Cell Transplantation 26(5) Abstracts

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Cell Transplantation, Vol. 26, pp. 735-751, 2017
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DOI: https://doi.org/10.3727/096368916X
694256
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Review

Conceptual Design and Procedure for an Autonomous Intramyocardial Injection Catheter

Weyland Cheng*† and Peter K. Law†

*Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan, P.R. China
†Cell Therapy Institute, Wuhan, P.R. China

This article discusses existing catheter systems and proposes a conceptual design and procedure for an autonomous cell injection catheter for the purpose of transferring committed myogenic or undifferentiated stem cells into the infarct boundary zones of the left ventricle. Operation of existing catheters used for cell delivery is far from optimal. Commercial injection catheters available are handheld devices operated manually by means of tip deflection and torque capabilities. Interventionists require a hefty learning curve and often encounter difficulties in catheter stabilization and infarct detection, resulting in lengthy operation times and nonprecise injections. We examined current technologies and proposed a design incorporating robotic positional control, feedback signals, and an adaptable operational sequence to overcome these problems. The design provides the basis for robotic catheter construction that is able to autonomously assist the physician in transferring myogenic cells to the left ventricle infarct boundary zones.

Key words: Autonomous catheter; Cell transfer therapy; Myocardial ischemia; Robotic catheters; Transendocardial injection

Received October 20, 2016; final acceptance February 9, 2017. Online prepub date: December 7, 2016.
Address correspondence to Weyland Cheng, Cell Therapy Institute, 858 Gaoxin Avenue, Building A2-2, East Lake Hi-Tech Development Zone, Wuhan, Hubei 430075, P.R. China. Tel: +86 15072349084; Fax: +86 027-59268323; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 753-764, 2017
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DOI: https://doi.org/10.3727/096368917X
695029
E-ISSN 1555-3892
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Hydrogen Sulfide Reduces Recruitment of CD11b+Gr-1+ Cells in Mice With Myocardial Infarction

Ting Wu,*1 Hua Li,†‡1 Bing Wu,* Lei Zhang,* San-wu Wu,* Jia-ning Wang,* and You-en Zhang*

*Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, P.R. China
†Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
‡State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai, P.R. China

The present study aimed to elucidate the mechanisms by which hydrogen sulfide (H2S) attenuates left ventricular remodeling after myocardial infarction (MI). MI was created in mice by left coronary artery ligation. One group of mice received injections of the H2S donor sodium hydrosulfide (NaHS) immediately before and 1 h after ligation, while the control group received saline alone. During both the subacute and chronic stages (1 and 4 weeks postinfarction, respectively), NaHS-treated mice demonstrated attenuation of cardiac dilation in the infarcted myocardium. Furthermore, fewer CD11b+Gr-1+
myeloid cells were detected in the infarct myocardium and peripheral blood from NaHS-treated mice, while more CD11b+Gr-1+ cells remained in the spleen and bone marrow in these animals. NaHS-treated mice also exhibited reduction in cardiomyocyte apoptosis, interstitial fibrosis, cardiac hypertrophy, and pulmonary edema, as well as overall better survival rates, when compared to controls. Thus, exogenous H2S has favorable effects on cardiac remodeling after MI. These observations further support the emerging concept that H2S treatment might have therapeutic benefits in the setting of ischemia-induced heart failure.

Key words: Hydrogen sulfide (H2S); Inflammation; Myeloid cells; Cardiac remodeling; Myocardial infarction (MI)

Received August 24, 2016; final acceptance March 2, 2017. Online prepub date: February 9, 2017.
1These authors provided equal contribution to this work.
Address correspondence to You-en Zhang, Ph.D., Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei University of Medicine, No. 39 Chaoyang Road, Shiyan 442000, P.R. China. Tel: +86-0719-8637305; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 765-772, 2017
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DOI: https://doi.org/10.3727/096368916X
693446
E-ISSN 1555-3892
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Developing a Rapid Algorithm to Enable Rapid Characterization of Alginate Microcapsules

Ka Hei Chan,* Rahul Krishnan,* Michael Alexander,* and Jonathan R. T. Lakey*†

*Department of Surgery, University of California, Irvine, CA, USA
†Department of Biomedical Engineering, University of California, Irvine, CA, USA

The islets of Langerhans are endocrine tissue clusters that secrete hormones that regulate the body’s glucose, carbohydrate, and fat metabolism, the most important of which is insulin, a hormone secreted by b-cells within the islets. In certain instances, a person’s own immune system attacks and destroys them, leading to the development of type 1 diabetes (T1D), a life-long condition that needs daily insulin administration to maintain health and prolong survival. Islet transplantation is a surgical procedure that has demonstrated the ability to normalize blood sugar levels for up to a few years, but the need for chronic immunosuppression relegates it to a last resort that is often only used sparingly and in seriously ill patients. Islet microencapsulation is a biomedical innovation designed to protect islets from the immune system by coating them with a biocompatible polymer, and this new technology has demonstrated various degrees of success in small- and large-animal studies. This success is significantly impacted by microcapsule morphology and encapsulation efficiency. Since hundreds of thousands of microcapsules are generated during the process, characterization of encapsulated islets without the help of some degree of automation would be difficult, time-consuming, and error prone due to inherent observer bias. We have developed an image analysis algorithm that can analyze hundreds of microencapsulated islets and characterize their size, shape, circularity, and distortion with minimal observer bias. This algorithm can be easily adapted to similar nano- or microencapsulation technologies to implement stricter quality control and improve biomaterial device design and success.

