Cell Transplantation 25(2) Abstracts

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Cell Transplantation, Vol. 25, pp. 201-215, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688128
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Xenogeneic Mesenchymal Stromal Cells Improve Wound Healing and Modulate the Immune Response in an Extensive Burn Model

Carolina Caliari-Oliveira,*† Juliana Navarro Ueda Yaochite,*† Leandra Náira Zambelli Ramalho,‡ Patrícia Vianna Bonini Palma,† Daniela Carlos,* Fernando de Queiróz Cunha,§ Daurea Abadia De Souza,¶ Marco Andrey Cipriani Frade,# Dimas Tadeu Covas,†# Kelen Cristina Ribeiro Malmegrim,†** Maria Carolina Oliveira,†# and Julio César Voltarelli (in memoriam)

*Department of Biochemistry and Immunology, Basic and Applied Immunology Program, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
†Center for Cell-Based Therapy (CEPID-FAPESP), Regional Blood Center of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
‡Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
§Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
¶Department of Internal Medicine, School of Medicine of Federal University of Uberlândia, Minas Gerais, Brazil
#Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
**Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil

Major skin burns are difficult to treat. Patients often require special care and long-term hospitalization. Besides specific complications associated with the wounds themselves, there may be impairment of the immune system and of other organs. Mesenchymal stromal cells (MSCs) are a recent therapeutic alternative to treat burns, mainly aiming to accelerate the healing process. Several MSC properties favor their use as therapeutic approach, as they promote angiogenesis, stimulate regeneration, and enhance theimmunoregulatory function. Moreover, since patients with extensive burns require urgent treatment and because the expansion of autologous MSCs is a time-consuming process, in this present study we chose to evaluate the therapeutic potential of xenogeneic MSCs in the treatment of severe burns in rats. MSCs were isolated from mouse bone marrow, expanded in vitro, and intradermally injected in the periphery of burn wounds. MSC-treated rats presented higher survival rates (76.19%) than control animals treated with PBS (60.86%, p < 0.05). In addition, 60 days after the thermal injury, the MSC-treated group showed larger proportion of healed areas within the burn wounds (90.81 ± 5.05%) than the PBS-treated group (76.11 ± 3.46%, p = 0.03). We also observed that CD4+
and CD8+ T cells in spleens and in damaged skin, as well as the percentage of neutrophils in the burned area, were modulated by MSC treatment. Plasma cytokine (TGF-β, IL-10, IL-6, and CINC-1) levels were also altered in the MSC-treated rats, when compared to controls. Number of injected GFP+ MSCs progressively decreased over time, and 60 days after injection, few MSCs were still detected in the skin of treated animals. This study demonstrates the therapeutic effectiveness of intradermal application of MSCs in a rat model of deep burns, providing basis for future regenerative therapies in patients suffering from deep burn injuries.

Key words: Burns; Mesenchymal stromal cells (MSCs); Cell therapy; Regenerative medicine; Immunomodulation

Received December 11, 2014; final acceptance May 1, 2015. Online prepub date: May 7, 2015.
Address correspondence to Carolina Caliari-Oliveira, Department of Biochemistry and Immunology, Basic and Applied Immunology Program, Ribeirão Preto Medical School, University of São Paulo, Tenente Catão Roxo, 2501, Monte Alegre, 14051-140, Ribeirão Preto, São Paulo, Brazil. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 217-228, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688182
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Characterization of HLA-G and Related Immunosuppressive Effects in Human Umbilical Cord Stroma-Derived Stem Cells

Dah-Ching Ding,*†‡ Hsiang-Lan Chou,‡ Yu-Hsun Chang,†§ Wei-Ting Hung,‡ Hwan-Wun Liu,†¶ and Tang-Yuan Chu*†

*Department of Obstetrics and Gynecology, Buddhist Tzu-Chi Buddhist General Hospital, Hualien, Taiwan
†Graduate Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
‡Stem Cell Laboratory, Department of Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
§Department of Pediatrics, Buddhist Tzu-Chi Buddhist General Hospital, Hualien, Taiwan
¶Department of Occupational Medicine, Buddhist Tzu-Chi General Hospital, Hualien, Taiwan

Mesenchymal stem cells (MSCs) and especially those derived from fetal tissues exert a potent immunosuppressive effect that can be enhanced under inflammatory conditions. This study aimed to explore the immunosuppressive properties of human umbilical cord mesenchymal stem cells (HUCMSCs). We found that HLA-G, the nonclassical HLA allele with strong immune-inhibitory properties, was much more expressed on the HUCMSCs than on MSCs of other origins. Flow cytometry revealed that 90.8% of the HUCMSCs expressed HLA-G. RT-PCR revealed expression of HLA-G1, HLA-G5, and HLA-G7 in all of four HUCMSC lines. In a mixed lymphocyte reaction assay, the HUCMSCs inhibited the proliferation of lymphocytes by 35 ± 3% and could be reversed by treatment with an HLA-G blocking antibody. Upon coculture with the HUCMSCs, peripheral blood mononuclear cells expressed lower levels of proinflammatory mediators such as IL-6, TNF-α, and VEGF-α. This immunosuppressive effect was enhanced when the HUCMSCs were pretreated with IFN-γ, such that the expression of HLA-G was highly activated and HLA-DR diminished. The same phenomenon was not observed in MSCs derived from bone marrow or the placenta. In a xenograft rejection assay, the HUCMSCs survived in immunocompetent mice, whereas primary fibroblasts did not survive. This study confirms the HLA-G-related immunosuppressive property of HUCMSCs, which is more potent than MSCs of other origin. A good tolerance of this mesenchymal stem cell in allogeneic transplantation can thus be anticipated.

