Cell Transplantation 22(3) Abstracts

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Cell Transplantation, Vol. 22, pp. 381-391, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X656072
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Composite Brains: Toward a Systems Theory of Neural Reconstruction

Stephen Polgar

School of Health Sciences and Human Biosciences, La Trobe University, Bundoora, Victoria, Australia

The results of uncontrolled, open-label clinical trials indicate that reconstructive cellular therapies have the capacity to produce meaningful functional improvements in patients with brain disorders. However, the transplantation of fetal cells has not progressed to viable best practice treatment for any brain disorder. A conceptual approach, referred to as the Repair Model, has served as a useful heuristic for initiating research in the field and guiding the development of new practices. Analysis of evidence for the treatment of Parkinson’s disease indicates that recovery following neural grafting is a complex process influenced by factors beyond the replacement of neurons. An alternative approach, the Composite Brain Model, is outlined to address limitations of the Repair Model. A hierarchical, open-system model is proposed, which aims to track the interactions between the grafted cells, the host brain, and the environment. The Composite Brain Model emphasizes the importance of the interactions between the patient, their physical and social environment, and the provision of rehabilitation during recovery. It is proposed that the Composite Brain Model is useful in providing an alternative perspective for research, theory building, and practice.

Key words: Cellular therapy; Parkinson’s disease (PD); Neural grafting; Rehabilitation; Neural plasticity; Functional recovery

Received December 5, 2011; final acceptance May 15, 2012. Online prepub date: September 21, 2012.
Address correspondence to Stephen Polgar, School of Health Sciences and Human Biosciences, La Trobe University, Bundoora, VIC 3086, Australia. Tel: +61-3-9479-1748; Fax: +61-3-9479-1783; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 393-412, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X656081
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Human Mesenchymal Precursor Cells (Stro-1+) From Spinal Cord Injury Patients Improve Functional Recovery and Tissue Sparing in an Acute Spinal Cord Injury Rat Model

Stuart I. Hodgetts,* Paul J. Simmons,† and Giles W. Plant*‡

*Eileen Bond Spinal Cord Research Laboratory, School of Anatomy and Human Biology, University of Western Australia, Perth, Western Australia
†Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA
‡Stanford Partnership for Spinal Cord Injury and Repair, Stanford Institute for Neuro-Innovation and Translational Neurosciences and Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA

This study aimed to determine the potential of purified (Stro-1+) human mesenchymal precursor cells (hMPCs) to repair the injured spinal cord (SC) after transplantation into T-cell-deficient athymic RNU nude rats following acute moderate contusive spinal cord injury (SCI). hMPCs were isolated from the bone marrow (BM) stroma of SCI patients and transplanted as a suspension graft in medium [with or without immunosuppression using cyclosporin A (CsA)]. Extensive anatomical analysis shows statistically significant improvement in functional recovery, tissue sparing, and cyst reduction. We provide quantitative assessment of supraspinal projections in combination with functional outcomes. hMPC-transplanted animals consistently achieved mean BBB scores of 15 at 8 weeks postinjury. Quantitative histological staining revealed that graft-recipient animals possessed more intact spinal tissue and reduced cyst formation than controls. Fluorogold (FG) retrograde tracing revealed sparing/regeneration of supraspinal and local propriospinal axonal pathways, but no statistical differences were observed compared to controls. Immunohistochemical analysis revealed increased serotonergic (5-HT) and sensory (CGRP) axonal growth within and surrounding transplanted donor hMPCs 2 weeks posttransplantation, but no evidence of hMPC transdifferentiation was seen. Although hMPCs initially survive at 2 weeks posttransplantation, their numbers were dramatically reduced and no cells were detected at 8 weeks posttransplantation using retroviral/lentiviral GFP labeling and a human nuclear antigen (HNA) antibody. Additional immunosuppression with CsA did not improve hMPC survival or their ability to promote tissue sparing or functional recovery. We propose Stro-1+-selected hMPCs provide (i) a reproducible source for stem cell transplantation for SC therapy and (ii) a positive host microenvironment resulting in the promotion of tissue sparing/repair that subsequently improves behavioral outcomes after SCI. Our results provide a new candidate for consideration as a stem cell therapy for the repair of traumatic CNS injury.