Key words: Alginate; Microcapsules; Type 1 diabetes (T1D); Image analysis; Automation

Received August 11, 2015; final acceptance December 12, 2016. Online prepub date: October 10, 2016.
Address correspondence to Jonathan R. T. Lakey, Ph.D., Clinical Islet Program, University of California, Irvine, 333 City Boulevard West, Suite 1600, Orange, CA 92868, USA. Tel: 714-456-5386; Fax: 714-456-6188; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 773-787, 2017
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DOI: https://doi.org/10.3727/096368916X
692654
E-ISSN 1555-3892
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StemCell Keep™ Is Effective for Cryopreservation of Human Embryonic Stem Cells by Vitrification

Akemi Ota,*† Kazuaki Matsumura,‡ Jun-Jae Lee,* Shoichiro Sumi,§ and Soung-Hyu Hyon

*Department of Medical Simulation Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
BioVerde Inc., Kyoto, Japan
‡School of Materials Science, Japan Advanced Institute of Science and Technology, Nomi, Ishikawa, Japan
§Department of Organ Reconstruction, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
¶Center for Fiber and Textile Science, Kyoto Institute for Technology, Kyoto, Japan

Safe and stable cryopreservation is critical for research involving human embryonic stem cells (hESCs). Dimethyl sulfoxide (DMSO) is a popular cryoprotective agent; however, its cytotoxicity cannot be ignored. Thus, there is a need for an alternate cryoprotectant. We reported previously that a novel cryopreservation reagent, StemCell Keep™ (SCK), was effective for cryopreserving human induced pluripotent stem cells (hiPSCs) by vitrification. Because hESCs and hiPSCs are not identical, the current study examined the use of SCK on hESCshESCs cryopreserved with SCK were thawed and cultured on SNL 76/7 cells, which were derived from a mouse fibroblast STO cell line transformed with neomycin resistance and murine LIF genes. After cryopreservation, cultured hESCs were assessed for their attachment ability and characterized by alkaline phosphatase (AP) and immunocytochemical (ICC) staining, fluorescence-activated cell sorting (FACS), reverse transcription polymerase chain reaction (RT-PCR), and karyotyping. The proliferation of SCK-cryopreserved hESCs cultured on SNL cells, or in feeder-free conditions, was higher than that of cells preserved in a solution of 2 M DMSO, 1 M acetamide, and 3 M propylene glycol (DAP). The cell number with SCK-cryopreserved hESCs was about twice that of hESCs cryopreserved in DAP. The pluripotency of SCK-cryopreserved hESCs was similar to that of DAP-cryopreserved hESCs based on AP staining. Data from ICC, FACS, and RT-PCR analyses showed that stem cell markers were continually expressed on SCK-cryopreserved hESCs. The teratoma assay showed that SCK-cryopreserved hESCs differentiated into three germ layers. Furthermore, SCK-cryopreserved hESCs had normal karyotypes. These data indicate that SCK was effective for cryopreservation of hESCs by vitrification.

Key words: Cryopreservation; Human embryonic stem cells (hESCs); Vitrification; Dimethyl sulfoxide free; Polyampholytes

Received December 28, 2015; final acceptance December 13, 2016. Online prepub date: August 5, 2016.
Address correspondence to Suong-Hyu Hyon, Center for Fiber and Textile Science, Kyoto Institute of Technology (KIT), Advanced Chemical Technology Center in Kyoto (ACT Kyoto) 402, Satellite Laboratory of KIT, 105 Jibucho, Fushimi-ku, Kyoto 612-8374, Japan. Tel: +81-75-748-1468; Fax: +81-75-748-1468; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it



Cell Transplantation, Vol. 26, pp. 789-794, 2017
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DOI: https://doi.org/10.3727/096368916X
693428
E-ISSN 1555-3892
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In Vitro Microvibration Increases Implantation Rate After Embryonic Cell Transplantation

Vladimir Isachenko,* Karl Sterzik,† Robert Maettner,† Evgenia Isachenko,* Plamen Todorov,‡ Gohar Rahimi,* Peter Mallmann,* Erwin Strehler,† Igor Pereligin,§ José Luis Alabart,¶ and Markus Merzenich#

