Cell Transplantation 26(2) Abstracts

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Cell Transplantation, Vol. 26, pp. 173-189, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
692212
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Human Adipose-Derived Stem Cells Suppress Elastase-Induced Murine Abdominal Aortic Inflammation and Aneurysm Expansion Through Paracrine Factors

Jie Xie,*†‡ Thomas J. Jones,*† Dongni Feng,*† Todd G. Cook,* Andrea A. Jester,‡ Ru Yi,*† Yameena T. Jawed,*† Clifford Babbey,§ Keith L. March,*†¶ and Michael P. Murphy*†§‡

*Indiana Center for Vascular Biology and Medicine (ICVBM), Indianapolis, IN, USA
†Richard L. Roudebush VA Center for Regenerative Medicine, Indianapolis, IN, USA
‡Indiana University Department of Surgery (IUSM), Indianapolis, IN, USA
§Indiana University Center for Aortic Disease (IU-CAD), Indianapolis, IN, USA
Krannert Institute of Cardiology, Indianapolis, IN, USA

Abdominal aortic aneurysm (AAA) is a potentially lethal disease associated with immune activation-induced aortic degradation. We hypothesized that xenotransplantation of human adipose-derived stem cells (hADSCs) would reduce aortic inflammation and attenuate expansion in a murine AAA model. Modulatory effects of ADSCs on immune cell subtypes associated with AAA progression were investigated using human peripheral blood mononuclear cells (hPBMNCs) cocultured with ADSCs. Murine AAA was induced through elastase application to the abdominal aorta in C57BL/6 mice. ADSCs were administered intravenously, and aortic changes were determined by ultrasonography and videomicrometry. Circulating monocytes, aortic neutrophils, CD28 T cells, FoxP3+ regulatory T cells (Tregs), and CD206+ M2 macrophages were assessed at multiple terminal time points. In vitro, ADSCs induced M2 macrophage and Treg phenotypes while inhibiting neutrophil transmigration and lymphocyte activation without cellular contact. Intravenous ADSC delivery reduced aneurysmal expansion starting from day 4 [from baseline: 54.8% (saline) vs. 16.9% (ADSCs),
n = 10 at baseline, n = 4 at day 4, p < 0.001], and the therapeutic effect persists through day 14 (from baseline: 64.1% saline vs. 24.6% ADSCs, n = 4, p < 0.01). ADSC administration increased aortic Tregs by 20-fold (n = 5, p <0.01), while decreasing CD4+CD28 (−28%), CD8+CD28 T cells (−61%), and Ly6G/C+ neutrophils (−43%, n = 5, p < 0.05). Circulating CD115+CXCR1LY6C+-activated monocytes decreased in the ADSC-treated group by day 7 (−60%, n = 10, p < 0.05), paralleled by an increase in aortic CD206+ M2 macrophages by 2.4-fold (n = 5, p < 0.05). Intravenously injected ADSCs transiently engrafted in the lung on day 1 without aortic engraftment at any time point. In conclusion, ADSCs exhibit pleiotropic immunomodulatory effects in vitro as well as in vivo during the development of AAA. The temporal evolution of these effects systemically as well as in aortic tissue suggests that ADSCs induce a sequence of anti-inflammatory cellular events mediated by paracrine factors, which leads to amelioration of AAA progression.

Key words: Abdominal aortic aneurysm (AAA); Adipose-derived stem cells (ADSCs); Regulatory T cells (Tregs); M2 macrophage; Paracrine signaling

Received January 27, 2016; final acceptance September 13, 2016. Online prepub date: July 18, 2016.
Address correspondence to Jie Xie, Richard L. Roudebush VA Medical Center, 1481 W 10th Street, C3113, Indianapolis, IN 46202, USA. Tel: (317) 988-4976; Fax: (317) 988-9325; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 191-204, 2017
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DOI: https://doi.org/10.3727/096368916X
692708
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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CXCR4 Overexpression in Human Adipose Tissue-Derived Stem Cells Improves Homing and Engraftment in an Animal Limb Ischemia Model

MiJung Kim,*† Dong-Ik Kim,‡ Eun Key Kim,§ and Chan-Wha Kim†

*Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, South Korea
†Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, South Korea
‡Division of Vascular Surgery, School of Medicine, SungKyunKwan University, Seoul, South Korea
§Department of Plastic Surgery, University of Ulsan College of Medicine, Seoul, South Korea

We investigated the effects of transplantation of CXCR4-overexpressing adipose tissue-derived stem cells (ADSCs) into a mouse diabetic hindlimb ischemia model on homing and engraftment as early as 48 h after transplant. CXCR4-overexpressing ADSCs were intramuscularly or intravenously injected into diabetic mice with hindlimb ischemia. After 48 h, muscle tissues in the femur and tibia were collected, and the CXCR4 expression pattern was analyzed by immunofluorescence staining. The homing and engraftment of transplanted CXCR4-overexpressing ADSCs into the ischemic area were significantly increased, and intravenous (systemic) injection resulted in the more effective delivery of stem cells to the target site 48 h posttransplantation. Furthermore, CXCR4-overexpressing ADSCs more efficiently contributed to long-term engraftment and muscle tissue regeneration than normal ADSCs in a limb ischemia model. In addition, the homing and engraftment of ADSCs were correlated with the CXCR4 transfection efficiency. These results demonstrated that enhanced CXCR4 signaling could significantly improve the early homing and engraftment of ADSCs into ischemic areas as well as the long-term engraftment and ultimate muscle tissue regeneration. 

