Cell Transplantation 23(9) Abstracts

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Cell Transplantation, Vol. 23, pp. 1045-1059, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368913X667709
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Paracrine Mechanisms of Mesenchymal Stem Cell-Based Therapy: Current Status and Perspectives

Xiaoting Liang,* Yue Ding,*† Yuelin Zhang,* Hung-Fat Tse,*‡ and Qizhou Lian*‡§

*Cardiology Division, Department of Medicine, University of Hong Kong, Hong Kong
†Organ Transplantation Institute, Xiamen University, Fujian Province, PR China
‡Research Centre of Heart, Brain, Hormone, and Healthy Aging, Li KaShing Faculty of Medicine, University of Hong Kong, Hong Kong
§Department of Ophthalmology, Li KaShing Faculty of Medicine, University of Hong Kong, Hong Kong

Mesenchymal stem cells (MSCs) are one of a few stem cell types to be applied in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair. In addition to their multipotent differentiation potential, a strong paracrine capacity has been proposed as the principal mechanism that contributes to tissue repair. Apart from cytokine/chemokine secretion, MSCs also display a strong capacity for mitochondrial transfer and microvesicle (exosomes) secretion in response to injury with subsequent promotion of tissue regeneration. These unique properties of MSCs make them an invaluable cell type to repair damaged tissues/organs. Although MSCs offer great promise in the treatment of degenerative diseases and inflammatory disorders, there are still many challenges to overcome prior to their widespread clinical application. Particularly, their in-depth paracrine mechanisms remain a matter for debate and exploration. This review will highlight the discovery of the paracrine mechanism of MSCs, regulation of the paracrine biology of MSCs, important paracrine factors of MSCs in modulation of tissue repair, exosome and mitochondrial transfer for tissue repair, and the future perspective for MSC-based therapy.

Key words: Mesenchymal stem cells (MSCs); Mechanism; Paracrine effects

Received November 26, 2012; final acceptance April 24, 2013. Online prepub date: May 14, 2013.
Address correspondence to Qizhou Lian, M.D., Ph.D., Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong. Tel: +852-21899752; Fax: +852-28162095; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 1061-1073, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368913X666999
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Activin B Promotes BMSC-Mediated Cutaneous Wound Healing by Regulating Cell Migration Via the JNK–ERK Signaling Pathway

Min Zhang,*1 Li Sun,*1 Xueer Wang,* Shixuan Chen,* Yanan Kong,* Nuyun Liu,† Yinghua Chen,* Qin Jia,* Lu Zhang,†‡ and Lin Zhang*

*Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
†Elderly Health Services Research Center, Southern Medical University, Guangzhou, China
‡Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

Bone marrow-derived mesenchymal stem cells (BMSCs) are able to differentiate into various types of skin cells and participate in skin regeneration and repair. Activin signaling can regulate wound healing and reepithelialization. The present study assessed the impact of activin B on BMSC-mediated cutaneous wound healing in rats and explored the possible mechanism involved. We found that CFSE-labeled BMSCs participated in wound healing in vivo, and compared to administration with PBS, activin B, or BMSCs, activin B plus BMSCs significantly promoted wound healing and hair follicle regeneration. Activin B induced actin stress fiber formation and cell migration in BMSCs in vitro. Activation of JNK and ERK, but not p38, was required for activin B-induced actin stress fiber formation and BMSC migration. These results show that activin B may promote BMSC-mediated wound healing by inducing actin stress fiber formation and BMSC migration via the ERK and JNK signal pathways. Combined administration of BMSCs and cytokines may be a promising therapeutic strategy for the management of skin wounds.