*Department of Obstetrics and Gynecology, University Maternal Hospital, Cologne University, Cologne, Germany
†Department of Reproductive Medicine, Christian-Lauritzen Institute, Ulm, Germany
‡Institute of Biology and Immunology of Reproduction, Sofia, Bulgaria
§IVF Center “Genesis Dnepr,” Dnipro, Ukraine
Servicio de Investigación Agroalimentaria (DGA), Zaragoza, Spain
#MedEvent Dr. Merzenich GmbH, Cologne, Germany

In natural conditions the oocyte and embryo are subjected to ever-changing dynamic processes. However, the routine assisted reproductive technologies today involve the use of static in vitro culture systems. The objective was to determine whether there is any difference in the viability of embryos after in vitro culture under static and mechanical microvibration conditions. The viability of embryonic cells (9,624 embryos) generated from 4,436 couples after in vitro culture was evaluated. For groups ≤29, 30–34, 35–39, and ≥40 years, the following rates of high-quality embryos without fragmentation (two to four blastomeres on day 2; six to eight blastomeres and compacting morula on day 3; blastocyst, expanded and hatching blastocyst on day 5) were detected (static vs. vibration, respectively): 65% versus 71%, 44% versus 69%, 67% versus 76% (for statistically significant differences between respective rates in these three groups, p < 0.05), and 67% versus 66% ( p > 0.1). The following baby-take-home rates were determined for groups ≤29, 30–34, 35–39, and ≥40 years (static vs. vibration, respectively): 30% versus 31% ( p > 0.1, increasing only on the level of tendency), 28% versus 37%, 23% versus 29%, and 9% versus 15% (differences between respective rates in these three groups with p < 0.05). It was concluded that in vitro culture of embryos under microvibration (with a mimic of conditions in nature whereby oviductal fluid is mechanically agitated by the epithelial cilia) significantly increases the baby-take-home rate for patients 30 years and older.

Key words: Embryonic cell transplantation; In vitro culture; Microvibration; Baby-take-home rate

Received July 10, 2016; final acceptance December 14, 2016. Online prepub date: October 7, 2016.
Address correspondence to Dr. (SU) Vladimir Isachenko, Department of Obstetrics and Gynecology, University Maternal Hospital, Cologne University, Kerpener Str. 34, 50931 Cologne, Germany. Tel: +49-221-4784924; Fax: +49-221-4785247; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 795-803, 2017
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DOI: https://doi.org/10.3727/096368916X
693301
E-ISSN 1555-3892
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Changes in Sexual Behavior of Orchidectomized Rats Under Influence of Allotransplantation of Testicular Interstitial Cell Suspension

Bo Deng,* Tatyana Bondarenko,† and Oleksandr Pakhomov

*Department of Physiology, Henan University of Science and Technology, Henan, Luoyang, P.R. China
†Department of Cryoendocrinology, The Institute for Problems of Cryobiology and Cryomedicine, National Academy of Sciences of Ukraine, Kharkiv, Ukraine

Transplantation of hormone-producing cells is an experimental endocrine dysfunction treatment. The present study investigated the effects of orchidectomy (OE) and transplantation of interstitial cell suspension (ICS) on rat sexual behavior. Adult experimental animals were divided into two populations. One of these populations had sexual experience before the experiment and the other did not. Each population was divided into three groups: control group and two orchidectomizedgroups. One of the orchidectomized groups was treated with ICS, and the other was treated with the vehicle. The changes in the sexual behavior were investigated on the following parameters: mount latency (ML), intromission latency (IL), ejaculation latency (EL), mount frequency (MF), intromission frequency (IF), copulatory efficacy (CE), and IF/EL ratio. The investigation of these changes lasted 4 weeks after ICS transplantation. The parameters of sexual behavior reflected a decrease in sexual function after OE at the beginning of the observation, especially for the animals that did not have a sexual experience. However, it was shown that sexual activity increased in the following 4 weeks. We have indicated that the loss of gonads attenuated the capacity to acquire sexual experience; nonetheless, it did not mean that the animals completely lost this capacity. Transplantation of ICS facilitated the maintenance of male sexual behavior after OE, fractionally enlarged the size of regressed seminal vesicles of the animals, and increased the free testosterone (T) level. These findings suggest the ICS can be considered as a temporal source of androgens, which can facilitate a restoration of sexual activity.