Key words: Adipose tissue-derived stem cells (ADSCs); C-X-C chemokine receptor type 4 (CXCR4); Homing and engraftment; Diabetic limb ischemia; Muscle tissue regeneration

Received May 20, 2016; final acceptance November 20, 2016. Online prepub date: August 5, 2016.
Address correspondence to MiJung Kim, Ph.D., Division of Life Sciences, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145 Anam-Ro, Sungbuk-Gu, Seoul 136-701, South Korea. Tel: +82-2-3290-3939; Fax: +82-2-3290-3957; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Chan-Wha Kim, Ph.D., Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 205-214, 2017
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DOI: https://doi.org/10.3727/096368916X
692933
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) Trial: Rationale and Design

Tarun Chakravarty,* Raj R. Makkar,* Deborah D. Ascheim,† Jay H. Traverse,‡ Richard Schatz,§ Anthony DeMaria,¶ Gary S. Francis,‡ Thomas J. Povsic,# Rachel R. Smith,† Joao A. Lima,** Janice M. Pogoda,†† Linda Marban,† and Timothy D. Henry*

*Cedars-Sinai Heart Institute, Los Angeles, CA, USA
Capricor Therapeutics Inc., Los Angeles, CA, USA
‡Minneapolis Heart Institute, Minneapolis, MN, USA
§Scripps Medical Center, La Jolla, CA, USA
¶University of California San Diego, San Diego, CA, USA
#Duke Clinical Research Institute, Duke Medicine, Durham, NC, USA
**Johns Hopkins Hospital, Baltimore, MD, USA
††Columbus Biometrics, LLC, Columbus, OH, USA

Autologous cardiosphere-derived cells (CDCs) were the first therapeutic modality to demonstrate myocardial regeneration with a decrease in scar size and an increase in viable, functional tissue. Widespread applicability of autologous CDC therapy is limited by the need for patient-specific myocardial biopsy, cell processing, and quality control, resulting in delays to therapy and inherent logistical and economic constraints. Preclinical data had demonstrated equivalent efficiency of allogeneic to autologous CDCs. The ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial is a multicenter randomized, double-blind, placebo controlled phase 1/2 safety and efficacy trial of intracoronary delivery of allogeneic CDCs (CAP-1002) in patients with myocardial infarction (MI) and ischemic left ventricular dysfunction. The phase 1 safety cohort enrolled 14 patients in an open-label, nonrandomized, dose-escalation safety trial. The phase 2 trial is a doubleblind, randomized, placebo-controlled trial that will compare intracoronary CDCs to placebo in a 2:1 allocation and will enroll up to 120 patients. The primary endpoint for both phases is safety at 1 month. For phase 2, the primary efficacy endpoint is relative change from baseline in infarct size at 12 months, as assessed by magnetic resonance imaging. The ALLSTAR trial employs a “seamless” WOVE 1 design that enables continuous enrollment from phase 1 to phase 2 and will evaluate the safety of intracoronary administration of allogeneic CDCs and its efficacy in decreasing infarct size in post-MI patients.

Key words: Stem cells; ST elevation MI; Trial design; Myocardial infarction (MI); Regenerative medicine

Received April 5, 2016; final acceptance September 29, 2016. Online prepub date: August 18, 2016.
Address correspondence to Timothy D. Henry, 127 S. San Vicente Boulevard, Suite A3100, Los Angeles, CA 90048, USA. Tel: (424) 315-2699; Fax: (310) 423-3522; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 215-228, 2017
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DOI: https://doi.org/10.3727/096368916X
692951
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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A Nerve Conduit Containing a Vascular Bundle and Implanted With Bone Marrow Stromal Cells and Decellularized Allogenic Nerve Matrix

Yukitoshi Kaizawa,* Ryosuke Kakinoki,† Ryosuke Ikeguchi,* Soichi Ohta,* Takashi Noguchi,* Hisataka Takeuchi,* Hiroki Oda,* Hirofumi Yurie,* and Shuichi Matsuda*

*Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
†Department of Orthopaedic Surgery, Faculty of Medicine, Kindai University, Sayama, Osaka, Japan

Cells, scaffolds, growth factors, and vascularity are essential for nerve regeneration. Previously, we reported that the insertion of a vascular bundle and the implantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) into a nerve conduit promoted peripheral nerve regeneration. In this study, the efficacy of nerve conduits containing a vascular bundle, BM-MSCs, and thermally decellularized allogenic nerve matrix (DANM) was investigated using a rat sciatic nerve model with a 20-mm defect. Lewis rats were used as the sciatic nerve model and for the preparation of BM-MSCs, and Dark Agouti rats were used for the preparation of the DANM. The revascularization and the immunogenicity of the DANM were investigated histologically. The regeneration of nerves through nerve conduits containing vessels, BM-MSCs, and DANM (VBD group) was evaluated based on electrophysiological, morphometric, and reinnervated muscle weight measurements and compared with that of vessel-containing conduits that were implanted with BM-MSCs (VB group). The DANM that was implanted into vessel-containing tubes (VCTs) was revascularized by neovascular vessels that originated from the inserted vascular bundle 5–7 days after surgery. The number of CD8+ cells found in the DANM in the VCT was significantly smaller than that detected in the untreated allogenic nerve segment. The regenerated nerve in the VBD group was significantly superior to that in the VB group with regard to the amplitude of the compound muscle action potential detected in the pedal adductor muscle; the number, diameter, and myelin thickness of the myelinated axons; and the tibialis anterior muscle weight at 12 and 24 weeks. The additional implantation of the DANM into the BM-MSC-implanted VCT optimized the axonal regeneration through the conduit. Nerve conduits constructed with vascularity, cells, and scaffolds could be an effective strategy for the treatment of peripheral nerve injuries with significant segmental defects.