Key words: Spinal cord (SC); Transplantation; Cellular therapy; Mesenchymal precursors; Contusion

Received April 12, 2011; final acceptance May 3, 2012. Online prepub date: September 21, 2012.
Address correspondence to Associate Professor Giles W. Plant, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Lorry I. Lokey Stem Cell Research Building, Stanford University, 265 Campus Drive, Stanford CA 94305, USA. Tel: +1-650-724-3388; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 413-422, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X656090
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Isolation of Mesenchymal Stem Cells From Shoulder Rotator Cuff: A Potential Source for Muscle and Tendon Repair

Chih-Chien Tsai,*†1 Tung-Fu Huang,‡§1 Hsiao-Li Ma,‡§ En-Rung Chiang,*‡§ and Shih-Chieh Hung*†‡§¶

*Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
†Stem Cell Laboratory, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
‡Department of Orthopaedics, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
§Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
¶Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan

The self-healing potential of each tissue belongs to endogenous stem cells residing in the tissue; however, there are currently no reports mentioned for the isolation of human rotator cuff-derived mesenchymal stem cells (RC-MSCs) since. To isolate RC-MSCs, minced rotator cuff samples were first digested with enzymes and the single cell suspensions were seeded in plastic culture dishes. Twenty-four hours later, nonadherent cells were removed and the adherent cells were further cultured. The RC-MSCs had fibroblast-like morphology and were positive for the putative surface markers of MSCs, such as CD44, CD73, CD90, CD105, and CD166, and negative for the putative markers of hematopoietic cells, such as CD34, CD45, and CD133. Similar to BM-MSCs, RC-MSCs were demonstrated to have the potential to undergo osteogenic, adipogenic, and chondrogenic differentiation. Upon induction in the defined media, RC-MSCs also expressed lineage-specific genes, such as Runx 2 and osteocalcin in osteogenic induction, PPAR-g and LPL in adipogenic differentiation, and aggrecan and Col2a1 in chondrogenic differentiation. The multipotent feature of RC-MSCs in the myogenic injury model was further strengthened by the increase in myogenic potential both in vitro and in vivo when compared with BM-MSCs. These results demonstrate the successful isolation of MSCs from human rotator cuffs and encourage the application of RC-MSCs in myogenic regeneration.

Key words: Mesenchymal stem cells (MSCs); Rotator cuff (RC); Muscle repair

Received October 6, 2011; final acceptance April 15, 2012. Online prepub date: September 21, 2012.
1These authors provided equal contribution to this work.
Address correspondence to Shih-Chieh Hung, M.D., Ph.D., Department of Medical Research and Education, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Road, Taipei, 11217, Taiwan. Tel: +886-2-287512121, ext. 3450; Fax: +886-2-28267396; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 423-436, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X653246
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Copyright © 2013 Cognizant Comm. Corp.
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A Novel Strategy to Enhance Mesenchymal Stem Cell Migration Capacity and Promote Tissue Repair in an Injury Specific Fashion

C. Xinaris,* M. Morigi,* V. Benedetti,* B. Imberti,* A. S. Fabricio,† E. Squarcina,‡ A. Benigni,* E. Gagliardini,* and G. Remuzzi*§

*“Mario Negri” Institute for Pharmacological Research, Bergamo, Italy
†Regional Center for Biomarkers-ABO Foundation, Venice, Italy
‡Istituto Oncologico Veneto (IOV)-IRCCS, Padova, Italy
§Unit of Nephrology and Dialysis, Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy

Mesenchymal stem cells (MSCs) of bone marrow origin appear to be an attractive candidate for cell-based therapies. However, the major barrier to the effective implementation of MSC-based therapies is the lack of specific homing of exogenously infused cells and overall the inability to drive them to the diseased or damaged tissue. In order to circumvent these limitations, we developed a preconditioning strategy to optimize MSC migration efficiency and potentiate their beneficial effect at the site of injury. Initially, we screened different molecules by using an in vitro injury–migration setting, and subsequently, we evaluated the effectiveness of the different strategies in mice with acute kidney injury (AKI). Our results showed that preconditioning of MSCs with IGF-1 before infusion improved cell migration capacity and restored normal renal function after AKI. The present study demonstrates that promoting migration of MSCs could increase their therapeutic potential and indicates a new therapeutic paradigm for organ repair.