Key words: Sexual behavior; Androgen level; Orchidectomy (OE); Testis transplantation

Received April 25, 2016; final acceptance February 9, 2017. Online prepub date: September 30, 2016.
Address correspondence to Oleksandr Pakhomov, Ph.D., Department of Cryoendocrinology, The Institute for Problems of Cryobiology and Cryomedicine, National Academy of Sciences of Ukraine, 23 Pereyaslavskaya Street, Kharkiv 61016, Ukraine. Tel: +380997642996; Fax: +380573730084; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 805-820, 2017
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DOI: https://doi.org/10.3727/096368916X
694274
E-ISSN 1555-3892
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Precise Regulation of miR-210 Is Critical for the Cellular Homeostasis Maintenance and Transplantation Efficacy Enhancement of Mesenchymal Stem Cells in Acute Liver Failure Therapy

Yingxia Liu,*1 Yongjia Xiong,†1 Feiyue Xing,† Hao Gao,‡ Xiaogang Wang,§ Liumin He,† Chaoran Ren,¶ Lei Liu,* Kwok-Fai So,¶ and Jia Xiao*†#

*State Key Discipline of Infectious Diseases, Shenzhen Third People’s Hospital, Shenzhen, P.R. China
†Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, P.R. China
‡Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, P.R. China
§Department of Cell Biology and Institute of Biomedicine, Jinan University, Guangzhou, P.R. China
¶Guangdong Medical Key Laboratory of Brain Function and Diseases, GMH Institute of Central Nervous System Regeneration, Jinan University, Guangzhou, P.R. China
#School of Biomedical Sciences, The University of Hong Kong, Hong Kong, P.R. China

Stem cell transplantation is a promising clinical strategy to cure acute liver failure. However, a low cell survival ratio after transplantation significantly impairs its therapeutic efficacy. This is partly due to insufficient resistance of transplanted stem cells to severe oxidative and inflammatory stress at the injury sites. In the current study, we demonstrated that a small molecule zeaxanthin dipalmitate (ZD) could enhance the defensive abilities against adverse stresses of human adipose-derived mesenchymal stem cells (hADMSCs) in vitro and increase their therapeutic outcomes of acute liver failure after transplantation in vivo. Treatment with ZD dramatically improved cell survival and suppressed apoptosis, inflammation, and reactive oxygen species (ROS) production of hADMSCs through the PKC/Raf-1/MAPK/NF-κB pathway to maintain a reasonably high expression level of microRNA-210 (miR-210). The regulation loop between miR-210 and cellular/mitochondrial ROS production was found to be linked by the ROS inhibitor iron–sulfur cluster assembly proteins (ISCU). Pretreatment with ZD and stable knockdown of miR-210 significantly improved and impaired the stem cell transplantation efficacy through the alteration of hepatic cell expansion and injury amelioration, respectively. Vehicle treatment with ZD did not pose any adverse effect on cell homeostasis or healthy animal. In conclusion, elevating endogenous antioxidant level of hADMSCs with ZD significantly enhances their hepatic tissue-repairing capabilities. Maintenance of a physiological level of miR-210 is critical for hADMSC homeostasis.

Key words: Acute liver failure (ALF); Mesenchymal stem cells (MSCs); MicroRNA-210; Zeaxanthin dipalmitate (ZD)

Received May 12, 2016; final acceptance January 9, 2017. Online prepub date: December 13, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Kwok-Fai So, Ph.D., Guangdong Medical Key Laboratory of Brain Function and Diseases, GMH Institute of Central Nervous System Regeneration, 8th Floor, 2nd Science and Technology Building, Jinan University, Guangzhou 510632, P.R. China. Tel: +86-20-85223563; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Jia Xiao, Ph.D., State Key Discipline of Infectious Diseases, 8th Floor, Medical Technology Building, Shenzhen Third People’s Hospital, Shenzhen 518112, P.R. China. Tel: +86-755-61236314; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 821-840, 2017
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DOI: https://doi.org/10.3727/096368916X
693662
E-ISSN 1555-3892
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Human Muse Cells, Nontumorigenic Pluripotent-Like Stem Cells, Have Liver Regeneration Capacity Through Specific Homing and Cell Replacement in a Mouse Model of Liver Fibrosis

Masahiro Iseki,*† Yoshihiro Kushida,* Shohei Wakao,* Takahiro Akimoto,* Masamichi Mizuma,† Fuyuhiko Motoi,† Ryuta Asada,‡ Shinobu Shimizu,§ Michiaki Unno,† Gregorio Chazenbalk,¶ and Mari Dezawa*

*Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
†Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
‡Translational Research Center, Gifu University Graduate School of Medicine, Gifu, Japan
§Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
¶Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA

Muse cells, a novel type of nontumorigenic pluripotent-like stem cells, reside in the bone marrow, skin, and adipose tissue and are collectable as cells positive for pluripotent surface marker SSEA-3. They are able to differentiate into cells representative of all three germ layers. The capacity of intravenously injected human bone marrow-derived Muse cells to repair an immunodeficient mouse model of liver fibrosis was evaluated in this study. The cells exhibited the ability to spontaneously differentiate into hepatoblast/hepatocyte lineage cells in vitro. They demonstrated a high migration capacity toward the serum and liver section of carbon tetrachloride-treated mice in vitro. In vivo, they specifically accumulated in the liver, but not in other organs except, to a lesser extent, in the lungs at 2 weeks after intravenous injection in the liver fibrosis model. After homing, Muse cells spontaneously differentiated in vivo into HepPar-1 (71.1 ± 15.2%), human albumin (54.3 ± 8.2%), and anti-trypsin (47.9 ± 4.6%)-positive cells without fusing with host hepatocytes, and expressed mature functional markers such as human CYP1A2 and human Glc-6-Pase at 8 weeks after injection. Recovery in serum, total bilirubin, and albumin and significant attenuation of fibrosis were recognized with statistical differences between the Muse cell-transplanted group and the control groups, which received the vehicle or the same number of a non-Muse cell population of MSCs (MSCs in which Muse cells were eliminated). Thus, unlike ESCs and iPSCs, Muse cells are unique in their efficient migration and integration into the damaged liver after intravenous injection, nontumorigenicity, and spontaneous differentiation into hepatocytes, rendering induction into hepatocytes prior to transplantation unnecessary. They may repair liver fibrosis by two simple steps: expansion after collection from the bone marrow and intravenous injection. A therapeutic strategy such as this is feasible and may provide significant advancements toward liver regeneration in patients with liver disease.

Key words: Pluripotent stem cells; Mesenchymal stem cells (MSCs); Liver cirrhosis; Hepatocytes; Fibrolysis

Received April 5, 2016; final acceptance February 1, 2017. Online prepub date: November 2, 2016.
Address correspondence to Mari Dezawa, M.D., Ph.D., Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. Tel: +81-22-717-8025; Fax: +81-22-717-8030; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 841-854, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368917X
694822
E-ISSN 1555-3892
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Phenotypical and Functional Characteristics of In Vitro-Expanded Adipose-Derived Mesenchymal Stromal Cells From Patients With Systematic Sclerosis

Chiara Capelli,* Eleonora Zaccara,† Paola Cipriani,‡ Paola Di Benedetto,‡ Wanda Maglione,† Romina Andracco,† Gabriele Di Luca,† Francesca Pignataro,† Roberto Giacomelli,‡ Martino Introna,* ClaudioVitali,§ and Nicoletta Del Papa†

*USS Centro di Terapia Cellulare “G. Lanzani,” USC Hematology, ASST Papa Giovanni XXIII, Bergamo, Italy
†Scleroderma Clinic, Rheumatology Department, ASST G. Pini-CTO, Milano, Italy
‡Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L’Aquila, L’Aquila, Italy
§Rheumatology Unit, Istituto San Giuseppe, Como, Italy

Mesenchymal stromal cells (MSCs) have received attention as an ideal source of regenerative cells because of their multipotent differentiation potential. Adipose tissue is an attractive source of MSCs. Recent studies have shown that autologous fat grafting may be effective in the treatment of systemic sclerosis (SSc), but no specific study exists that aimed at investigating whether adipose tissue-derived stromal cells (ADSCs) from SSc patients maintain normal phenotypic and functional characteristics. The purpose of the current study was to investigate whether ADSCs from patients with SSc (SSc-ADSCs) are phenotypically and functionally identical to those from healthy controls (HC-ADSCs). Adipose tissue samples were obtained from 10 patients with SSc and from 8 HCs. Both MSC populations were evaluated for their capacity to (a) express specific MSC surface antigens by flow cytometry analysis, (b) proliferate, (c) differentiate along the adipogenic and osteogenic lineages, (d) suppress in vitro lymphocyte proliferation induced by a mitogenic stimulus, and (e) support endothelial cell (EC) tube formation. ADSCs from SSc patients and HCs showed similar surface phenotype and multilineagedifferentiation capabilities. In PBMC proliferation inhibition assays, no significant differences were observed between SSc- and HC-ADSCs. Using ADSC/EC cocultures, both SSc- and HC-ADSCs improved tube formation by both HC- and SSc-ECs. This effect was enhanced under hypoxic conditions in all of the coculturesSSc-ADSCs exhibited the same phenotypic pattern, proliferation and differentiation potentials, and immunosuppressive properties as those from HCs. The proangiogenic activity shown by SSc-ADSCs, namely, under hypoxic conditions, suggests that autologous ADSC grafting may represent a possible therapeutic option for SSc.

Key words: Systemic sclerosis (SSc); Adipose tissue; Mesenchymal stromal cells (MSCs)

Received September 20, 2016; final acceptance February 28, 2017. Online prepub date: January 31, 2017.
Address correspondence to Nicoletta Del Papa, M.D., U.O.C. Day Hospital Reumatologia, ASST G. Pini-CTO, Piazza Cardinal Ferrari 1, 20122 Milano, Italy. Tel: +39-0258296415; Fax: +39-0258296495; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 855-866, 2017
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DOI: https://doi.org/10.3727/096368916X
693833
E-ISSN 1555-3892
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Are Adipose-Derived Stem Cells From Liver Falciform Ligaments Another Possible Source of Mesenchymal Stem Cells?