Key words: Umbilical cord; Mesenchymal stem cells (MSCs); Immunosuppression; Mixed lymphocyte reaction; Histocompatibility locus antigen-G

Received May 21, 2014; final acceptance April 21, 2015. Online prepub date: June 3, 2015.
Address correspondence to Tang-Yuan Chu, M.D., Ph.D., Department of Obstetrics and Gynecology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan, R.O.C. Tel: +886-3-8561825, ext. 2224; Fax: +886-3-8577161; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 229-242, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687967
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Influence of Immunogenicity of Allogeneic Bone Marrow Mesenchymal Stem Cells on Bone Tissue Engineering

JingGuo Wu,1 Qian Wang,1 Xin Fu, XiaoWei Wu, CongMin GuJianHai Bi, FangNan Xie, Ning Kang, Xia Liu, Li Yan, YiLin Cao, and Ran Xiao

Research Center of Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China

Allogeneic bone marrow mesenchymal stem cell (allo-BMSC)-based tissue-engineered bone (TEB) has great potential for bone defect repair. However, the immunogenicities and biological roles of allo-BMSCs are still controversial. In this study, we established an animal model of critical-sized mandibular defect in beagle dogs and compared the repairing effects of allo-BMSC-based TEB with autogenic BMSC (auto-BMSC)-based TEB without the administration of immunosuppressants. During the first 2 weeks postimplantation, a transient immune response in the allo-BMSC group was detected with an increase in proinflammation cytokines TNF-α, IFN-γ, and IL-2, a declination of anti-inflammation cytokine IL-10, and an increase in percentages of CD4+
and CD8+ T-cell subsets in peripheral blood. Nevertheless, there was no significant difference in bone union achievement, bone mineral density, and biomechanical properties between the two groups at 12 and 24 weeks postimplantation. Further subcutaneous implantation of allo-BMSCs/scaffold also exhibited the similar transient immune responses in the first 2 weeks postimplantation but followed by a decreased bone formation at 4 and 8 weeks postimplantation. These findings indicate that allo-BMSCs can induce a transient immunoreaction, which may temporally delay the osteogenesis of allo-BMSC/scaffold complex in early stage of in vivo implantation, whereas the long-term engineered bone formation was not affected.

Key words: Bone tissue engineering; Allogeneic bone marrow mesenchymal stem cells (allo-BMSCs); Immunogenicity; Mandibular bone defect; Ectopic implantation

Received October 9, 2014; final acceptance March 12, 2015. Online prepub date: April 7, 2015.
1These authors provided equal contribution to this work.
Address correspondence to Ran Xiao, Research Center of Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P. R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or YiLin Cao, Research Center of Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, P. R. China. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 243-259, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688470
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Effects of Transplantation of CTLA4Ig-Overexpressing Adipose Tissue-Derived Mesenchymal Stem Cells in Mice With Sustained Severe Rheumatoid Arthritis

Eun Wha Choi,*† Il Seob Shin,‡ Ji Woo Song,* MinJae Lee,* Tae Won Yun,* Jehoon Yang,*† Kyu-Sil Choi,*† and Sung-Joo Kim*§¶

*Laboratory Animal Research Center, Samsung Biomedical Research Institute, Gangnam-gu, Seoul, Republic of Korea
†School of Medicine, Sungkyunkwan University, Gangnam-gu, Seoul, Republic of Korea
Biostar Stem Cell Research Center, K-STEMCELL, Geumcheon-gu, Seoul, Republic of Korea
§Transplantation Research Center, Samsung Biomedical Research Institute, Samsung Medical Center, Gangnam-gu, Seoul, Republic of Korea
¶Department of Surgery, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Republic of Korea

CTLA4Ig has therapeutic potential for rheumatoid arthritis patients unresponsive to methotrexate (MTX) or TNF-α blockers. However, recombinant CTLA4Ig proteins are short acting and expensive. Adipose tissue-derived mesenchymal stem cells (ASCs) present an ideal stem cell source for practical regenerative medicine due to their abundant availability and their beneficial properties including immunomodulation, homing activity, paracrine effects, and differentiation ability. Therefore, we aimed to determine whether CTLA4Ig and human ASCs show synergistic effects on immunomodulation and clinical improvement of sustained severe rheumatoid arthritis in a mouse model. hASCs overexpressing CTLA4Ig (CTLA4Ig–hASC) were serially transplanted into mice with collagen-induced arthritis. Arthritic mice were subjected to four treatments based on their arthritis score on day 62 postimmunization: control (C group), hASC (H group), CTLA4Ig–hASC (CT group), and MTX (MTX group). A group of healthy mice was used as a normal control (N). Mice in the N and C groups were infused with 150 μl saline, and 2 × 106
hASCs or CTLA4Ig–hASCs in 150 μl of saline were intravenously administered to those in the H and CT groups, respectively, on days 63, 70, 77, and 84 after CII immunization. About 1 mg/kg of methotrexate was intraperitoneally administered to the MTX group three times a week for 4 weeks. Serial hASC and CTLA4Ig–hASC transplantation modulated various cytokines and chemokines related to the development of rheumatoid arthritis. Both treatments protected against destruction of cartilage, with CTLA4Ig–hASCs being most effective. Serum levels of CII autoantibodies and C-telopeptide of type II collagen were significantly low in the group transplanted with CTLA4Ig–hASCs. In vitro, ASC and CTLA4Ig–hASC treatment significantly decreased T-bet and GATA-3 expression in splenocytes from arthritic mice, and CTLA4Ig–hASC treatment significantly increased the ratio of Treg/Th17 (CD4+CD25+FoxP3+/CD4+CD25+RORγt) cells. Serial hASC and CTLA4Ig–hASC transplantation offers promising treatment for rheumatoid arthritis, and CTLA4Ig–hASCs showed stronger therapeutic effects than nontransduced hASCs.