Key words: Peripheral nerve injury; Vascularity; Allogenic nerve tissue; Nerve conduit; Bone marrow-derived mesenchymal stem cells (BM-MSCs)

Received February 25, 2016; final acceptance December 7, 2016. Online prepub date: September 21, 2016.
Address correspondence to Ryosuke Kakinoki, Department of Orthopaedic Surgery, Faculty of Medicine, Kindai University, 377-2 Oono-higashi, Osaka-sayama, Osaka 589-8511, Japan. Tel: +81-72-366-0221; Fax: +81-72-366-0206; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 229-242, 2017
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DOI: https://doi.org/10.3727/096368916X
693536
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Bone Marrow Stromal Cells Combined With Sodium Ferulate and n-Butylidenephthalide Promote the Effect of Therapeutic Angiogenesis via Advancing Astrocyte-Derived Trophic Factors After Ischemic Stroke

Qian Zhang,*1 Zhen-Wei Chen,*1 Yong-Hua Zhao,* Bo-Wen Liu,* Nai-Wei Liu,* Chien-Chih Ke,† and Hong-Mei Tan‡

*State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, P.R. China
†Biomedical Imaging Research Center, National Yang Ming University, Taipei, Taiwan
‡Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China

Being a potential candidate for stroke treatment, bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) have been demonstrated to be able to enhance angiogenesis and proliferation of reactive astrocytes, which subsequently leads to the amelioration of neurological injury. Increasing evidence further indicates that combining BM-MSCs with certain agents, such as simvastatin, may improve therapeutic effects. Sodium ferulate (SF) and
n-butylidenephthalide(BP), two main components of Radix Angelica Sinensis, are proven to be important regulators of stem cells in cell migration, differentiation, and pluripotency maintenance. This study aimed to investigate whether combining BM-MSCs with SF and BP had better therapeutic effect in the treatment of stroke, and the underlying molecular basis for the therapeutic effects was also investigated. The results showed that combination treatment notably reduced neurological injury after stroke and increased the expression of astrocyte-derived vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and von Willebrand factor-positive vascular density in the ischemic boundary zone as evaluated by immunofluorescence staining. After treatment with BM-MSCs plus SF and BP, astrocytes showed increased expression of VEGF and BDNF by upregulating protein kinase B/mammalian target of rapamycin (AKT/mTOR) expression in an oxygen- and glucose-deprived (OGD) environment. Human umbilical vein endothelial cells (HUVECs) incubated with the conditioned medium (CM) derived from OGD astrocytes treated with BM-MSCs plus SF and BP showed significantly increased migration and tube formation compared with those incubated with the CM derived from OGD astrocytes treated with BM-MSCs alone. These results demonstrate that combination treatment enhances the expression of astrocyte-derived VEGF and BDNF, which contribute to angiogenesis after cerebral ischemia, and the underlying mechanism is associated with activation of the astrocytic AKT/mTOR signaling pathway. Our study provides a potential therapeutic approach for ischemic stroke.

Key words: Angiogenesis; Astrocytes; Bone marrow-derived stromal cells (BM-MSCs); n-Butylidenephthalide (BP); Sodium ferulate (SF)

Received July 14, 2016; final acceptance November 28, 2016. Online prepub date: October 21, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Dr. Yong-Hua Zhao, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao 999078, P.R. China. Tel: 853-88972702; Fax: 853-28825123; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 243-257, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693031
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
Printed in the USA. All rights reserved

Secondary Release of Exosomes From Astrocytes Contributes to the Increase in Neural Plasticity and Improvement of Functional Recovery After Stroke in Rats Treated With Exosomes Harvested From MicroRNA 133b-Overexpressing Multipotent Mesenchymal Stromal Cells

Hongqi Xin,* Fengjie Wang,* Yanfeng Li,* Qing-e Lu,* Wing Lee Cheung,† Yi Zhang,* Zheng Gang Zhang,* and Michael Chopp*‡

*Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
†Department of Emergency Medicine, Henry Ford Hospital, Detroit, MI, USA
‡Department of Physics, Oakland University, Rochester, MI, USA

We previously demonstrated that multipotent mesenchymal stromal cells (MSCs) that overexpress microRNA 133b (miR-133b) significantly improve functional recovery in rats subjected to middle cerebral artery occlusion (MCAO) compared with naive MSCs and that exosomes generated from naive MSCs mediate the therapeutic benefits of MSC therapy for stroke. Here we investigated whether exosomes isolated from miR-133boverexpressing MSCs (Ex-miR-133b+) exert amplified therapeutic effects. Rats subjected to 2 h of MCAO were intra-arterially injected with Ex-miR-133b+, exosomes from MSCs infected by blank vector (Ex-Con), or phosphate-buffered saline (PBS) and were sacrificed 28 days after MCAO. Compared with the PBS treatment, both exosome treatment groups exhibited significant improvement of functional recovery. Ex-miR-133b+ treatment significantly increased functional improvement and neurite remodeling/brain plasticity in the ischemic boundary area compared with the Ex-Con treatment. Treatment with Ex-miR-133b+ also significantly increased brain exosome content compared with Ex-Con treatment. To elucidate mechanisms underlying the enhanced therapeutic effects of Ex-miR-133b+, astrocytes cultured under oxygen- and glucose-deprived (OGD) conditions were incubated with exosomes harvested from naive MSCs (Ex-Naive), miR-133b downregulated MSCs (Ex-miR-133b), and Ex-miR-133b+. Compared with the Ex-Naive treatment, Ex-miR-133b+ significantly increased exosomes released by OGD astrocytes, whereas Ex-miR-133b significantly decreased the release. Also, exosomes harvested from OGD astrocytes treated with Ex-miR-133b+ significantly increased neurite branching and elongation of cultured cortical embryonic rat neurons compared with the exosomes from OGD astrocytes subjected to Ex-Con. Our data suggest that exosomes harvested from miR-133b-overexpressing MSCs improve neural plasticity and functional recovery after stroke with a contribution from a stimulated secondary release of neurite-promoting exosomes from astrocytes.

