina Ning,* Yujing Cao,* and Enkui Duan*

*State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, P.R. China
†Department of Histology and Embryology, School of Basic Medical Sciences, Anhui Medical University, Hefei, P.R. China
‡University of Chinese Academy of Sciences, Beijing, P.R. China

Hair follicle stem cells (HFSCs) are considered one of the useful donor cell types for skin regenerative medicine owing to their robust proliferative capacity and multipotency. However, methods for easily and effectively obtaining HFSCs from a limited skin biopsy are still lacking. Here we report a novel approach for obtaining a subpopulation of HFSCs from a small skin sample from the rat tail, which uses the sebaceous glands (SGs) to capture the adjacent HFSCs. By means of organ culture, keratinocytes were expanded from the detached SGs, which also included adherent HFSCs from the hair follicle that could be passaged at the single-cell level. These SG-captured keratinocytes strongly expressed the basal layer markers K14, integrin a6, and p63; the bulge stem cell marker K15; and the upper isthmus stem cell marker Plet1. Furthermore, we reconstituted new epidermis, hair follicles, and SGs from the SG-captured keratinocytes using an easily operated, modified skin reconstitution assay based on silicone gel sheeting. This study suggests that the SGs could be an accessible capturer to harvest the adjacent HFSC subpopulation, particularly when the donor tissue is limited.

Key words: Hair follicle stem cells (HFSCs); Hair follicle; Sebaceous glands (SGs); Skin reconstitution

Received January 31, 2016; final acceptance August 25, 2016. Online prepub date: June 9, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Enkui Duan, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing 100101, P.R. China. Tel: +86-10-64807310; Fax: +86-10-64807310; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it