Key words: Rheumatoid arthritis; CTLA4Ig; Adipose tissue-derived mesenchymal stem cells (ASCs); Collagen-induced arthritis; Autoimmune disease

Received March 12, 2014; final acceptance June 17, 2015. Online prepub date: June 17, 2015.
Address correspondence to Eun Wha Choi, D.V.M., Ph.D., Research Associate Professor, Laboratory Animal Research Center, Samsung Biomedical Research Institute, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Republic of Korea. Tel: 82-2-3410-3700; Fax: 82-2-3410-1885; E-mail: vet.cew@gmail. com or Sung-Joo Kim, M.D., Ph.D., Professor, Transplantation Research Center, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea. Tel: 82-2-3410-3476; Fax: 82-2-3410-0040; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 261-273, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688155
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Adipose-Derived Mesenchymal Stem Cells (ADSCs) With the Potential to Ameliorate Platelet Recovery, Enhance Megakaryopoiesis, and Inhibit Apoptosis of Bone Marrow Cells in a Mouse Model of Radiation-Induced Thrombocytopenia

Jiamin Zhang,* Shiyuan Zhou,* Yi Zhou,* Feier Feng,* Qianming Wang,* Xiaolu Zhu,* Jingzhong Zhao,† Haixia Fu,* Meng Lv,* Huisheng Ai,‡ Xiaojun Huang,* and Xiaohui Zhang*

*Peking University People’s Hospital, Peking University Institute of Hematology, Beijing, China
†Peking University People’s Hospital, Department of Clinical Laboratory, Beijing, China
‡Department of Hematology, Affiliated Hospital to the Academy of Military Medicine Science, Beijing, China

Substantial damage to the bone marrow can be caused by exposure to radiation, which can then develop into severe thrombocytopenia. In this study, we investigated the in vivo impact of adipose-derived mesenchymal stem cells (ADSCs) on megakaryopoiesisand platelet recovery in irradiated mice. Radiation markedly reduced peripheral blood counts. Recovery of both platelets and WBCs was better in the ADSC-treated group compared with the saline group and the fibroblast group 21 days after irradiation. A significant increase in the total CFU and MK-CFU after irradiation was observed in the ADSC group compared with the saline group and the fibroblast group. Further, the proportion of CD41+
cells in the ADSC group was significantly higher than that in the saline group and the fibroblast group. ADSC treatment significantly improved the cellularity and decreased the apoptotic cells in the bone marrow while normal fibroblasts did not. Administration of ADSCs upregulated protein expression of phosphorylatedAkt and Bcl-xL, whereas the expression of Bax, a protein related to apoptosis, was significantly lower in the ADSC group. In conclusion, this study suggests that ADSCs were capable of promoting platelet recovery, improving megakaryopoiesis, and inhibiting apoptosis of bone marrow cells in irradiated mice. The antiapoptotic effect of ADSCs is likely to be mediated via the PI3K/Akt pathway. These findings may provide a scientific basis for using ADSCs as a new therapy after irradiation.

Key words: Adipose-derived mesenchymal stem cells (ADSCs); Radiation; Thrombocytopenia; Megakaryocytopoiesis; Apoptosis

Received September 12, 2014; final acceptance April 17, 2015. Online prepub date: May 13, 2015.
Address correspondence to Xiaohui Zhang, Peking University People’s Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, China. Tel: +86 (010) 88324577; Fax: +86 (010) 88324577; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  orXiaojun Huang, Peking University People’s Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Xicheng District, Beijing, China. Tel: +86 (010) 88324577; Fax: +86 (010) 88324577; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 275-282, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688489
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Evidence of a Pivotal Role for the Distal Part of the Complement Cascade in the Diurnal Release of Hematopoietic Stem Cells Into Peripheral Blood

Sylwia Borkowska,*† Malwina Suszynska,* Janina Ratajczak,† and Mariusz Z. Ratajczak*‡

*Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, KY, USA
†Department of Physiology, Pomeranian Medical University, Szczecin, Poland
‡Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland

We found that diurnal activation of the three evolutionarily ancient proteolytic cascades in peripheral blood (PB), namely, the complement, coagulation, and fibrinolytic cascades, late at night or in the early morning hours, precedes the diurnal release of hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM) into PB in wild-type mice. Moreover, activation of the distal part of the complement cascade (ComC), involving cleavage of the fifth component (C5), seems to play a crucial role in pharmacological mobilization of HSPCs. In order to shed more light on the role of diurnal rhythms in the egress of HSPCs, we studied diurnal changes in the number of circulating HSPCs in C5-deficient mice and did not observe diurnal changes in the number of these cells circulating in PB in C5
−/− animals. Based on this finding, we conclude that activation of the distal part of the ComC, C5 cleavage, and release of C5a and desArgC5a are required in executing the diurnal release of HSPCs from BM into PB. Moreover, the fact that C5−/− mice still displayed normal activation of the coagulation and fibrinolytic cascades indicates that, of all the proteolytic cascades, the ComC is the dominant player regulating diurnal egress of HSPCs.

Key words: Diurnal rhythm; Circadian rhythm; Complement cascade (ComC); Fifth component (C5); Hematopoietic stem cells

Received May 18, 2015; final acceptance June 17, 2015. Online prepub date: June 17, 2015.
Address correspondence to Professor Mariusz Z. Ratajczak M.D., Ph.D., Stella and Henry Hoenig Endowed Chair, Professor and Director Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY 40202, USA. Tel: (502) 852-1788; Fax: (502) 852-3032; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 283-292, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688146
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Transplanted Peripheral Blood Stem Cells Mobilized by Granulocyte Colony-Stimulating Factor Promoted Hindlimb Functional Recovery After Spinal Cord Injury in Mice

Hiroshi Takahashi,* Masao Koda,* Masayuki Hashimoto,* Takeo Furuya,* Tsuyoshi Sakuma,* Kei Kato,* Akihiko Okawa,* Taigo Inada,* Koshiro Kamiya,* Mitsutoshi Ota,* Satoshi Maki,* Kazuhisa Takahashi,* Masashi Yamazaki,† and Chikato Mannoji

*Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
†Department of Orthopaedic Surgery, University of Tsukuba, Tsukuba-City, Ibaraki, Japan
‡Department of Orthopaedic Surgery, Chiba Aoba Municipal Hospital, Chiba, Japan

Granulocyte colony-stimulating factor (G-CSF) mobilizes peripheral blood stem cells (PBSCs) derived from bone marrow. We hypothesized that intraspinal transplantation of PBSCs mobilized by G-CSF could promote functional recovery after spinal cord injury. Spinal cords of adult nonobese diabetes/severe immunodeficiency mice were injured using an Infinite Horizon impactor (60 kdyn). One week after the injury, 3.0 μl of G-CSF-mobilized human mononuclear cells (MNCs; 0.5 × 105/μl), G-CSF-mobilized human CD34-positive PBSCs (CD34; 0.5 × 105/μl), or normal saline was injected to the lesion epicenter. We performed immunohistochemistry. Locomotor recovery was assessed by Basso Mouse Scale. The number of transplanted human cells decreased according to the time course. The CD31-positive area was significantly larger in the MNC and CD34 groups compared with the vehicle group. The number of serotonin-positive fibers was significantly larger in the MNC and CD34 groups than in the vehicle group. Immunohistochemistry revealed that the number of apoptotic oligodendrocytes was significantly smaller in cell-transplanted groups, and the areas of demyelination in the MNC- and CD34-transplanted mice were smaller than that in the vehicle group, indicating that cell transplantation suppressed oligodendrocyte apoptosis and demyelination. Both the MNC and CD34 groups showed significantly better hindlimb functional recovery compared with the vehicle group. There was no significant difference between the two types of transplanted cells. Intraspinal transplantation of G-CSF-mobilized MNCs or CD34-positive cells promoted angiogenesis, serotonergic fiber regeneration/sparing, and preservation of myelin, resulting in improved hindlimbfunction after spinal cord injury in comparison with vehicle-treated control mice. Transplantation of G-CSF-mobilized PBSCs has advantages for treatment of spinal cord injury in the ethical and immunological viewpoints, although further exploration is needed to move forward to clinical application.

Key words: Granulocyte colony-stimulating factor (G-CSF); Peripheral blood stem cells (PBSCs); Cell transplantation; Angiogenesis, Spinal cord injury (SCI)

Received October 31, 2014; final acceptance April 21, 2015. Online prepub date: May 13, 2015.
Address correspondence to Masao Koda, M.D., Ph.D., Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 2608670, Japan. Tel: +81-43-226-2117; Fax: +81-43-226-2116; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 293-299, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688551
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Functional Repair of Rat Corticospinal Tract Lesions Does Not Require Permanent Survival of an Immunoincompatible Transplant

Ying Li, Daqing Li, and Geoffrey Raisman

Spinal Repair Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, UK

Cell transplantation is one of the most promising strategies for repair of human spinal cord injuries. Animal studies from a number of laboratories have shown that transplantation of olfactory ensheathing cells cultured from biopsies of the olfactory bulb mediate axonal regeneration and remyelination and restore lost functions in spinal cord injuries. For translation from small laboratory experimental injuries to the large spinal cord injuries encountered in human patients the numbers of cells that can be obtained from a patient’s own olfactory bulb becomes a serious limiting factor. Furthermore, removal of an olfactory bulb requires invasive surgery and risks unilateral anosmia. We here report that xenografted mouse bulbar olfactory ensheathing cells immunoprotectedby daily cyclosporine restore directed forepaw reaching function in rats with chronic C1/2 unilateral corticospinal tract lesions. Once function had been established for 10 days, cyclosporine was withdrawn. Thirteen out of 13 rats continued to increase directed forepaw reaching. Immunohistochemistry shows that in all cases neurofilament-positive axons were present in the lesion, but that the grafted cells had been totally rejected. This implies that once grafted cells have acted as bridges for axon regeneration across the lesion site their continued presence is no longer necessary for maintaining the restored function. This raises the possibility that in the future a protocol of temporary immunoprotection might allow for the use of the larger available numbers ofimmunoincompatible allografted cells or cell lines, which would avoid the need for removing a patient’s olfactory bulb.

Key words: Xenograft; Olfactory ensheathing cells (OECs); Spinal cord injury; Astrocytes

Received April 22, 2015; final acceptance June 26, 2015. Online prepub date: June 30, 2015.
Address correspondence to Professor Geoffrey Raisman, F.R.S., Spinal Repair Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. Tel: +442076762172; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 301-311, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688236
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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PET Imaging of Serotonin Transporters With 4-[18F]-ADAM in a Parkinsonian Rat Model With Porcine Neural Xenografts

Chuang-Hsin Chiu,*† I-Hsun Li,‡§ Shao-Ju Weng,¶ Yuahn-Sieh Huang,¶ Shinn-Chih Wu,# Ta-Kai Chou,† Wen-Sheng Huang,** Mei-Hsiu Liao,†† Chyng-Yann Shiue,† Cheng-Yi Cheng,*† and Kuo-HsingMa*¶

*Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
†Department of Nuclear Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
‡Department of Pharmacy Practice, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
§School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
¶Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan
#Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
**Departments of Nuclear Medicine and Medical Research, Changhua Christian Hospital, Changhua, Taiwan
††Institute of Nuclear Energy Research, Taoyaun, Taiwan