Key words: MicroRNA 133b (miR-133b); Exosome; Multipotent mesenchymal stromal cell (MSCs); Neural plasticity; Astrocyte; Stroke; Functional recovery

Received June 13, 2016; final acceptance July 17, 2016. Online prepub date: September 26, 2016.
Address correspondence to Hongqi Xin, Ph.D., Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA. Tel: 313-916-7271; Fax: 313-916-1318; 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. 26, pp. 259-269, 2017
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DOI: https://doi.org/10.3727/096368916X
693527
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Efficacy of Two Delivery Routes for Transplanting Human Neural Progenitor Cells (NPCs) Into the Spastic Han–Wistar Rat, a Model of Ataxia

Toni L. Uhlendorf,* Ruslan L. Nuryyev,* Alex O. Kopyov,† Jessica Ochoa,† Shahab Younesi,* Randy W. Cohen,* and Oleg V. Kopyov

*Department of Biology, California State University, Northridge, Northridge, CA, USA
Celavie Biosciences LLC, Oxnard, CA, USA

An emerging avenue for recalcitrant neurodegenerative disease treatment is neural progenitor cell (NPC) transplantation. In this study, we investigated the effectiveness of two different delivery routes of human-derived NPC inoculation: injection into the common carotid artery or unilateral stereotactic implantation into the degenerating cerebellum and hippocampus of spastic Han–Wistar (sHW) rats, a model of ataxia. At 30 days of age, sHW mutants were implanted with osmotic pumps preloaded with cyclosporine. Ten days after pump implantation, the animals were given either 3,000,000 live human-derived NPCs (hNPCs;
n = 12) or 3,000,000 dead NPCs (dNPCs; n = 12) injected into the common carotid artery, or were given two unilateral implantations of 500,000 hNPCs into the cerebellum and 500,000 hNPCs into the hippocampus of each sHW rat (n = 12) or 500,000 dNPCs by unilateral implantation into the cerebellum and hippocampus (n = 12). We also compared treated sHW rats to untreated sHW rats: normal rats (n = 12) and sibling sHW rats (n = 12). Motor activity and animal weights were monitored every 5 days to ascertain effectiveness of the two types of delivery methods compared to the untreated mutant and normal animals. Mutant rats with hNPC implantations, but not dNPC or carotid artery injections, showed significant deceleration of motor deterioration (p < 0.05). These mutants with hNPC implantations also retained weight longer than dNPC mutants did (p < 0.05). At the end of the experiment, animals were sacrificed for histological evaluation. Using fluorescent markers (Qtracker) incorporated into the hNPC prior to implantation and human nuclear immunostaining, we observed few hNPCs in the brains of carotid artery-injected mutants. However, significant numbers of surviving hNPCs were seen using these techniques in mutant cerebellums and hippocampi implanted with hNPC. Our results show that direct implantation of hNPCs reduced ataxic symptoms in the sHW rat, demonstrating that stereotactic route of stem cell delivery correlates to improved clinical outcomes.

Key words: Cerebellum; Hippocampus; Carotid artery infusion; Intracerebral transplantation; Stereotactic; Stem cells

Received May 31, 2016; final acceptance November 23, 2016. Online prepub date: November 7, 2016.
Address correspondence to Randy W. Cohen, Department of Biology, California State University, Northridge, Northridge, CA 91330, USA. Tel: 818-677-2352; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 271-281, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
692852
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Establishment and Characterization of Immortalized Minipig Neural Stem Cell Line

Sung S. Choi,*1 Seung-Bin Yoon,†1 Sang-Rae Lee,†1 Sun-Uk Kim,† Young Joo Cha,‡ Daniel Lee,§ Seung U. Kim,¶ Kyu-Tae Chang,† and Hong J. Lee*

*Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Republic of Korea
†National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungju, Republic of Korea
‡Department of Laboratory Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea
§Seonbu High School, Ansan, Republic of Korea
¶Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada

Despite the increasing importance of minipigs in biomedical research, there has been relatively little research concerning minipig-derived adult stem cells as a promising research tool that could be used to develop stem cell-based therapies. We first generated immortalized neural stem cells (iNSCs) from primary minipig olfactory bulb cells (pmpOBCs) and defined the characteristics of the cell line. Primary neural cells were prepared from minipig neonate olfactory bulbs and immortalized by infection with retrovirus carrying the
v-myc gene. The minipig iNSCs (mpiNSCs) had normal karyotypes and expressed NSC-specific markers, including nestin, vimentin, Musashi1, and SOX2, suggesting a similarity to human NSCs. On the basis of the global gene expression profiles from the microarray analysis, neurogenesis-associated transcript levels were predominantly altered in mpiNSCs compared with pmpOBCs. These findings increase our understanding of minipig stem cells and contribute to the utility of mpiNSCs as resources for immortalized stem cell experiments.