Sang Woo Lee,*† Jae Uk Chong,* Seon Ok Min,*† Seon Young Bak,† and Kyung Sik Kim*†‡

*Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
†Graduate Program of Nano Science and Technology, Graduate School of Yonsei University, Seoul, South Korea
‡Cell Therapy Center, Severance Hospital, Seoul, South Korea

Falciform ligaments in the liver are surrounded by adipose tissue. We investigated the capability of adipose-derived stem cells from human liver falciform ligaments (hLF-ADSCs) to differentiate into hepatic-type cells and confirmed the functional capacity of the cells. Mesenchymal stem cells (MSCs) were isolated from the liver falciform ligament and abdominal subcutaneous adipose tissue in patients undergoing partial hepatectomy for liver disease. Cells were cultivated in MSC culture medium. Properties of MSCs were confirmed by flow cytometry, RT-PCR analysis, immunocytochemistry assays, and multilineage differentiation. Hepatic induction was performed using a three-step differentiation protocol with various growth factors. Morphology, capacity for expansion, and characteristics were similar between hLF-ADSCs and adipose-derived stem cells from human abdominal subcutaneous adipose tissue (hAS-ADSCs). However, hematopoietic– and mesenchymal–epithelial transition (MET)-related surface markers (CD133, CD34, CD45, and E-cadherin) had a higher expression in hLF-ADSCs. The hepatic induction marker genes had a higher expression in hLF-ADSCs on days 7 and 10 after the hepatic induction. Albumin secretion was similar between hLF-ADSCs and hAS-ADSCs at 20 days after the hepatic induction. The hLF-ADSCs had a different pattern of surface marker expression relative to hAS-ADSCs. However, proliferation, multilineage capacity, and hepatic induction were similar between the cell types. Accordingly, it may be a useful source of MSCs for patients with liver disease.

Key words: Adipose tissue; Mesenchymal stem cells (MSCs); Liver; Organ specificity; Cell therapy

Received October 26, 2015; final acceptance January 31, 2017. Online prepub date: November 24, 2016.
Address correspondence to Kyung Sik Kim, M.D., Ph.D., Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-roSeodaemun-gu120-752 Seoul, South Korea. Tel: 82-2-2228-2125; Fax: 82-2-313-8289; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 867-878, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368917X
694705
E-ISSN 1555-3892
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Effect of Bone Marrow Aspirate Concentrate–Platelet-Rich Plasma on Tendon-Derived Stem Cells and Rotator Cuff Tendon Tear

Sun Jeong Kim,* Da Hyun Song,* Jong Wook Park,* Silvia Park,† and Sang Jun Kim*

*Department of Physical and Rehabilitation Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
†Department of Internal Medicine, Division of Hemato-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Bone marrow aspirate concentrates (BMACs) and platelet-rich plasma (PRP) are good sources to control the differentiation of tendon-derived stem cells (TDSCs), but there has been no study about the effect of the BMAC–PRP complex on TDSCs and tendinopathy. The aim of this study was to investigate the effect of BMAC–PRP on the TDSCs and to find the therapeutic effect of BMAC–PRP on the rotator cuff tendon tear. The chondrogenic and osteogenic potential of TDSCs decreased, but the adipogenic potential of TDSCs revealed no significant difference when they were cocultured with BMAC–PRP. Cell proliferation was significantly greater in TDSCs cocultured with BMAC–PRP than in TDSCs. The degree of wound closure (percentage) was different between TDSCs and TDSCs with BMAC–PRP. There was no significant difference in expression of collagen type I and type III in immunocytochemical staining in the presence of BMAC–PRP. Initial visual analog scale (VAS) score was 5.8 ± 1.9, which changed to 5.0 ± 2.3 at 3 weeks and 2.8 ± 2.3 at 3 months after the BMAC–PRP injection ( p < 0.01). The American Shoulder Elbow Surgeon score changed from 39.4 ± 13.0 at baseline to 52.9 ± 22.9 at 3 weeks and 71.8 ± 19.7 at 3 months after the injection p < 0.01). The initial torn area of the rotator cuff tendon was 30.2 ± 24.5 mm2, and this area was reduced to 22.5 ± 18.9 mm2
at 3 months, but the change was not significant p > 0.05). The data indicate that BMAC–PRP enhances the proliferation and migration of TDSCs and prevents the aberrant chondrogenic and osteogenic differentiation of TDSCs, which might provide a mechanistic basis for the therapeutic benefits of BMAC–PRP for rotator cuff tendon tear.