Parkinson’s disease (PD) is a neurodegenerative disease characterized by a loss of dopaminergic neurons in the nigrostriatal pathway. Apart from effective strategies to halt the underlying neuronal degeneration, cell replacement now offers novel prospects for PD therapy. Porcine embryonic neural tissue has been considered an alternative source to human fetal grafts in neurodegenerative disorders because its use avoids major practical and ethical issues. This study was undertaken to evaluate the effects of embryonic day 27 (E27) porcine mesencephalic tissue transplantation in a PD rat model using animal positron emission tomography (PET) coupled with 4-[18F]-ADAM, a serotonin transporter (SERT) imaging agent. The parkinsonian rat was induced by injecting 6-hydroxydopamine into the medial forebrain bundle (MFB) of the right nigrostriatal pathway. The apomorphine-induced rotation behavioral test and 4-[18F]-ADAM/animal PET scanning were carried out following 6-OHDA lesioning. At the second week following 6-OHDA lesioning, the parkinsonian rat rotates substantially on apomorphine-induced contralateral turning. In addition, the mean striatal-specific uptake ratio (SUR) of 4-[18F]-ADAM decreased by 44%. After transplantation, the number of drug-induced rotations decreased markedly, and the mean SUR of 4-[18F]-ADAM and the level of SERT immunoreactivity (SERT-ir) in striatum were partially restored. The mean SUR level was restored to 71% compared to that for the contralateral intact side, which together with the abundant survival of tyrosine hydroxylase (TH) neurons accounted for functional recovery at the fourth week postgraft. In regard to the extent of donor-derived cells, we found the neurons of the xenografts from E27 transgenic pigs harboring red fluorescent protein (RFP) localized with TH-ir cells and SERT-ir in the grafted area. Thus, transplanted E27 porcine mesencephalic tissue may restore dopaminergic and serotonergic systems in the parkinsonian rat. The 4-[18F]-ADAM/animal PET can be used to detect serotonergic neuron loss in PD and monitor the efficacy of therapy.

Key words: Parkinson’s disease (PD); Rat model; Xenograft; Serotonin transporter; 4-[18F]-ADAM

Received April 3, 2014; final acceptance May 15, 2015. Online prepub date: May 20, 2014.
Address correspondence to Kuo-Hsing Ma, Ph.D., Department of Biology and Anatomy, National Defense Medical Center, Taipei, No. 161, Sec. 6, Min-Chuan E. Rd., Neihu 114, Taipei, Taiwan. Tel: +886-2-87923100, ext. 18160; Fax: +886-2-87923159; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Cheng-Yi Cheng, M.D., Ph.D., Department of Nuclear Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, No. 325, Sec. 2, Chenggong Rd., Neihu 114, Taipei, Taiwan. Tel: +886-2-87923311, ext. 16709; Fax: +886-2-87927217; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 313-326, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688209
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Bone Marrow-Derived Mesenchymal Stem Cells Improve Diabetic Neuropathy by Direct Modulation of Both Angiogenesis and Myelination in Peripheral Nerves

Ji Woong Han,* Dabin Choi,* Min Young Lee,* Yang Hoon Huh,† and Young-sup Yoon*

*Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
†Division of Electron Microscopic Research, Korea Basic Science Institute, Daejeon, Korea

Recent evidence has suggested that diabetic neuropathy (DN) is pathophysiologically related to both impaired angiogenesis and a deficiency of neurotrophic factors in the nerves. It is widely known that vascular and neural growths are intimately associated. Mesenchymal stem cells (MSCs) promote angiogenesis in ischemic diseases and have neuroprotective effects, particularly on Schwann cells. Accordingly, we investigated whether DN could be improved by local transplantation of MSCs by augmenting angiogenesis and neural regeneration such as remyelination. In sciatic nerves of streptozotocin (STZ)-induced diabetic rats, motor and sensory nerve conduction velocities (NCVs) and capillary density were reduced, and axonal atrophy and demyelination were observed. After injection of bone marrow-derived MSCs (BM-MSCs) into hindlimb muscles, NCVs were restored to near-normal levels. Histological examination demonstrated that injected MSCs were preferentially and durably engrafted in the sciatic nerves, and a portion of the engrafted MSCs were distinctively localized close to vasa nervora of sciatic nerves. Furthermore, vasa nervora increased in density, and the ultrastructure of myelinated fibers in nerves was observed to be restored. Real-time RT-PCR experiments showed that gene expression of multiple factors involved in angiogenesis, neural function, and myelination were increased in the MSC-injected nerves. These findings suggest that MSC transplantation improved DN through direct peripheral nerve angiogenesis, neurotrophic effects, and restoration of myelination.

Key words: Bone marrow; Diabetic neuropathy (DN); Angiogenesis; Myelination; Mesenchymal stem cells (MSCs)

Received November 24, 2014; final acceptance May 7, 2015. Online prepub date: May 13, 2015.
Address correspondence to Young-sup Yoon, M.D., Ph.D., F.A.H.A., Professor of Medicine, Department of Medicine, Division of Cardiology, Emory University School of Medicine, 101 Woodruff Circle, WMB 3009, Atlanta, GA 30322, USA. Tel: +1.404.727.8176; Fax: +1.404.727.3988; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 327-342, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688506
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Porcine Islet-Specific Tolerance Induced by the Combination of Anti-LFA-1 and Anti-CD154 mAbs Is Dependent on PD-1

Hossein Arefanian,*†‡ Eric B.Tredget,* Dereck C. M. Mok,* Qahir Ramji,* Shahin Rafati,* Jose Rodriguez-Barbosa Gregory S. Korbutt,* Ray V. Rajotte,* Ron G. Gill,¶ and Gina R. Rayat*

*Alberta Diabetes Institute, Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
†Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Tehran, Iran
‡Pancreatic Islet Biology and Transplantation Unit, Dasman Diabetes Institute, Kuwait, Dasman, Kuwait
§Institute of Biomedicine (Immunobiology), University of Leon, Campus de Vegazana s/n, Leon, Spain
¶Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA

We previously demonstrated that short-term administration of a combination of anti-LFA-1 and anti-CD154 monoclonal antibodies (mAbs) induces tolerance to neonatal porcine islet (NPI) xenografts that is mediated by regulatory T cells (Tregs) in B6 mice. In this study, we examined whether the coinhibitory molecule PD-1 is required for the induction and maintenance of tolerance to NPI xenografts. We also determined whether tolerance to NPI xenografts could be extended to allogeneic mouse or xenogeneic rat islet grafts since we previously demonstrated that tolerance to NPI xenografts could be extended to second-party NPI xenografts. Finally, we determined whether tolerance to NPI xenografts could be extended to allogeneic mouse or second-party porcine skin grafts. Diabetic B6 mice were transplanted with 2,000 NPIs under the kidney capsule and treated with short-term administration of a combination of anti-LFA-1 and anti-CD154 mAbs. Some of these mice were also treated simultaneously with anti-PD-1 mAbat >150 days posttransplantation. Spleen cells from some of the tolerant B6 mice were used for proliferation assays or were injected into B6 rag−/− mice with established islet grafts from allogeneic or xenogeneic donors. All B6 mice treated with anti-LFA-1 and anti-CD154 mAbs achieved and maintained normoglycemia until the end of the study; however, some mice that were treated with anti-PD-1 mAb became diabetic. All B6 rag−/− mouse recipients of first- and second-party NPIs maintained normoglycemiaafter reconstitution with spleen cells from tolerant B6 mice, while all B6 rag−/− mouse recipients of allogeneic mouse or xenogeneic rat islets rejected their grafts after cell reconstitution. Tolerant B6 mice rejected their allogeneic mouse or xenogeneic second-party porcine skin grafts while remaining normoglycemic until the end of the study. These results show that porcine islet-specific tolerance is dependent on PD-1, which could not be extended to skin grafts.

Key words: Islet xenograft; Species-specific tolerance; Tissue-specific tolerance, PD-1/PD-1L pathway; Monoclonal antibody (mAb)

Received January 9, 2015; final acceptance June 24, 2015. Online prepub date: June 23, 2015.
Address correspondence to Gina R. Rayat, 5-002C Li Ka Shing Centre for Health Research Innovation, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada T6G 2E1. Tel: (780) 492-6894; Fax: (780) 492-5501; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 343-352, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688119
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Human Serum Versus Human Serum Albumin Supplementation in Human Islet Pretransplantation Culture: In Vitro and In Vivo Assessment

Montserrat Nacher,*† Elisabet Estil·les,*† Ainhoa Garcia,†‡ Belen Nadal,†‡¶ Mar Pairo,*† Cristofer Garcia,* Lluis Secanella,* Anna Novials,†‡§ and Eduard Montanya*†¶

*Hospital Universitari Bellvitge-IDIBELLL, Hospitalet de Llobregat, Barcelona, Spain
†CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM) Barcelona, Spain
‡Diabetes and Obesity Laboratory, Institut d’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
§Hospital Clinic, Barcelona, Spain
¶University of Barcelona, Barcelona, Spain

There is conflicting evidence favoring both the use of human serum (HS) and of human serum albumin (HSA) in human islet culture. We evaluated the effects of HS versus HSA supplementation on 1) in vitro β-cell viability and function and 2) in vivo islet graft revascularization, islet viability, β-cell death, and metabolic outcome after transplantation. Islets isolated from 14 cadaveric organ donors were cultured for 3 days in CMRL 1066 medium supplemented with HS or HSA. After 3 days in culture, β-cell apoptosis was lower in HS group (1.41 ± 0.27 vs. 2.38 ± 0.39%, p = 0.029), and the recovery of islets was 77 ± 11% and 54 ± 1% in HS- and HAS-cultured groups, respectively. Glucose-stimulated insulin secretion (GSIS) was higher in HS group (29.4, range 10.4–99.9, vs. 22.3, range 8.7–70.6, p = 0.031). In vivo viability and revascularization was determined in HS- and HSA-cultured islets transplanted into the anterior chamber of the eye of Balb/c mice (n = 14), and β-cell apoptosis in paraffin-embedded mouse eyes. Islet viability and β-cell apoptosis were similar in both groups. Revascularization was observed in one graft (HS group) on day 10 after transplantation. Islet function was determined in streptozotocin (STZ)-diabetic nude mice (n = 33) transplanted with 2,000 IEQs cultured with HS or HSA that showed similar blood glucose levels and percentage of normoglycemic animals over time. In conclusion, human islets cultured in medium supplemented with HS showed higher survival in vitro, as well as islet viability and function. The higher in vitro survival increased the number of islets available for transplantation. However, the beneficial effect on viability and function did not translate into an improved metabolic evolution when a similar number of HSA- and HS-cultured islets was transplanted.

Key words: Islet culture; Apoptosis; Insulin; Islet transplantation

Received June 11, 2014; final acceptance April 29, 2015. Online prepub date: May 7, 2015.
Address correspondence to Eduard Montanya, Department of Clinical Sciences, Campus de Bellvitge, University of Barcelona, 08907 L’Hospitalet de LlobregatBarcelona, Spain. Tel: +34-93-4037265; Fax: +34-93-2607561; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 353-364, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688245
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Numb Expression Contributes to the Maintenance of an Undifferentiated State in Human Epidermis

Gioacchin Iannolo,*†‡ Maria Rita Sciuto,†§¶ Simona Buccheri,†‡ Cristina Colarossi,† Ruggero De Maria,§ Lorenzo Memeo,† and Pier Giulio Conaldi

*Fondazione Ri.MED, Regenerative Medicine and Biomedical Technologies Unit, Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT, Palermo, Italy
†Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), Viagrande, Catania, Italy
‡Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo, Italy
§National Cancer Institute ‘Regina Elena’, Rome, Italy
¶Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy

The epidermis is a stratified epithelium with a stem cell subpopulation in the basal layer that constantly replicates and periodically detaches from the base, undergoing a differentiation process that involves various developmental signals and regulatory pathways. During the last 10 years, a number of studies tried to elucidate the intricate scenario that maintains the epithelial shield during the entire life span. In our study, we investigated the role of Numb in the skin compartment and, in particular, its involvement in stem cell maintenance. Numb expression in the skin compartment was assessed by immunofluorescence and immunohistochemistry analysis. We evaluated Numb expression in primary epithelial cells at various differentiative stages. Moreover, we overexpressed Numb in the isolated population enriched for undifferentiated progenitors to establish its involvement in in vitro differentiation. We demonstrated that Numb in high-proliferating epithelial undifferentiated progenitors contributes to the maintenance of an undifferentiated state. This regulation involves the E3 ligases Itch binding. Moreover, the analysis of a cohort of cutaneous carcinomas showed that Numb is highly expressed in squamous cell carcinoma (SCC), where we observed a direct correlation between the expression of Numb and Ki-67. Our data indicate for the first time that Numb is involved in the maintenance of the undifferentiated proliferating stem cell pool in the epithelial basal layer and its expression could become a new marker in skin cancer.