Key words: Mesenchymal stem cells (MSCs); Migration; Insulin-like growth factor-1 (IGF-1); Acute kidney injury (AKI); Kidney repair

Received January 26, 2011; final acceptance April 30, 2012. Online prepub date: August 10, 2012.
Address correspondence to Christodoulos Xinaris, Ph.D., “Mario Negri” Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy. Tel: +39-035-42131; Fax: +39-035-319331; 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. 22, pp. 437-445, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X656162
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Platelet-Rich Plasma Enhances the Dermal Regeneration Efficacy of Human Adipose-Derived Stromal Cells Administered to Skin Wounds

Suk Ho Bhang,*1 Jooyeon Park,*1 Hee Seok Yang,* Jaehoon Shin,* and Byung-Soo Kim*†

*School of Chemical and Biological Engineering, Seoul National University, Seoul, Republic of Korea
†Bio-MAX Institute, Institute of Chemical Processes, Engineering Research Institute, Seoul National University, Seoul, Republic of Korea

The administration of human adipose-derived stromal cells (hASCs) enhances skin wound healing. However, poor survival of hASCs that are administered to avascular wound regions may limit the therapeutic efficacy of the hASCs. The aim of this study was to determine whether the coadministration of platelet-rich plasma (PRP) and hASCs enhanced the skin wound-healing efficacy of hASCs. Skin regeneration was examined in skin wounds of athymic mice that were either untreated or treated with hASCs, PRP, or both hASCs and PRP. Coadministration of PRP and hASCs resulted in better skin regeneration than hASC administration alone in part by significantly improving the proliferation of administered hASCs by the angiogenic growth factor secretion of the hASCs and surrounding mouse host cells in the wound areas and by promoting neovascularization in the wound beds.

Key words: Angiogenesis; Angiogenic factor; Human adipose-derived stromal cells (hASCs); Platelet-rich plasma (PRP); Wound healing

Received June 20, 2011; final acceptance April 16, 2012. Online prepub date: October 1, 2012.
1These authors provided equal contribution to this work.
Address correspondence to Byung-Soo Kim, School of Chemical and Biological Engineering, Seoul National University, Seoul 151–744, Republic of Korea. Tel.: +82-2-880-1509; Fax: +82-2-888-1604; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 447-459, 2013
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DOI: http://dx.doi.org/10.3727/096368912X640583
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Copyright © 2013 Cognizant Comm. Corp.
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Inhibition of Kupffer Cell Activity Improves Transplantation of Human Adipose-Derived Stem Cells and Liver Functions

Il-Hwa Hong,* Seon-Young Han,*† Mi-Ran Ki,* Young-Mi Moon,‡ Jin-Kyu Park,* Sang-Young You,*† Eun-Mi Lee,*† Ah-Young Kim,*† Eun-Joo Lee,*† Jae-Ho Jeong,‡ Kyung-Sun Kang,§ and Kyu-Shik Jeong*†

*College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea
†Stem Cell Therapeutic Research Institute, Kyungpook National University, Daegu, Republic of Korea
‡Division of Plastic Surgery, Yeungnam University Medical Center, Daegu, Republic of Korea
§Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea

Numerous approaches to cell transplantation of the hepatic or the extrahepatic origin into liver tissue have been developed; however, the efficiency of cell transplantation remains low and liver functions are not well corrected. The liver is a highly immunoreactive organ that contains many resident macrophages known as Kupffer cells. Here, we show that the inhibition of Kupffer cell activity improves stem cell transplantation into liver tissue and corrects some of the liver functions under conditions of liver injury. We found that, when Kupffer cells were inhibited by glycine, numerous adipose-derived stem cells (ASCs) were successfully transplanted into livers, and these transplanted cells showed hepatoprotective effects, including decrease of liver injury factors, increase of liver regeneration, and albumin production. On the contrary, injected ASCs without glycine recruited numerous Kupffer cells, not lymphocytes, and showed low transplantation efficiency. Intriguingly, successfully transplanted ASCs in liver tissue modulated Kupffer cell activity to inhibit tumor necrosis factor-α secretion. Thus, our data show that Kupffer cell inactivation is an important step in order to improve ASC transplantation efficiency and therapeutic potential in liver injuries. In addition, the hepatoprotective function of glycine has synergic effects on liver protection and the engraftment of ASCs.