Key words: Activin B; Skin; Wound healing; Bone marrow-derived mesenchymal stem cells (BMSCs); c-JUN NH2-terminal protein kinase (JNK); Extracellular signal regulated kinase (ERK)

Received March 27, 2012; final acceptance April 9, 2013. Online prepub date: April 12, 2013.
1These authors provided equal contribution to this work.
Address correspondence to Dr. Lin Zhang, Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. Tel: +8602061648205; Fax: +8602061648205; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Dr. Lu Zhang, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. Tel: +8602061648205; Fax: +8602061648205; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 1075-1085, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368913X665576
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Efficacy and Safety of Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Type 2 Diabetes Mellitus: A Randomized Placebo-Controlled Study

Anil Bhansali,* Premkumar Asokumar,* Rama Walia,* Shobhit Bhansali,* Vivek Gupta,† Ashish Jain,‡ Naresh Sachdeva,* Rati Ram Sharma,‡ Neelam Marwaha,‡ and Niranjan Khandelwal†

*Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
†Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh, India
‡Department of Transfusion Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India

There is a growing interest in cell-based therapies in T2DM as β-cell failure is progressive and inexorable with the advancing duration of disease. This prospective, randomized, single-blinded placebo-controlled study evaluates the efficacy and safety of autologous bone marrow-derived stem cell transplantation (ABMSCT) in T2DM. Twenty-one patients with triple oral antidiabetic drug failure and requiring insulin ≥0.4 IU per kg per day with HbA1c <7.5% were randomly assigned to an intervention (n = 11) and control group (n = 10) and followed for 12 months. Patients in the intervention group received ABMSCT through a targeted approach, and after 12 weeks, a second dose of stem cells was administered through the antecubital vein after mobilization with G-CSF, while the control group underwent a sham procedure. The primary end point was a reduction in insulin requirement by ≥50% from baseline while maintaining HbA1c <7%. Nine out of the 11 (82%) patients in the intervention group achieved the primary end point, whereas none of the patients in the control group did over the study period (p = 0.002). The insulin requirement decreased by 66.7% in the intervention group from 42.0 (31.0–64.0) IU per day to 14.0 (0.0–30.0) IU per day (p = 0.011), while in controls it decreased by 32.1% from 40.5 (31.8–44.3) IU per day to 27.5 (23.5–33.3) IU per day (p = 0.008) at 12 months. The reduction in insulin requirement was significantly more in the intervention group compared to controls at both 6 (p = 0.001) and 12 months (p = 0.004). There was a modest but nonsignificant increase in HbA1c (%) in cases from 6.9% (6.4–7.2%) to 7.1% (6.6–7.5%) as well as in controls from 6.9% (6.2–7.0%) to 7.0% (6.9–7.5%). Ten out of 11 (91%) patients could maintain HbA1c <7% in the intervention group, whereas 6 out of 10 did (60%) in the control group (p = 0.167). The glucagon-stimulated C-peptide significantly increased in treated cases compared to controls (p = 0.036). The decrease in insulin requirement positively correlated with stimulated C-peptide (r = 0.8, p = 0.001). In conclusion, ABMSCT results in a significant decrease in the insulin dose requirement along with an improvement in the stimulated C-peptide levels in T2DM. However, a greater number of patients with a longer duration of follow-up are required to substantiate these observations.

Key words: Type 2 diabetes mellitus (T2DM); Autologous bone marrow-derived stem cell therapy; Targeted stem cell injection

Received May 28, 2012; final acceptance March 7, 2013. Online prepub date: April 2, 2013.
Address correspondence to Dr. Anil Bhansali, Professor and Head, Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 1087-1098, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X661319
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Improvement in Poor Graft Function After Allogeneic Hematopoietic Stem Cell Transplantation Upon Administration of Mesenchymal Stem Cells From Third-Party Donors: A Pilot Prospective Study

Xiaodan Liu,*†1 Meiqing Wu,*1 Yanwen Peng,‡ Xiaoyong Chen,‡ Jing Sun,* Fen Huang,* Zhiping Fan,* Hongsheng Zhou,* Xiuli Wu,* Guopan Yu,* Xian Zhang,* Yonghua Li,§ Yang Xiao,§ Chaoyang Song,¶ Andy Peng Xiang,‡ and Qifa Liu*

*Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
†Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, China
‡Center for Stem Cell Biology and Tissue Engineering, The Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
§Department of Hematology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China
¶Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China