Key words: Numb; Keratinocyte; Stem cell; p63; Notch

Received March 14, 2014; final acceptance May 18, 2015. Online prepub date: May 20, 2015.
Address correspondence to Gioacchin Iannolo, Fondazione Ri.MED, ISMETT, Via Tricomi 5, 90127 Palermo, Italy. Tel: +39 091 21 92 496; Fax: +39-091-2192422; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 365-376, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X687930
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Use of Amniotic Microparticles Coated With Fibroblasts Overexpressing SDF-1α to Create an Environment Conducive to Neovascularization for Repair of Full-Thickness Skin Defects

Yun-qing Zhang,*1 Shi-zhao Ji,*1 He Fang,*1 Yong-jun Zheng,* Peng-fei Luo,* Hai-bin Wu,* Min-juan Wu,† Zhi-hong Wang,* Shi-chu Xiao,* and Zhao-fan Xia*

*Burns Institute of People’s Liberation Army, Changhai Hospital, the Second Military Medical University, Shanghai, People’s Republic of China
†Department of Histology and Embryology, College of Basic Medical Science, the Second Military Medical University, Shanghai, People’s Republic of China

As angiogenesis and vasculogenesis involve the complex network structures of various types of cells, extracellular matrix components, and cytokines, it is still difficult to exactly mimic the microenvironment of vascularization in vivo. In our study, we constructed a complex containing highly proliferative fibroblasts that can secrete extracellular matrix components and growth factors to chemotaxize endothelial progenitor cells (EPCs) in an attempt to create an ideal microenvironment for quick vascularization. Amniotic membrane microparticles (mAM) rich in type IV collagen (COL IV) and laminin (LN) were prepared, and human dermal fibroblasts (HDF) were infected with lentivirus (LV) of overexpression of SDF-1α to construct SDF-1αovHDF. Using the rotary cell culture system (RCCS), mAM was loaded with HDF or SDF-1αovHDF to construct HDF-mAM and SDF-1αovHDF-mAM complexes. The complexes were able to secrete various types of active peptides (IL-6, IL-8, TGF-β, and bFGF) during in vitro culture. In addition, SDF-1αovHDF-mAM complex highly expressed SDF-1α. Transwell assay showed SDF-1αovHDF-mAM complex had an apparent chemotactic effect on EPCs. Transplantation of complexes onto full-thickness skin defects of C57BL mice further demonstrated that SDF-1α expression and the number of peripheral EPCs at days 3, 5, and 7 in the SDF-1αovHDF-mAM group were significantly higher than that in other groups (p < 0.01). The local microvascular density at day 10 of transplantation showed that the microvascular density in the SDF-1αovHDF-mAM group was significantly higher than that in HDF-mAM group (p < 0.01). In conclusion, HDF-mAM had a strong proliferative activity and could be used to create a sound microenvironment for quick vascularization by secreting multiple cytokines and extracellular matrix components. Overexpression of SDF-1α could chemotaxize EPCs to reach local wounds, thus further accelerating angiogenesis in the transplant site. The technique described may prove to be a new model for accelerating vascularization of tissue and organ transplants and chronic ischemic wounds.

Key words: Vascularization; Fibroblast; Skin substitute; Endothelial progenitor cells (EPCs); Stromal cell-derived factor-1α (SDF-1α)

Received May 19, 2014; final acceptance March 16, 2015. Online prepub date: April 7, 2015.
1These authors provided equal contribution to this work.
Address correspondence to Zhaofan Xia, Burns Institute of People’s Liberation Army, Changhai Hospital, the Second Military Medical University, Shanghai 200433, China. Tel: +86-21-31161821; Fax: +86-21-65589829; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Shichu Xiao, Burns Institute of People’s Liberation Army, Changhai Hospital, the Second Military Medical University, Shanghai 200433, China. Tel: +86-21-31161825; Fax: +86-21-65589829; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 377-399, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688227
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Investigation of Transcriptional Gene Profiling in Normal Murine Hair Follicular Substructures Using Next-Generation Sequencing to Provide Potential Insights Into Skin Disease

Jaein Lee,*† Kang-In Lee,† and Hyung Min Chung‡

*Department of Laboratory Medicine, CHA Gangnam Medical Center, College of Medicine, CHA University, Seoul, Republic of Korea
†Department of Biomedical Science, CHA University, College of Life Science, Seoul, Republic of Korea
‡Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Republic of Korea

Skin diseases, including hair-related diseases and neoplasia, are a major public health problem. While their prevalence is increasing, their treatment options are limited. Researchers have tried to investigate the genes and signal pathways underlying hair follicles (HFs) to develop genetically targeted therapies through microarrays, which represent an appropriate modality for the analysis of small genomes. To enable the comprehensive transcriptome analysis of large and/or complex transcriptomes, we performed RNA-seq using next-generation sequencing (NGS). We isolated interfollicular keratinocytes (IFKs), HFs, and dermal fibroblasts including dermal papilla cells (DFs-DPCs) from normal C57BL/6 murine skin, transplanted combinations of these samples into nude mice, and followed the mice over time. Sustained hair growth was supported by HFs and DFs-DPCs. We then investigated the pathways and the relevant gene ontology associated with any identified differentially expressed genes (DEGs). In addition, in the culture and flow cytometry (FCM), the HFs had a more quiescent cell cycle pattern than did the IFKs and DFs-DPCs. Therefore, the representative cell cycle-related gene expression of IFKs, HFs, and DFs-DPCs
was analyzed by NGS. Our study will allow researchers to further investigate the potential interactions and signaling pathways that are active in HF-related diseases and cancer and may aid in future bioengineering applications.