Key words: Adipose-derived stem cells (ASCs); Glycine; Kupffer cells; Liver; Tumor necrosis factor-α (TNF-α)

Received July 26, 2011; final acceptance March 27, 2012. Online prepub date: April 26, 2012.
Address correspondence to Kyu-Shik Jeong, D.V.M., Ph.D., Department of Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea. Tel: +82-53-950-5975; Fax: +82-53-950-5955; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 461-468, 2013
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DOI: http://dx.doi.org/10.3727/096368912X656063
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Influenza Virus Infects Bone Marrow Mesenchymal Stromal Cells In Vitro: Implications for Bone Marrow Transplantation

Mahesh Khatri and Yehia M. Saif

Food Animal Health Research Program, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, OH, USA

Mesenchymal stromal cells (MSCs) have differentiation, immunomodulatory, and self-renewal properties and are, therefore, an attractive tool for regenerative medicine and autoimmune diseases. MSCs may be of great value to treat graft-versus-host disease. Influenza virus causes highly contagious seasonal infection and occasional pandemics. The infection is severe in children, elderly, and immunocompromised hosts including hematopoietic stem cell transplant patients. The objective of this study was to determine if MSCs are permissive to influenza virus replication. We isolated MSCs from the bone marrow of 4- to 6-week-old germ-free pigs. Swine and human influenza virus strains were used to infect MSCs in vitro. MSCs expressed known influenza virus a-2,3 and a-2,6 sialic acid receptors and supported replication of swine and human influenza viruses. Viral infection of MSCs resulted in cell lysis and proinflammatory cytokine production. These findings demonstrate that bone marrow-derived MSCs are susceptible to influenza virus. The data also suggest that transplantation of bone marrow MSCs from influenza virus-infected donors may transmit infection to recipients. Also, MSCs may get infected if infused into a patient with an ongoing influenza virus infection.

Key words: Mesenchymal stromal cells (MSCs); Influenza virus; Cell therapy

Received October 17, 2011; final acceptance April 7, 2012. Online prepub date: September 21, 2012.
Address correspondence to Dr. Mahesh Khatri, Food Animal Health Research Program, Ohio Agricultural Research and Development Center, The Ohio State University, 1680 Madison Avenue, Wooster, OH 44691, USA. Tel: +1-330-263-3751; Fax: +1-330-263-3677; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 469-476, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X656135
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Humoral Immune Response Following Seasonal Influenza Vaccine in Islet Transplant Recipients

Moacyr Silva, Jr.,* Atul Humar,* A. M. James Shapiro,* Peter Senior,* Katja Hoschler,† Aliyah Baluch,* Leticia E. Wilson,* and Deepali Kumar*

*Alberta Transplant Institute, University of Alberta, Edmonton, Alberta, Canada
†Health Protection Agency, Center for Infections, London, UK