Key words: Bone marrow; Platelet; Rotator cuff; Tendon; Stem cells

Received May 28, 2016; final acceptance February 1, 2017. Online prepub date: January 20, 2017.
Address correspondence to Sang Jun Kim, Department of Physical and Rehabilitation Medicine, Samsung Medical Center, 50th Street, IrwonroGangnamgu, Seoul 06351, South Korea. Tel: +82-2-3410-6069; Fax: +82-2-3410-0057; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 879-890, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693789
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Human Bone Progenitor Cells for Clinical Application: What Kind of Immune Reaction Does Fetal Xenograft Tissue Trigger in Immunocompetent Rats?

Tanja C. Hausherr,* Katja Nuss,† Eric Thein,‡ Lee A. Applegate,§ and Dominique P. Pioletti*

*Laboratory of Biomechanical Orthopedics, Ecole Polytechnique Fédéreale de Lausanne, Lausanne, Switzerland
†Musculoskeletal Research Unit, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
‡Orthopedic and Traumatology Department, University Hospital of Lausanne (CHUV), Lausanne, Switzerland
§Regenerative Therapy Unit, Plastic and Reconstructive Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

The potential of human fetal bone cells for successful bone regeneration has been shown in vivo. In particular, it has been demonstrated that the seeding of these cells in porous poly-(L-lactic acid)/β-tricalcium phosphate scaffolds improved the bone formation compared to cell-free scaffolds in skulls of rats. However, even if the outcome is an improvement of bone formation, a thorough analysis concerning any immune responses, due to the implantation of a xenograft tissue, is not known. As the immune response and skeletal system relationship may contribute to either the success or failure of an implant, we were interested in evaluating the presence of any immune cells and specific reactions of human fetal cells (also called human bone progenitor cells) once implanted in femoral condyles of rats. For this purpose, (1) cell-free scaffolds, (2) human bone progenitor cells, or (3) osteogenic human bone progenitor cells within scaffolds were implanted over 3, 7, 14 days, and 12 weeks. The key finding is that human bone progenitor cells and osteogenic human bone progenitor cells do not trigger any particular specific immune reactions in immunocompetent rats but are noted to delay some bone formation.

Key words: Bone tissue engineering (BTE); Scaffold; Cell therapy; Human bone progenitor cells (hBPCs); Immune response

Received August 30, 2016; final acceptance February 8, 2017. Online prepub date: November 21, 2016.
Address correspondence to Professor Dominique P. Pioletti, Laboratory of Biomechanical Orthopedics, Ecole Polytechnique Fédérale de Lausanne, Station 9, CH-1015 Lausanne, Switzerland. Tel: +41 (0) 21 693 83 41; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 891-900, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368917X
695038
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Clinical Study of NeuroRegen Scaffold Combined With Human Mesenchymal Stem Cells for the Repair of Chronic Complete Spinal Cord Injury

Yannan Zhao,*1 Fengwu Tang,†1 Zhifeng Xiao,*1 Guang Han,†1 NuoWang,* Na Yin,† Bing Chen,* Xianfeng Jiang,† Chen Yun,† Wanjun Han,† Changyu Zhao,† Shixiang Cheng,† Sai Zhang,† and Jianwu Dai*

*State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, P.R. China
†Neurology and Neurosurgery Hospital, Affiliated Hospital of Logistics University of Chinese Armed Police Forces (CAPF), Tianjin, P.R. China

Regeneration of damaged neurons and recovery of sensation and motor function after complete spinal cord injury (SCI) are challenging. We previously developed a collagen scaffold, NeuroRegen, to promote axonal growth along collagen fibers and inhibit glial scar formation after SCI. When functionalized with multiple biomolecules, this scaffold promoted neurological regeneration and functional recovery in animals with SCI. In this study, eight patients with chronic complete SCI were enrolled to examine the safety and efficacy of implanting NeuroRegen scaffold with human umbilical cord mesenchymal stem cells (hUCB-MSCs). Using intraoperative neurophysiological monitoring, we identified and surgically resected scar tissues to eliminate the inhibitory effect of glial scarring on nerve regeneration. We then implanted NeuroRegen scaffold loaded with hUCB-MSCs into the resection sites. No adverse events (infection, fever, headache, allergic reaction, shock, perioperative complications, aggravation of neurological status, or cancer) were observed during 1 year of follow-up. Primary efficacy outcomes, including expansion of sensation level and motor-evoked potential (MEP)-responsive area, increased finger activity, enhanced trunk stability, defecation sensation, and autonomic neural function recovery, were observed in some patients. Our findings suggest that combined application of NeuroRegen scaffold and hUCB-MSCs is safe and feasible for clinical therapy in patients with chronic SCI. Our study suggests that construction of a regenerative microenvironment using a scaffold-based strategy may be a possible future approach to SCI repair.