Key words: Next-generation sequencing (NGS); Hair follicle (HF); Differentially expressed genes (DEGs); Cell cycle

Received April 22, 2014; final acceptance May 15, 2015. Online prepub date: May 20, 2015.
Address correspondence to Jaein Lee, M.D., 650-1 Yeoksam 1-dong, Gangnam-gu, Seoul 135-907, Republic of Korea. Tel: +82 2 3468 2816; Fax: +82 2 3468 2619; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it , This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Hyung Min Chung, Ph.D., 120 Neungdong-roGwangjin-gu, Seoul 143-701, Republic of Korea. Tel: +82 2 2049 6232; Fax: +82 2 455-9012; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it , This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 401-410, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688191
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Intra-arterial Administration of Placenta-Derived Decidual Stromal Cells to the Superior Mesenteric Artery in the Rabbit: Distribution of Cells, Feasibility, and Safety

Fabian Arnberg,*†‡ Johan Lundberg,*† Annie Olsson,§ Erik Samén,*† Nasren Jaff,* Emma Jussing,*† Ulrika Dahlén,§ Silvia Nava,¶# Rimma Axelsson,** Olle Ringdén,¶# Helen Kaipe,¶# and StaffanHolmin*†

*Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
†Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
‡Department of Radiology, Karolinska University Hospital, Stockholm, Sweden
§Department of Medical Physics, Karolinska University Hospital, Stockholm, Sweden
¶Division of Therapeutic Immunology, Karolinska Institutet, Stockholm, Sweden
#Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
**Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden

Selective administration of mesenchymal stromal cells to the mesenteric arteries is a potential technique to overcome pulmonary trapping and increase the density of transplanted cells in extensive mural inflammation of the intestine, such as in inflammatory bowel disease and graft-versus-host disease. We injected 5 × 106 111In-oxine-labeled human decidual stromal cells (DSCs) to the rabbit superior mesenteric artery (SMA) using clinical routine catheters guided by an angiographical system under sterile conditions. We used longitudinal single-photon emission tomography at 6 h and at 1, 2, and 5 days to assess trafficking and distribution of DSCs. We used digital subtraction angiography, computed tomography, and hematoxylin and eosin stainings to determine biodistribution of cells and to assess safety end points. We found that selective injection of human DSCs to the rabbit SMA does not result in acute embolic complications. Furthermore, we found that IV administration resulted in extensive retention of the radiolabeled DSCs in the lungs, corroborating previous studies on pulmonary trapping. In sharp contrast, selective injections to the SMA resulted in uptake distributed in the intestine supplied by the SMA and in the liver, indicating that this approach could significantly increase the fraction of injected DSCs reaching the target tissue.

Key words: Cell transplantation; Intra-arterial; Decidual stromal cells (DSCs); Inflammatory bowel disease (IBD)

Received January 29, 2015; final acceptance May 12, 2015. Online prepub date: May 13, 2015.
Address correspondence to Staffan Holmin, M.D., Ph.D., Department of Neuroradiology, Karolinska University Hospital, SolnaSE-171 76 Stockholm, Sweden. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 411-424, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X688137
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Directed Differentiation of Oligodendrocyte Progenitor Cells From Mouse Induced Pluripotent Stem Cells

Dino Terzic,*†1 Jacob R. Maxon,*1 Leah Krevitt,* Christina DiBartolomeo,* Tarini Goyal,* Walter C. Low,*† James R. Dutton,*2 and Ann M. Parr*†2

*Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
†Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA

Several neurological disorders, such as multiple sclerosis, the leukodystrophies, and traumatic injury, result in loss of myelin in the central nervous system (CNS). These disorders may benefit from cell-based therapies that prevent further demyelination or are able to restore lost myelin. One potential therapeutic strategy for these disorders is the manufacture of oligodendrocyte progenitor cells (OPCs) by the directed differentiation of pluripotent stem cells, including induced pluripotent stem cells (iPSCs). It has been proposed that OPCs could be transplanted into demyelinated or dysmyelinated regions of the CNS, where they would migrate to the area of injury before terminally differentiating into myelinating oligodendrocytes. OPCs derived from mouse iPSCs are particularly useful for modeling this therapeutic approach and for studying the biology of oligodendrocyte progenitors because of the availability of mouse models of neurological disorders associated with myelin deficiency. Moreover, the utility of miPSC-derived OPCs would be significantly enhanced by the adoption of a consistent, reproducible differentiation protocol that allows OPCs derived from different cell lines to be robustly characterized and compared. Here we describe a standardized, defined protocol that reliably directs the differentiation of miPSCs to generate high yields of OPCs that are capable of maturing into oligodendrocytes.

Key words: Oligodendrocyte progenitor cells (OPCs); Induced pluripotent stem cells (iPSCs); Differentiation; Transplantation; Myelin

Received February 17, 2015; final acceptance May 6, 2015. Online prepub date: May 7, 2015.
1These authors provided equal contribution to this work.
2These authors provided equal contribution to this work.
Address correspondence to Ann M. Parr, M.D., Ph.D., Assistant Professor, Department of Neurosurgery, University of Minnesota, D427 Mayo Bldg., MMC96, 420 Delaware St. SE, Minneapolis, MN 55455, USA. Tel: +1-612-624-6666; Fax: +1-612-624-0644; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it