Key words: Minipig; Olfactory bulb; Neural stem cells (NSCs); v-myc; Immortalization

Received February 04, 2016; final acceptance October 27, 2016. Online prepub date: August 12, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Kyu-Tae Chang, Ph.D., National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Republic of Korea. Tel: +82-43-240-6300; Fax: +82-43-240-6309; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Hong J. Lee, Ph.D., Biomedical Research Institute, Chung-Ang University, College of Medicine, Seoul 156-756, Republic of Korea. Tel: +82-70-7555-2174; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 283-292, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693347
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Safety of Intra-Arterial Injection With Tumor-Activated T Cells to the Rabbit Brain Evaluated by MRI and SPECT/CT

Johan Lundberg,*† Emma Jussing,*† Zhenjiang Liu,‡ Qingda Meng,‡ Martin Rao,‡ Erik Samén,*† Rikard Grankvist,*† Peter Damberg,*§ Ernest Dodoo,‡ Markus Maeurer,‡¶ and Staffan Holmin*†

*Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
†Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
‡Therapeutic Immunology Unit, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
§Karolinska Experimental Research and Imaging Center, Karolinska University Hospital, Stockholm, Sweden
¶Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden

Glioblastoma multiforme (GBM) is the most common and most severe form of malignant gliomas. The prognosis is poor with current combinations of pharmaceutical, radiotherapy, and surgical therapy. A continuous search for new treatments has therefore been ongoing for many years. Therapy with tumor-infiltrating lymphocytes (TILs) is a clinically promising strategy to treat various cancers, including GBM. An endovascular intraarterial injection of TILs as a method of delivery may, instead of intravenous infusion, result in better retention of effector cells within the tumor. Prior to clinical trials of intra-arterial injections with any cells, preclinical safety data with special emphasis on embolic–ischemic events are necessary to obtain. We used native rabbits as a model for intra-arterial injections with routine clinical catheter material and a clinical angiography suite. We selectively infused a total dose of 20 million activated T cells at a cell concentration of 4,000 cells/
ml over 8 min of injection time. The rabbits were evaluated for ischemic lesions by 9.4 T magnetic resonance imaging (MRI) (n = 6), and for tracking of injected cells, single-photon emission computed tomography/computed tomography (SPECT/CT) was used (n = 2). In this study, we show that we can selectively infuse activated T cells to a CNS volume of 3.5 cm3 (estimated from the volumetric MRI) without catastrophic embolic–ischemic adverse events. We had one adverse event with a limited basal ganglia infarction, probably due to catheter-induced mechanical occlusion of one of the lateral lenticulostriatal arteries. The cells pass through the native brain without leaving SPECT signals. The cells then, over the first hours, end up in the liver to a large extent and to a lesser degree by the spleen, pancreas, and kidneys. Virtually no uptake could be detected in the lungs. This indicates a difference in biodistribution as opposed to other cell types when infused intravenously.

Key words: Endovascular; Intra-arterial (IA); Tumor-infiltrating lymphocytes (TILs); Magnetic resonance imaging (MRI); Single-photon emission computed tomography/computed tomography (SPECT/CT); Rabbit

Received July 4, 2016; final acceptance November 2, 2016. Online prepub date: October 7, 2016.
Address correspondence to Johan Lundberg, M.D., Ph.D., Department of Neuroradiology, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden. Tel: +46-73-6258594; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 293-307, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
692690
E-ISSN 1555-3892
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Significantly Accelerated Wound Healing of Full-Thickness Skin Using a Novel Composite Gel of Porcine Acellular Dermal Matrix and Human Peripheral Blood Cells

Vijay K. Kuna,*1 Arvind M. Padma,*1 Joakim Håkansson,† Jan Nygren,‡ Robert Sjöback,‡ Sarunas Petronis,† and Suchitra Sumitran-Holgersson*

*Laboratory for Transplantation and Regenerative Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
†Department of Chemistry, Materials and Surfaces, SP Technical Research Institute of Sweden, Borås, Sweden
‡TATAA Biocenter, Gothenburg, Sweden

Here we report the fabrication of a novel composite gel from decellularized gal-gal-knockout porcine skin and human peripheral blood mononuclear cells (hPBMCs) for full-thickness skin wound healing. Decellularized skin extracellular matrix (ECM) powder was prepared via chemical treatment, freeze drying, and homogenization. The powder was mixed with culture medium containing hyaluronic acid to generate a pig skin gel (PSG). The effect of the gel in regeneration of full-thickness wounds was studied in nude mice. We found significantly accelerated wound closure already on day 15 in animals treated with PSG only or PSG + hPBMCs compared to untreated and hyaluronic acid-treated controls (
p < 0.05). Addition of the hPBMCs to the gel resulted in marked increase of host blood vessels as well as the presence of human blood vessels. At day 25, histologically, the wounds in animals treated with PSG only or PSG + hPBMCs were completely closed compared to those of controls. Thus, the gel facilitated generation of new skin with well-arranged epidermal cells and restored bilayer structure of the epidermis and dermis. These results suggest that porcine skin ECM gel together with human cells may be a novel and promising biomaterial for medical applications especially for patients with acute and chronic skin wounds.