Key words: Spinal cord injury (SCI); Scaffold; Mesenchymal stem cells (MSCs); Scar resection

Received October 16, 2016; final acceptance March 3, 2017. Online prepub date: February 9, 2017.
1These authors provided equal contribution to this work.
Address correspondence to Jianwu Dai, Ph.D., State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 3 NanyitiaoZhongguancun, Beijing 100190, P.R. China. Tel: 86-10-82614426; Fax: 86-10-82614420; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Sai Zhang, Neurology and Neurosurgery Hospital, Affiliated Hospital of Logistics University of Chinese Armed Police Forces (CAPF), Tianjin, P.R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 901-911, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693798
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Transgenic Expression of Glucagon-Like Peptide-1 (GLP-1) and Activated Muscarinic Receptor (M3R) Significantly Improves Pig Islet Secretory Function

Nizar I. Mourad,* Andrea Perota,† Daela Xhema,* Cesare Galli,† and Pierre Gianello*

*Pôle de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, Brussels, Belgium
Laboratorio di Tecnologie della RiproduzioneAvantea, Cremona, Italy

Porcine islets show notoriously low insulin secretion levels in response to glucose stimulation. While this is somehow expected in the case of immature islets isolated from fetal and neonatal pigs, disappointingly low secretory responses are frequently reported in studies using in vitro-maturated fetal and neonatal islets and even fully differentiated adult islets. Herein we show that b-cell-specific expression of a modified glucagonlike peptide-1 (GLP-1) and of a constitutively activated type 3 muscarinic receptor (M3R) efficiently amplifies glucose-stimulated insulin secretion (GSIS). Both adult and neonatal isolated pig islets were treated with adenoviral expression vectors carrying sequences encoding for GLP-1 and/or M3R. GSIS from transduced and control islets was evaluated during static incubation and dynamic perifusion assays. While expression of GLP-1 did not affect basal or stimulated insulin secretion, activated M3R produced a twofold increase in both first and second phases of GSIS. Coexpression of GLP-1 and M3R caused an even greater increase in the secretory response, which was amplified fourfold compared to controls. In conclusion, our work highlights pig islet insulin secretion deficiencies and proposes concomitant activation of cAMP-dependent and cholinergic pathways as a solution to ameliorate GSIS from pig islets used for transplantation.

Key words: Porcine islets; Insulin secretion; Xenotransplantation; Glucagon-like peptide-1 (GLP-1); Muscarinic receptor; Glucokinase

Received September 21, 2016; final acceptance January 20, 2017. Online prepub date: November 22, 2016.
Address correspondence to Pierre Gianello, M.D., Ph.D., Université Catholique de Louvain, SSS/IREC/CHEX, Avenue Hippocrate 55, Bte B1.55.04, B-1200 Brussels, Belgium. Tel: +(32)27645586; Fax: +(32)27645589; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 913-924, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368917X
695353
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Transplantation of Cultured Olfactory Bulb Cells Prevents Abnormal Sensory Responses During Recovery From Dorsal Root Avulsion in the Rat

Andrew Collins,* Daqing Li,* Stephen B. McMahon,† Geoffrey Raisman,*1 and Ying Li*

*Spinal Repair Unit, Department of Brain Repair and Rehabilitation, University College London Institute of Neurology, Queen Square, London, UK
†The Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King’s College London Guy’s Campus, London Bridge, London, UK

The central branches of the C7 and C8 dorsal roots were avulsed close to their entry point into the spinal cord in adult rats. The forepaw responses to heat and cold stimuli were tested at 1, 2, and 3 weeks after injury. Over this period, the paws were sensitive to both stimuli at 1–2 weeks and returned toward normal at 3 weeks. Immunohistology showed no evidence of axonal regeneration into the spinal cord in a control group of rats with avulsion only, implying that adjacent dorsal roots and their corresponding dermatomes were involved in the recovery. In a further group of rats, a mixture of bulbar olfactory ensheathing cells and olfactory nerve fibroblasts were transplanted into the gap between the avulsed roots and the spinal cord at the time of avulsion. These rats showed no evidence of either loss of sensation or exaggerated responses to stimuli at any of the time points from 1 to 3 weeks. Immunohistology showed that the transplanted cells formed a complete bridge, and the central branches of the dorsal root fibers had regenerated into the dorsal horn of the spinal cord. These regenerating axons, including Tuj1 and CGRP immunoreactive fibers, were ensheathed by the olfactory ensheathing cells. This confirms our previous demonstration of central regeneration by these transplants and suggests that such transplants may provide a useful means to prevent the development of abnormal sensations such as allodynia after spinal root lesions.

Key words: Transplantation; Pain; Spinal roots; Repair; Injury

Received January 4, 2017; final acceptance March 24, 2017. Online prepub date: March 23, 2017.
1Sadly, Dr. Geoffrey Raisman died on January 27, 2017, shortly after this manuscript was submitted.
Address correspondence to Dr. Andrew Collins, Spinal Repair Unit, Department of Brain Repair and Rehabilitation, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK. Tel: 02034484480; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it