Poor graft function (PGF) is a refractory complication that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present study, we prospectively evaluated the efficacy and safety of mesenchymal stem cells (MSCs) expanded from the bone marrow of a third-party donor to patients with PGF after allo-HSCT. Twenty patients with PGF (7 with primary and 13 with secondary PGF) received MSCs (1 × 106/kg) one to three times at 28-day intervals. Seventeen patients were responsive to MSCs, whereas three were not. Within the first 100 days after MSC treatment, 13 patients developed 20 episodes of infection. Moreover, five patients experienced cytomegalovirus-DNA viremia, and seven experienced Epstein–Barr virus (EBV)–DNA viremia within the first 100 days after MSC treatment; three of the latter developed EBV-associated posttransplant lymphoproliferative disorders (PTLD) within the follow-up period. Grade II acute graft-versus-host disease (GVHD) occurred in one patient, and local chronic GVHD occurred in two patients after receiving MSC treatment, including one acute GVHD and one chronic GVHD, respectively, after accepting donor lymphocyte infusions due to PTLD. After a follow-up period of an average of 508 days (range 166–904 days) posttransplantation, 11 patients died. No short-term toxic side effects were observed after MSC treatment. Two patients experienced leukemic relapse. With the exception of three patients with PTLD, no secondary tumors occurred. These results indicate that MSCs derived from the bone marrow of a third-party donor are beneficial in the treatment of both primary and secondary PGF that develops after allo-HSCT. However, additional studies will be needed to determine whether such treatment might increase the risk of EBV infection and reactivation or the development of EBV-associated PTLD.

Key words: Poor graft function (PGF); Mesenchymal stem cells (MSCs); Allogeneic hematopoietic stem cell transplantation (allo-HSCT); Third-party donors

Received March 2, 2012; final acceptance December 12, 2012. Online prepub date: January 2, 2013.
1These authors provided equal contribution to this work.
Address correspondence to Qifa Liu, Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 5l05l5, China. Tel: +86-020-61641612; Fax: +86-020-61641612; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Andy Peng Xiang, Center for Stem Cell Biology and Tissue Engineering, the Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou 510080, China. Tel: +86-020-87335858; Fax: +86-020-87335858; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 1099-1110, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368913X665585
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Mutual Interaction Between Human Multipotent Adult Progenitor Cells and NK Cells

Sandra A. Jacobs,*1 Jeroen Plessers,*1 Jef Pinxteren,† Valerie D. Roobrouck,‡ Catherine M. Verfaillie,‡ and Stefaan W. Van Gool*

*Department of Microbiology and Immunology, Laboratory of Pediatric Immunology, KU Leuven, Leuven, Belgium
†ReGenesys, Heverlee, Belgium
‡Department of Development and Regeneration, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium

Human multipotent adult progenitor cells (hMAPCs) are isolated from bone marrow with a more extensive expansion capacity compared to human mesenchymal stem cells (hMSCs) and with the ability to differentiate into endothelium. Like hMSCs, hMAPCs inhibit T-cell proliferation induced by alloantigens. In this study, we tested the interaction between hMAPCs and natural killer (NK) cells. We assessed the susceptibility of hMAPCs to NK cell-mediated lysis and the immunomodulation of hMAPCs on NK cell function during IL-2-driven stimulation and the cytolytic effector phase. Human MAPCs express the ligands PVR and ULBP-2/5/6, which are recognized by activating NK cell receptors. However, they also express MHC class I molecules, which induce inhibitory signals in NK cells. Freshly isolated NK cells at different effector:target ratios did not kill hMAPCs as assessed by an MTT and 51Cr-release assay, while hMAPCs impaired the cytotoxic activity of resting NK cells against the NK-sensitive K562 leukemia cell line. By contrast, IL-2-stimulated NK cells were capable of killing hMAPCs, and preactivated NK cells were not influenced during their cytotoxic effector function against K562 cells by hMAPCs. When added during the 6-day preactivation phase with IL-2, hMAPCs dose-dependently reduced NK cell proliferation in an IDO-dependent manner, but they did not influence the induction of cytotoxic capacity by IL-2. This study indicates that human MAPCs mutually interact with NK cells.