Annual influenza vaccine is recommended for organ transplant recipients, but immunogenicity is known to be suboptimal. Islet transplant recipients receive immunosuppressive therapy, but there are no data on the immunogenicity of influenza vaccine in this population. In this prospective cohort study, adult islet transplant recipients at least 3 months posttransplant were enrolled. All patients received the 2010–2011 seasonal influenza vaccine. Serum was obtained pre- and postvaccination to determine humoral response to each of the three influenza strains included in the vaccine. Adverse effects of vaccine were also noted. A total of 61 islet transplant recipients were enrolled and completed the study protocol. The median time from last transplant was 1.9 years (range 0.26–11.4 years), and most patients had undergone multiple prior islet transplant procedures (90.2%). Overall immunogenicity of the vaccine was poor. Seroconversion rates to H1N1, H3N2, and B antigens were 34.4%, 29.5%, and 9.8%, respectively. In the subset not seroprotected at baseline, a protective antibody titer postvaccination was achieved in 58.6%, 41.9%, and 34.5% of patients, respectively. Patients within the first year of transplant were significantly less likely to seroconvert to at least one antigen (23.5% vs. 54.5%; p = 0.029). Alemtuzumab recipients trended toward lower seroconversion rates (25% vs. 51%; p = 0.11). No vaccine-related safety concerns were identified. Seasonal influenza vaccine had suboptimal immunogenicity in islet transplant recipients especially those who were less than 1 year posttransplant or had received alemtuzumab induction. Novel strategies for protection in this group of patients need further study.

Key words: Immunogenicity; Immunosuppression; Infection

Received September 15, 2011; final acceptance April 5, 2012. Online prepub date: September 21, 2011.
Address correspondence to Deepali Kumar, M.D., M.Sc., FRCPC, Alberta Institute for Transplant Sciences, University of Alberta, 6-030 Katz Center for Health Research, Edmonton, Alberta, Canada T6G 2E1. Tel: +1 (780) 492-3885; Fax: +1 (780) 492-4805; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 477-491, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X657459
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Clinical Transplantation of Individualized Recipient Serum-Adapted Cornea Reduces the Risk of Graft Rejection After Keratoplasty

Solon Thanos,* Zissis Gatzioufas,* Maurice Schallenberg,* Simone König,† Hans-Werner Meyer-Rüsenberg,‡ and Holger Busse§

*Institute of Experimental Ophthalmology, School of Medicine, University of Münster, Münster, Germany
†Integrated Functional Genomics (IFG), Interdisciplinary Center for Clinical Research, Medical Faculty, Westphalian Wilhelms-University, Münster, Germany
‡Eye Hospital Hagen, Hagen, Germany
§University Eye Hospital, Clinical Department, Münster, Germany

Corneal diseases cause severe visual impairment that necessitates corneal transplantation and frequently repetitive procedures due to graft rejection. We tested the hypothesis that exposure of donor corneas to recipient serum-derived factors during eye banking triggers a preoperative adaptation that is beneficial for postoperative tolerance. Donor corneas were incubated in a medium containing human serum (HS) obtained in each case from the prospective graft recipient in order to individually expose the donor cornea to the recipient’s serum. All recipient serum-adapted corneas (RSACs) fulfilled the clinical criteria required by the national law and were transplanted successfully. The postoperative ophthalmological examination extended up to 8 years. All RSACs were tolerated by their recipients and did not cause postoperative complications and no rejection. Proteomic analysis of corneas cultivated in culture medium containing either fetal calf serum (FCS) that is routinely used for cornea banking or HS revealed different patterns of proteins. HS-cultured corneas showed a greater proteomic similarity with native human corneas than did the FCS-cultured corneas, indicating a differential nutrification of the cultured corneal tissue by HS-derived factors. The clinical results show for the first time that postoperative complications such as tissue intolerance and graft rejection might be managed if the corneal tissue is individually adapted to the recipient’s serum trophic factors. This new donor tissue treatment procedure offers incontrovertible advantages and could be adapted for low-risk eyes as well as other transplantable tissues.


Key words: Cornea diseases; Keratoplasty; Graft rejection; Cornea culture

Received August 6, 2010; final acceptance April 30, 2012. Online prepub date: October 3, 2012.
Address correspondence to Solon Thanos, Institute of Experimental Ophthalmology, School of Medicine, University of Münster, Domagkstrasse 15, 48149 Münster, Germany. Tel: +49-251-8356915; Fax: +49-251-8356916; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 493-503, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X652977
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In Situ Electrostimulation Drives a Regenerative Shift in the Zone of Infarcted Myocardium