Key words: Scaffolds; Tissue engineering; Regenerative medicine; Porcine skin; Decellularization; Wound healing

Received December 14, 2015; final acceptance October 7, 2016. Online prepub date: August 5, 2016.
1These authors provided equal contribution to this work.
Address correspondence to Professor Suchitra Sumitran-Holgersson, Laboratory for Transplantation and Regenerative Medicine, Sahlgrenska Science Park, Medicinaregatan 8A, 2nd Floor, S-413 46 Gothenburg, Sweden. Tel: + 46 727490808; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 309-317, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693554
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Human Recombinant Antithrombin (ATryn®) Administration Improves Survival and Prevents Intravascular Coagulation After Intraportal Islet Transplantation in a Piglet Model

Valery Gmyr,*†‡ Caroline Bonner,*† Ericka Moerman,*†‡ Antoine Tournoys,§ Nathalie Delalleau,*†‡ Audrey Quenon,*† Julien Thevenet,*†‡ Mikael Chetboun,*†§ Julie Kerr-Conte,*†‡ François Pattou,*†‡§ Thomas Hubert,*†‡§ and Merce Jourdain*†‡§

*European Genomic Institute for Diabetes, Lille, France
Inserm UMR 1190, Translational Research for Diabetes, Lille, France
‡University of Lille 2, Lille, France
§Lille University Hospital, Lille, France

Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1DM). However, pancreatic islet inflammation after transplantation induced by innate immune responses is likely to hinder graft function. This is mediated by incompatibility between islets and the blood interface, known as instant bloodmediated inflammatory reaction (IBMIR). Herein we hypothesized that portal venous administration of islet cells with human recombinant antithrombin (ATryn
®), a serine protease inhibitor (serpin), which plays a central role in the physiological regulation of coagulation and exerts indirect anti-inflammatory activities, may offset coagulation abnormalities such as disseminated intravascular coagulation (DIC) and IBMIR. The current prospective, randomized experiment was conducted using an established preclinical pig model. Three groups were constituted for digested pancreatic tissue transplantation (0.15 ml/kg): control, NaCl 0.9% (n = 7); gold standard, heparin (25 UI/kg) (n = 7); and human recombinant ATryn® (500 UI/kg) (n = 7). Blood samples were collected over time (T0 to 24 h), and biochemical, coagulation, and inflammatory parameters were evaluated. In both the control and heparin groups, one animal died after a portal thrombosis, while no deaths occurred in the ATryn®-treated group. As expected, islet transplantation was associated with an increase in plasma IL-6 or TNF-a levels in all three groups. However, DIC was only observed in the control group, an effect that was suppressed after ATryn® administration. ATryn® administration increased antithrombin activity by 800%, which remained at 200% for the remaining period of the study, without any hemorrhagic complications. These studies suggest that coadministration of ATryn® and pancreatic islets via intraportal transplantation may be a valuable therapeutic approach for DIC without risk for islets and subjects.

Key words: Antithrombin (AT); Instant blood-mediated inflammatory reaction (IBMIR); Disseminated intravascular coagulation (DIC); Piglet; Intraportal islet transplantation

Received July 19, 2016; final acceptance November 28, 2016. Online prepub date: October 27, 2016.
Address correspondence to Professor Merce Jourdain, M.D., Ph.D., Inserm UMR 1190, Translational Research for Diabetes, 1 Place de Verdun, 59045 Lille Cedex, France. Tel: +33 (0) 3 20 44 64 36; Fax: +33 (0) 3 20 62 76 62; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 319-326, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693482
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Monocyte-Derived Dendritic Cells Impair Early Graft Function Following Allogeneic Islet Transplantation

Kevin V. Chow,*†‡ Emma M. Carrington,*† Yifan Zhan,*†1 Andrew M. Lew,*†§1 and Robyn M. Sutherland*†1

*Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
†Department of Medical Biology, University of Melbourne, Parkville, Australia
‡Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia
§Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia

Islet transplantation can cure type 1 diabetes but is limited by lack of donor organs and early graft dysfunction, such that many patients require multiple transplants to achieve insulin independence. Monocyte-derived dendritic cells (moDCs) arise during inflammation and allograft encounters where they can promote various innate and adaptive immune responses. To determine whether moDCs impair early graft function following allogeneic islet transplantation, we transplanted MHC-mismatched BALB/c (H-2d) islets into diabetic C57BL/6-CCR2. DTR recipients (H-2b) treated with either saline (control) or diphtheria toxin (DT) to deplete moDCs. Graft function was assessed by blood glucose (BG) measurement. DT treatment resulted in specific depletion of graft site moDCs posttransplant. Despite equivalent pretransplant BG levels [27.0
± 1.3 vs. 29.6 ± 1.1 mM, not significant (ns)], DT recipients achieved lower posttransplant BG levels and better rates of normoglycemia than control recipients (11.0 ± 1.9 vs. 19.1 ± 1.4 mM, p = 0.004) at 1 day posttransplant in diabetic recipients. When a suboptimal donor dose of 200 islets was transplanted, DT-induced moDCdepletion resulted in normoglycemia in 78% compared to 25% of control recipients (p = 0.03). As well as amelioration of graft dysfunction in the immediate peritransplant period, prolonged DT administration (15 days posttransplant) resulted in improved graft survival (21 vs. 11 days, p = 0.005). moDCs impair early graft function post-allogeneic islet transplantation. moDC depletion may allow for improved early graft function, permit transplantation with lower islet masses, and enhance graft survival.