Key words: Human multipotent adult progenitor cells (hMAPCs); Natural killer (NK) cells; NK cell-mediated cytotoxicity; Immunomodulation

Received June 29, 2012; final acceptance March 9, 2013. Online prepub date: April 2, 2013.
1These authors provided equal contribution to this work.
Address correspondence to Sandra Anne Bert Jacobs, Laboratory of Pediatric Immunology, KU Leuven, O&N 1 box 811, Herestraat 49, 3000 Leuven, Belgium. Tel: +3216332211; Fax: +3216346035; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 1111-1125, 2014
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DOI: http://dx.doi.org/10.3727/096368913X670165
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Amnion-Derived Multipotent Progenitor Cells Inhibit Blood Monocyte Differentiation Into Mature Dendritic Cells

Richard Banas,* Carrie Miller,* Lynda Guzik,† and Adriana Zeevi‡

*Stemnion, Inc., Pittsburgh, PA, USA
†McGowen Institute of Regenerative Medicine, Pittsburgh, PA, USA
‡University of Pittsburgh, Pittsburgh, PA, USA

Cells derived from the placenta have become the focus of extensive research concerning their ability to be used for regenerative medicine or cellular therapies. In a previous study, we characterized amnion-derived multipotent progenitor cells, or AMP cells, by in vitro methods and showed they were able to inhibit antigen-specific T-cell proliferation in a cell-to-cell contact-dependent fashion. Here we examine specific mechanisms involved in immunomodulation by AMP cells. We found that AMP cells significantly inhibited monocyte-derived myeloid dendritic cell (DC) maturation when placed in coculture. Cocultured monocytes retained the nondifferentiated macrophage marker CD14 while exhibiting significant reduction in DC maturation markers CD83 and CD1a, indicating an immature DC maturation state that is pivotal in determining its immune stimulatory or regulatory status. This effect was again dependent on cell-to-cell contact interaction. We also found a significant shift in cytokines present in the microenvironment of cocultures, which indicated a regulatory DC function rather than a stimulatory cell type. Here supernatants taken from AMP cell/monocyte cocultures yielded significant levels of regulatory cytokines, such as PGE2, IL-6, IL-10, and MIC-1. The soluble form of HLA-G was also found at higher levels in cocultures. In contrast, supernatants contained significantly less amounts of the T-cell-stimulating factor IL-12, which is normally produced by activated DCs. Interestingly, cocultured monocytes acquired significant expression of HLA-G on their cell surface over time. HLA-G has multifaceted immunological implications and may be a key molecule in influencing these cells to behave as regulatory DCs. Together, the influence of AMP cells on maturing DCs may favor a regulatory pathway that can be useful for therapeutic applications for immune-mediated disorders or transplantation therapies.

Key words: Amnion; Amnion-derived multipotent progenitor (AMP) cells; Amniotic epithelial cells (AECs); Monocytes; Dendritic cells (DCs)

Received April 16, 2013; final acceptance June 28, 2013. Online prepub date: July 11, 2013.
Address correspondence to Richard A. Banas, M.S., Research Associate, Stemnion, Inc., 100 Technology Drive, Suite 200, Pittsburgh, PA 15219-3138, USA. Tel: +1-412-402-9913; Fax: +1-412-452-9480; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 1127-1142, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368913X666421
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Adult Human Hepatocytes Promote CD4+ T-Cell Hyporesponsiveness Via Interleukin-10-Producing Allogeneic Dendritic Cells

Gwenaelle Sana,* Catherine Lombard,* Olivier Vosters,*† Nawal Jazouli,* Floriane Andre,* Xavier Stephenne,* Francoise Smets,* Mustapha Najimi,* and Etienne M. Sokal*

*Universite Catholique de Louvain and Cliniques Universitaires Saint-Luc, Laboratory of Pediatric Hepatology and Cell Therapy, Brussels, Belgium
†IRIBHM, Universite Libre de Bruxelles, Brussels, Belgium