Cristiano Spadaccio,* Alberto Rainer,† Federico De Marco,‡ Mario Lusini,* Paolo Gallo,§ Pietro Sedati,¶ Andrea Onetti Muda,# Stefano De Porcellinis,** Chiara Gregorj,†† Giuseppe Avvisati,†† Marcella Trombetta,† Massimo Chello,* Elvio Covino,* David A. Bull,‡‡ Amit N. Patel,‡‡ and Jorge A. Genovese*‡‡

*Center for Integrated Research, Department of Cardiovascular Science, Unit of Cardiac Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
†Center for Integrated Research, Laboratory of Tissue Engineering, Università Campus Bio-Medico di Roma, Rome, Italy
‡Laboratory of Virology, Regina Elena Institute for Cancer Research, Rome, Italy
§Center for Integrated Research, Department of Cardiovascular Science, Unit of Cardiology, Università Campus Bio-Medico di Roma, Rome, Italy
¶Center for Integrated Research, Unit of Image Diagnostics, Università Campus Bio-Medico di Roma, Rome, Italy
#Center for Integrated Research, Department of Pathology, Università Campus Bio-Medico di Roma, Rome, Italy
**Biomatica Srl, Rome, Italy
††Center for Integrated Research, Department of Hematology, Università Campus Bio-Medico di Roma, Rome, Italy
‡‡Division of Cardiothoracic Surgery, Department of Surgery, University of Utah, Salt Lake City, UT, USA

Electrostimulation represents a well-known trophic factor for different tissues. In vitro electrostimulation of non-stem and stem cells induces myogenic predifferentiation and may be a powerful tool to generate cells with the capacity to respond to local areas of injury. We evaluated the effects of in vivo electrostimulation on infarcted myocardium using a miniaturized multiparameter implantable stimulator in rats. Parameters of electrostimulation were organized to avoid a direct driving or pacing of native heart rhythm. Electrical stimuli were delivered for 14 days across the scar site. In situ electrostimulation used as a cell-free, cytokine-free stimulation system, improved myocardial function, and increased angiogenesis through endothelial progenitor cell migration and production of vascular endothelial growth factor (VEGF). In situ electrostimulation represents a novel means to stimulate repair of the heart and other organs, as well as to precondition tissues for treatment with cell-based therapies.

Key words: Stem cells; Myocardium; Infarct; Electrostimulation (ES)

Received April 14, 2011; final acceptance March 30, 2012. Onlne prepub date: July 10, 2012.
Address correspondence to Jorge A. Genovese at his current address: School of Medicine, Maimonides University, Hidalgo 775 6to Piso, (C1405BCK) Ciudad Autonoma de Bueneos Aires, Argentina. Tel: +541149051101/1113, ext. 1234; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 507-511, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X636849
E-ISSN 1555-3892
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Putative Population of Adipose-Derived Stem Cells Isolated From Mediastinal Tissue During Cardiac Surgery

Amit N. Patel, James Yockman, Vanessa Vargas, and David A. Bull

Division of Cardiothoracic Surgery, University of Utah, Salt Lake City, UT, USA

Mesenchymal stem cells have been isolated from various adult human tissues and are valuable for not only therapeutic applications but for the study of tissue homeostasis and disease progression. Subcutaneous adipose depots have been shown to contain large amounts of stem cells. There is little information that has been reported to date describing the isolation and characterization of mesenchymal stem cells from visceral adipose tissue. In this study, we describe a mesenchymal stem cell population isolated from mediastinal adipose depots. The cells express CD44, CD105, CD166, and CD90 and are negative for hematopoietic markers CD34, CD45, and HLA-DR. In addition, the cells have a multilineage potential, with the ability to differentiate into adipogenic, osteogenic, and chondrogenic cell types. The biological function of visceral adipose tissue remains largely unknown and uncharacterized. However, the proximity of adipose tissue to the heart suggests a potential role in the pathogenesis of cardiovascular disease in obesity. In addition, with the ability of fat to regulate metabolic activity in humans, this novel stem cell source may be useful to further study the mechanisms involved in metabolic disorders.