Key words: Monocyte-derived dendritic cells (moDCs); Islet transplantation

Received March 23, 2016; final acceptance December 8, 2016. Online prepub date: October 13, 2016.
1Co-senior authors.
Address correspondence to Andrew M. Lew, The Walter and Eliza Hall Institute of Medical Research (WEHI), 1G Royal Parade, Parkville, VIC 3052, Australia. Tel: 61-3-9245-2555; Fax: 61-3-9347-0852; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Robyn M. Sutherland, WEHI, 1G Royal Parade, Parkville, VIC 3052, Australia. Tel: 61-3-9245-2555; Fax: 61-3-9347-0852; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 327-337, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693329
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Thrombospondin-1-Derived Peptide RFYVVMWK Improves the Adhesive Phenotype of CD34+ Cells From Atherosclerotic Patients With Type 2 Diabetes

Sylvie Cointe,*† Éric Rhéaume,‡ Catherine Martel,‡ Olivier Blanc-Brude,§ Evemie Dubé,¶ Florence Sabatier,*†# Françoise Dignat-George,*† Jean-Claude Tardif,‡ and Arnaud Bonnefoy

*VRCM, UMR-S1076, Aix-Marseille Université, INSERM, UFR de Pharmacie, Marseille, France
†Hematology and Vascular Biology Department, CHU La Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France
‡Department of Medicine, Université de Montréal; Montreal Heart Institute Research Center, Montreal, Canada
§PARCC UMRs970, Hôpital Européen Georges Pompidou, Paris, France
¶CHU Sainte-Justine, University of Montreal, Montreal, Canada
#Cell Therapy Department, CHU La Conception, Assistance Publique-Hôpitaux de Marseille, INSERM CBT-1409, Marseille, France

CD34+ progenitor cells are growing in use for vascular repair. However, in diabetic individuals with cardiovascular diseases, these cells have dysfunctional engraftment capabilities, which compromise their use for autologous cell therapy. The thrombospondin-1-derived peptide RFYVVMWK has previously been reported to stimulate cell adhesiveness through CD47 and integrin activation pathways. Our aim was to test whether RFYVVMWK preconditioning could modulate CD34+ cell phenotype and enhance its proadhesive properties in diabetic patients. Peripheral blood mononuclear CD34+ cells isolated from 40 atherosclerotic patients with type 2 diabetes (T2D;
n = 20) or without (non-T2D; n = 20) were preconditioned with 30 μM RFYVVMWK or truncated peptide RFYVVM. CD34+ cell adhesion was assessed on a vitronectin–collagen matrix and on TNF-α or IL-1β-stimulated HUVEC monolayers. Adhesion receptors, platelet/CD34+ cell conjugates, and cell viability were analyzed by flow cytometry and confocal microscopy. RFYVVMWK increased the adhesion of T2D CD34+ cells by eightfold to the vitronectin–collagen matrix (p < 0.001) corresponding to a threefold increase compared to unstimulated non-T2D CD34+ cells. The peptide induced the formation of platelet/CD34+ conjugates and increased the expression of TSP-1, CD29, CD51/CD61, and CD62P in both T2D and non-T2D cells. However, RFYVVMWK treatment did not affect the viability/apoptosis of CD34+ progenitor cells. Inconclusion, priming CD34+ cells with RFYVVMWK may enhance their vascular engraftment during autologous proangiogenic cell therapy.

Key words: Thrombospondin-1 (TSP-1); Atherosclerosis; Type 2 diabetes (T2D); CD34; CD47

Received July 29, 2016; final acceptance November 28, 2016. Online prepub date: October 6, 2016.
Address correspondence to Arnaud Bonnefoy, Hemostasis Laboratory, CHU Sainte-Justine, University of Montreal, 3207 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T, Canada. Tel: 1-514-345-4931; Fax: 1-514-345-4841; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 339-350, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
692735
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Fetal Tissues Tested for Microbial Sterility by Culture- and PCR-Based Methods Can be Safely Used in Clinics

Yakov VitrenkoIryna KostenkoKateryna KulebyakinaAlla DudaMariya Klunnyk, and Khrystyna Sorochynska

Cell Therapy Center Emcell, Kyiv, Ukraine

Cell preparations to be used in clinical practice must be free of infectious agents. Safety concerns are especially elevated upon the use of human fetal tissues, which are otherwise highly advantageous in cell therapy. We demonstrate that treating fetal samples with antibiotic, extensive washing, and homogenization prior to cryoconservation efficiently removes microbes in general. Screening a large collection by an automatic culture system showed that 89.2% fetal tissue samples were sterile, while contamination was detected in 10.8% samples. Liver and chorion were contaminated more than the brain, kidney, lung, and soft tissues. Broadrange PCR from the bacterial 16s rRNA gene was adopted as a confirmatory assay; however, the concordance between the culture-based and PCR assays was weak. Taxonomic identification was done for contaminated samples by bacteriological methods and sequencing 16s rRNA PCR products. The two approaches revealed different spectra of taxonomic groups sharing only
Lactobacillus, the most frequently found genus. In addition, other representatives of vaginal microbiota were detected by culture-based identification, while PCR product sequencing has also revealed a subset of nosocomial microorganisms. Importantly, species known to cause sepsis were identified by both techniques, arguing for their indispensability and mutual complementarity. We suggest that most contaminations are taken up during collection of fetal material rather than originating froman in utero infection. In conclusion, a rigorous microbiological control by culture and PCR is a prerequisite for safe clinical use of fetal tissue suspensions.