The success of liver cell therapy remains closely dependent on how well the infused cells can be accepted after transplantation and is directly related to their degree of immunogenicity. In this study, we investigated the in vitro immunogenic properties of isolated human hepatocytes (hHeps) and adult-derived human liver progenitor cells (ADHLPCs), an alternative cell candidate for liver cell transplantation (LCT). The constitutive expression of immune markers was first analyzed on these liver-derived cells by flow cytometry. Human liver-derived cells were then cocultured with allogeneic human adult peripheral blood mononuclear cells (PBMCs), and the resulting activation and proliferation of PBMCs was evaluated, as well as the cytokine levels in the coculture supernatant. The effect of liver-derived cells on monocyte-derived dendritic cell (MoDC) properties was further analyzed in a secondary coculture with naive CD4+ T-cells. We report that hHeps and ADHLPCs expressed human leukocyte antigen (HLA) class I and Fas but did not express HLA-DR, Fas ligand, and costimulatory molecules. hHeps and ADHLPCs did not induce T-cell activation or proliferation. Moreover, hHeps induced a cell contact-dependent production of interleukin (IL)-10 that was not observed with ADHLPCs. The IL-10 was produced by myeloid DC subset characterized by an incomplete mature state. Furthermore, hHep-primed MoDCs induced an antigen-independent hyporesponsiveness of naive CD4+ T lymphocytes that was partially reversed by blocking IL-10, whereas nonprimed MoDCs (i.e., those cultured alone) did not. hHeps and ADHLPCs present a low immunogenic phenotype in vitro. Allogeneic hHeps, but not ADHLPCs, promote a cell contact-dependent production of IL-10 by myeloid DCs, which induces naive CD4+ T-cells antigen-independent hyporesponsiveness.

Key words: Cell transplantation; Liver cells; Immunogenicity; Anergy; Antigen-presenting cells

Received August 22, 2011; final acceptance March 27, 2013. Online prepub date: April 12, 2013.
Address correspondence to Etienne M. Sokal, Laboratory of Pediatric Hepatology and Cell Therapy, Universite Catholique de Louvain, Cliniques Universitaires Saint-Luc, Av. Hippocrate 10, B-1200 Brussels, Belgium. Tel: +32-2-7641387; Fax: +32-2-7648909; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 1143-1151, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368913X668627
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Hypothermic Storage of Human Hepatocytes for Transplantation

Roberto Gramignoli,* Kenneth Dorko,† Veysel Tahan,† Kristen J. Skvorak,† Ewa Ellis,‡ Carl Jorns,‡ Bo-Goran Ericzon,‡ Ira J. Fox,§ and Stephen C. Strom*

*Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital, Stockholm, Sweden
†Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
‡Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden
§Department of Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh PA, USA

Transplantation of human hepatocytes is gaining recognition as a bridge or an alternative to orthotopic liver transplantation for patients with acute liver failure and genetic defects. Since most patients require multiple cell infusions over an extended period of time, we investigated hepatic functions in cells maintained in University of Wisconsin solution at 4°C up to 72 h. Eleven different assessments of hepatic viability and function were investigated both pre- and posthypothermic storage, including plating efficiency, caspase-3/7 activity, ammonia metabolism, and drug-metabolizing capacity of isolated hepatocytes. Long-term function, basal, and induced cytochrome P450 activities were measured after exposure to prototypical inducing agents. Cells from 47 different human liver specimens were analyzed. Viability significantly decreased in cells cold stored in UW solution, while apoptosis level and plating efficiency were not significantly different from fresh cells. Luminescent and fluorescent methods assessed phases I and II activities both pre- and post-24–72 h of cold preservation. A robust induction (up to 200-fold) of phase I enzymes was observed in cultured cells. Phase II and ammonia metabolism remained stable during hypothermic storage, although the inductive effect of culture on each metabolic activity was eventually lost. Using techniques that characterize 11 measurements of hepatic viability and function from plating efficiency, to ammonia metabolism, to phases I and II drug metabolism, it was determined that while viability decreased, the remaining viable cells in cold-stored suspensions retained critical hepatic functions for up to 48 h at levels not significantly different from those observed in freshly isolated cells.

Key words: Hepatocyte transplantation (HTx); Human hepatocyte preservation; Cold storage; Hepatic functions

Received March 21, 2013; final acceptance May 22, 2013. Online prepub date: June 13, 2013.
Address correspondence to Stephen C. Strom, Ph.D., Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital, SE-141 86 Huddinge, Stockholm, Sweden. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 1153-1162, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368913X666980
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
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Hepatocyte Transplantation Ameliorates the Metabolic Abnormality in a Mouse Model of Acute Intermittent Porphyria

Zhaohui Yin,*† Staffan Wahlin,‡ Ewa C. S. Ellis,* Pauline Harper,§ Bo-Goran Ericzon,* and Greg Nowak*