Key words: Stem cells; Adipose; Mediastinal; Metabolic; Surgery

Received March 19, 2012; final acceptance March 20, 2012. Online prepub date: April 2, 2012.
Address correspondence to Amit N. Patel, M.D., M.S., Director of Clinical Regenerative Medicine, Associate Professor of Surgery, University of Utah, 30 N. 1900 E. SOM 3C127, Salt Lake City, UT 84132, USA. Tel: +1-801-587-7946; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 513-519, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X655064
E-ISSN 1555-3892
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Mesenchymal Stem Cell Population Isolated From the Subepithelial Layer of Umbilical Cord Tissue

Amit N. Patel, Vanessa Vargas, Patricia Revello, and David A. Bull

Division of Cardiothoracic Surgery, University of Utah, Salt Lake City, UT, USA

The therapeutic use of stem cells to treat diseases and injuries is a promising tool in regenerative medicine. The umbilical cord provides a rich source of stem cells; we have previously reported a population of stem cells isolated from Wharton’s jelly. In this report, we aimed to isolate a novel cell population that was different than those found in Wharton’s jelly. We isolated stem cells from the subepithelial layer of the umbilical cord; the cells could be expanded for greater than 90 population doubling and had mesenchymal stem cell characteristics, expressing CD9, SSEA4, CD44, CD90, CD166, CD73, and CD146 but were negative for STRO-1. The cells can be directionally differentiated and undergo osteo-, chondro-, adipo-, and cardiogenesis. In addition, we have identified for the first time that mesenchymal stem cells isolated from umbilical cord can produce microvesicles, termed exosomes. This is the first report describing a stem cell population isolated from the subepithelial layer of the umbilical cord. Given the growth capacity, multilineage potential, and most importantly the low levels of HLA-ABC, we propose that this novel cell isolated from the subepithelial layer of umbilical cord is an ideal candidate for allogeneic cell-based therapy.

Key words: Stem cells; Umbilical cord lining; Mesenchymal

Received April 17, 2012; final acceptance May 30, 2012. Online prepub date: September 12, 2012.
Address correspondence to Amit N. Patel, M.D., M.S., Director of Clinical Regenerative Medicine, Associate Professor of Surgery, University of Utah, 30 N. 1900 E. SOM 3C127, Salt Lake City, UT 84132, USA. Tel: +1-801-587-7946; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 521-528, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X636830
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
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Direct Intramyocardial Mesenchymal Stromal Cell Injections in Patients With Severe Refractory Angina: One-Year Follow-Up

Mandana Haack-Sorensen,* Tina Friis,* Anders B. Mathiasen,* Erik Jorgensen,* Louise Hansen,* Ebbe Dickmeiss,† Annette Ekblond,* and Jens Kastrup*

*Cardiac Stem Cell Laboratory and Catheterization Laboratory, The Hearth Centre, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark
†Department of Clinical Immunology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark

In patients with stable coronary artery disease (CAD) and refractory angina, we performed direct intramyocardial injections of autologous mesenchymal stromal cells (MSC) and followed the safety and efficacy of the treatment for 12 months. A total of 31 patients with stable CAD, moderate to severe angina, normal left ventricular ejection fraction, and no further revascularization options were included. Bone marrow MSCs were isolated and culture expanded for 6–8 weeks and then stimulated with vascular endothelial growth factor (VEGF) for 1 week. The 12-month follow-up demonstrated that it was safe to culture expand MSCs and use the cells for clinical treatment. The patients’ maximal metabolic equivalent (MET) during exercise increased from 4.23 MET at baseline to 4.72 MET at 12-month follow-up (p < 0.001), Canadian Cardiovascular Society Class (CCS) was reduced from 3.0 to 0.8 (p < 0.001), angina attacks per week from 13.8 to 3.2 (p < 0.001), and nitroglycerin consumption from 10.7 to 3.4 per week (p < 0.001). In addition, Seattle Angina Questionnaire (SAQ) evaluations demonstrated highly significant improvements in physical limitation, angina stability, angina frequency, and quality of life (p < 0.001 for all). It is safe in the intermediate/long term to treat patients with stable CAD using autologous culture expanded MSCs. Previously reported, early and highly significant improvements in exercise capacity and clinical symptoms persist after 12 months. The results are encouraging, and a larger controlled study is warranted.