Key words: Fetal tissues; Broad-range PCR; 16s rRNA sequencing; BacT/ALERT; Microbial contamination

Received May 23, 2016; final acceptance October 21, 2016. Online prepub date: August 5, 2016.
Address correspondence to Khrystyna Sorochynska, Cell Therapy Center Emcell, 37A Syretska Street, Kyiv 04073, Ukraine. Tel: +38 044 223 28 95; Fax: +38 044 468 80 29; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 351-364, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
692960
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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Adult-Derived Human Liver Stem/Progenitor Cells Infused 3 Days Postsurgery Improve Liver Regeneration in a Mouse Model of Extended Hepatectomy

Astrid Herrero,*† Julie Prigent,* Catherine Lombard,* Valerie Rosseels,* Martine Daujat-Chavanieu,‡ Karine Breckpot,§ Mustapha Najimi,* Gisele Deblandre,* and Etienne M. Sokal*

*Universite Catholique de Louvain, Institut de Recherche Experimentale et Clinique (IREC), Pediatric Hepatology and Cell Therapy, Brussels, Belgium
†Department of Digestive Surgery and Liver Transplantation, Saint Eloi Hospital, Montpellier, France
Institut of Regenerative Medicine and Biotherapy (IRMB), Montpellier, France
§ Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel (VUB), Brussels, Belgium

There is growing evidence that cell therapy constitutes a promising strategy for liver regenerative medicine. In the setting of hepatic cancer treatments, cell therapy could prove a useful therapeutic approach for managing the acute liver failure that occurs following extended hepatectomy. In this study, we examined the influence of delivering adult-derived human liver stem/progenitor cells (ADHLSCs) at two different early time points in an immunodeficient mouse model (
Rag2/IL2Rg/) that had undergone a 70% hepatectomy procedure. The hepatic mesenchymal cells were intrasplenically infused either immediately after surgery (n = 26) or following a critical 3-day period (n = 26). We evaluated the cells’ capacity to engraft at day 1 and day 7 following transplantation by means of human Alu qPCR quantification, along with histological assessment of human albumin and a-smooth muscle actin. In addition, cell proliferation (anti-mouse and human Ki-67 staining) and murine liver weight were measured in order to evaluate liver regeneration. At day 1 posttransplantation, the ratio of human to mouse cells was similar in both groups, whereas 1 week posttransplantation this ratio was significantly improved (p < 0.016) in mice receiving ADHLSC injection at day 3 posthepatectomy (1.7%), compared to those injected at the time of surgery (1%). On the basis of liver weight, mouse liver regeneration was more extensive 1 week posttransplantation in mice transplanted with ADHLSCs (+65.3%) compared to that of mice from the sham vehicle group (+42.7%). In conclusion, infusing ADHLSCs 3 days after extensive hepatectomy improves the cell engraftment and murine hepatic tissue regeneration, thereby confirming that ADHLSCs could be a promising cell source for liver cell therapy and hepatic tissue repair.

Key words: Hepatic stem/progenitor cells; Mesenchymal cells; Xenotransplantation; Liver failure; Engraftment; Alu qPCR

Received March 25, 2016; final acceptance October 24, 2016. Online prepub date: September 21, 2016.
Address correspondence to Professor Etienne M. SokalCliniques Universitaires Saint-Luc, Paediatric Gastroenterology and Hepatology, Avenue Hippocrate 10, B-1200 Brussels, Belgium. Tel: +32-(0)2-7641387; Fax: +32-(0)2-7648909; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 26, pp. 365-377, 2017
0963-6897/17 $90.00 + .00
DOI: https://doi.org/10.3727/096368916X
693040
E-ISSN 1555-3892
Copyright © 2017 Cognizant, LLC.
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β-Catenin Accumulation Is Associated With Increased Expression of Nanog Protein and Predicts Maintenance of MSC Self-Renewal

Sang-Jin Yu,*1,2 Hyun-Je Kim,*†2 Eui Seok Lee,‡ Chung-Gyu Park,*§¶ Su Jin Cho,# and Soung-Hoo Jeon*§¶

*Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea
†Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
‡Department of Oral and Maxillofacial Surgery, College of Medicine, Korea University, Guro Hospital, Seoul, Republic of Korea
§Institute for Endemic Disease, Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea
¶Translational Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea
#Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Republic of Korea

Human mesenchymal stem cells (hMSCs) are self-renewing cells with the ability to differentiate into organized, functional network of cells. Recent studies have revealed that activation of the Wnt/
β-catenin pathway by a glycogen synthase kinase (GSK)-3-specific pharmacological inhibitor, Bio, results in the maintenance of self-renewal in both mouse and human ES cells. The molecular mechanism behind the maintenance of hMSCs by these factors, however, is not fully understood. We found that rEGF enhances the level of β -catenin, a component of the Wnt/ β -catenin signaling pathway. Furthermore, it was found that β -catenin upregulates Nanog. EGF activates the β -catenin pathway via the Ras protein and also increased the Nanog protein and gene expression levels 2 h after rEGF treatment. These results suggest that adding EGF can enhance β -catenin and Nanog expression in MSCs and facilitate EGF-mediated maintenance of MSC self-renewal. EGF was shown to augment MSC proliferation while preserving early progenitors within MSC population and thus did not induce differentiation. Thus, EGF not only can be used to expand MSC in vitro but also be utilized to autologous transplantation of MSCs in vivo.

Key words: Human mesenchymal stem cells (hMSCs); Self-renewing cells; Epidermal growth factor (EGF); β -catenin

Received December 29, 2015; final acceptance December 7, 2016. Online prepub date: September 27, 2016.
1Current affiliation: FOS Clinic, SM Tower (3rd Floor), 334 Gangnam-Daero, Gangnam-Gu, Seoul 135-936, Republic of Korea.
2These authors provided equal contribution to this work.
Address correspondence to Soung-Hoo Jeon, Ph.D., Department of Microbiology and Immunology, Institute of Endemic Disease, Medical Research Center, Xenotransplantation Research Center, Cancer Research Institute, Seoul National University College of Medicine, 103 Daehak-roJongno-gu, 110-799 Seoul, Republic of Korea. Tel: +82-2-3668-7465; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Su Jin Cho, Department of Pediatrics, Ewha Womans University School of Medicine, 1071 Anyangcheon-roYangcheon ku, Seoul, 158-710 Republic of Korea. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it