*Division of Transplantation Surgery, Department for Clinical Science, Intervention and Technology CLINTEC, Karolinska University Hospital, Stockholm, Sweden
†Department of General Surgery, First Hospital of Shantou University Medical College, Shantou, Guangdong Province, China
‡Department of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
§Porphyria Centre Sweden, Division of Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden

Acute intermittent porphyria (AIP) is an autosomal dominant disorder characterized by insufficient porphobilinogen deaminase (PBGD) activity. When hepatic heme synthesis is induced, porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) accumulate, which causes clinical symptoms such as abdominal pain, neuropathy, and psychiatric disturbances. Our aim was to investigate if hepatocyte transplantation can prevent or minimize the metabolic alterations in an AIP mouse model. We transplanted wild-type hepatocytes into PBGD-deficient mice and induced heme synthesis with phenobarbital. ALA and PBG concentrations in plasma were monitored, and the gene transcriptions of hepatic enzymes ALAS1, PBGD, and CYP2A5 were analyzed. Results were compared with controls and correlated to the percentage of engrafted hepatocytes. The accumulation of ALA and PBG was reduced by approximately 50% after the second hepatocyte transplantation. We detected no difference in mRNA levels of PBGD, ALAS1, or CYP2A5. Engraftment corresponding to 2.7% of the total hepatocyte mass was achieved following two hepatocyte transplantations. A lack of precursor production in less than 3% of the hepatocytes resulted in a 50% reduction in plasma precursor concentrations. This disproportional finding suggests that ALA and PBG produced in PBGD-deficient hepatocytes crossed cellular membranes and was metabolized by transplanted cells. The lack of effect on enzyme mRNA levels suggests that no significant efflux of heme from normal to PBGD-deficient hepatocytes takes place. Further studies are needed to establish the minimal number of engrafted hepatocytes needed to completely correct the metabolic abnormality in AIP and whether amelioration of the metabolic defect by partial restoration of PBGD enzyme activity translates into a clinical effect in human AIP.

Key words: Acute intermittent porphyria (AIP); Hepatocyte transplantation; Porphobilinogen deaminase (PBGD); Mice

Received February 19, 2012; final acceptance April 4, 2013. Online prepub date: April 12, 2013.
Address correspondence to Staffan Wahlin, M.D., Ph.D., Department of Gastroenterology and Hepatology, K63, Karolinska Institutet, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46858587984; Fax: +46858582335; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 23, pp. 1163-1166, 2014
0963-6897/14 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368913X667691
E-ISSN 1555-3892
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Brief Communication

Effect of Epigallocatechin-3-Gallate on Graft-Versus-Host Disease

Jaebok Choi,* Matthew L. Cooper,* Edward D. Ziga,†1 Julie Ritchey,* and John F. DiPersio*

*Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
†Division of Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often complicated by alloreactive donor T-cell-mediated graft-versus-host disease (GvHD). The major polyphenol of green tea, epigallocatechin-3-gallate (EGCG), is an inhibitor of both DNA methyltransferase 1 (DNMT1) and signal transducer and activator of transcription 1 (STAT1), which are essential for induction of GvHD. Thus, in this report, we examine if in vivo administration of EGCG mitigates GvHD in several different animal models. While we concede that refinement of EGCG treatment might result in GvHD prevention, our results suggest that EGCG treatment might not be an effective therapy against GvHD in the clinic.

Key words: Graft-versus-host disease (GvHD); Allogeneic hematopoietic stem cell transplantation (allo-HSCT); Epigallocatechin-3-gallate (EGCG); DNA methyltransferase 1 (DNMT1); Interferon-g receptor signaling; Signal transducer and activator of transcription 1 (STAT1)

Received November 13, 2012; final acceptance April 24, 2013. Online prepub date: May 14, 2013.
1Current address: Blood & Marrow Transplant, University of Miami Miller School of Medicine, Miami, FL, USA.
Address correspondence to Jaebok Choi, Ph.D., Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8007, St. Louis, MO 63110, USA. Tel: +1-314-362-9349; Fax: +1-314-362-9333; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or John F. DiPersio, M.D., Ph.D., Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8007, St. Louis, MO 63110, USA. Tel: +1-314-454-8491; Fax: +1-314-454-7551; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it