Key words: Angiogenesis; Chronic myocardial ischemia; Coronary artery disease (CAD); Mesenchymal stromal cell (MSC); Refractory angina; Stem cell

Received March 27, 2011; final acceptance November 3, 2011. Online prepub date: April 2, 2012.
The trial is registered in ClinicalTrials.gov: NCT00260338.
Address correspondence to Jens Kastrup, M.D., D.MSc., FESC Professor, Cardiac Catheterization Laboratory 2014, The Hearth Centre, Rigshospitalet Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel: +45 3545 2819/2817; Fax: +45 35452705; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 529-533, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X637461
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Polymer-Based Restoration of Left Ventricular Mechanics

Randall J. Lee,*†‡ Andy Hinson,§ Sam Helgerson,§ Robert Bauernschmitt,¶ and Hani N. Sabbah#

*Cardiovascular Research Institute, University of California-San Francisco, San Francisco, CA, USA
†Department of Medicine, University of California-San Francisco, San Francisco, CA, USA
‡Institute for Regeneration Medicine, University of California-San Francisco, San Francisco, CA, USA
§LoneStar Heart, Inc., Laguna Hills, CA, USA
¶Isar Heart Center, IsarKliniken, Munich, Germany
#Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, MI, USA

Heart failure continues to be a major health care concern with relatively few options for severely advanced heart failure patients. The hallmark of heart failure is the progressive dilatation of the left ventricle, thinning of the left ventricular wall leading to increased wall stress and increased myocardial oxygen consumption. Applying Laplace’s law to the failing dilated ventricle, left ventricular augmentation utilizes a tissue engineering strategy to increase wall thickness and reduce chamber diameter, resulting in a decrease in wall stress and improved left ventricular function. A review of the rationale for an in situ tissue engineering approach for this treatment of heart failure and early clinical results of the Algisyl-LVR™ program are presented.

Key words: Congestive heart failure (HF); Left ventricular (LV) mechanics; Tissue engineering; Alginate hydrogel

Received March 29, 2011; final acceptance October 2, 2011. Online prepub date: March 28, 2012.
Address correspondence to Randall J. Lee, M.D., Ph.D., University of California-San Francisco, Box 1354, San Francisco, CA 94143, USA. Tel: +1-415-476-5706; Fax: +1-415-476-6260; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 535-543, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X638973
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Feasibility of Intracoronary GLP-1 Eluting CellBead™ Infusion in Acute Myocardial Infarction

Jaco H. Houtgraaf,* Renate de Jong,* Kim Monkhorst,† Dennie Tempel,* Esther van de Kamp,* Wijnand K. den Dekker,* Kushan Kazemi,* Imo Hoefer,‡ Gerard Pasterkamp,‡ Andrew L. Lewis,§ Peter W. Stratford,§ Christine Wallrapp,¶ Felix Zijlstra,# and Henricus J. Duckers*

*Molecular Cardiology Laboratory, Thoraxcenter, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
†Department of Pathology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
‡Experimental Cardiology, University Hospital Utrecht, Utrecht, The Netherlands
§Biocompatibles UK Ltd., Farnham, UK
¶CellMed AG, Alzenau, Germany
#Department of Cardiology, Thoraxcenter, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands

Cell therapy is a field of growing interest in the prevention of post acute myocardial infarction (AMI) heart failure. Stem cell retention upon local delivery to the heart, however, is still unsatisfactory. CellBeads were recently developed as a potential solution to this problem. CellBeads are 170-μm alginate microspheres that contain mesenchymal stem cells (MSCs) genetically modified to express glucagon-like peptide-1 (GLP-1) supplementary to inherent paracrine factors. GLP-1 is an incretin hormone that has both antiapoptotic and cardioprotective effects. Transplanting CellBeads in the post-AMI heart might induce cardiomyocyte salvage and ultimately abrogate adverse cardiac remodeling. We aimed to investigate the feasibility of intracoronary infusion of CellBeads in a large animal model of AMI. Four pigs were used in a pilot study to assess the maximal safe dose of CellBeads. In the remaining 21 animals, an AMI was induced by balloon occlusion of the left circumflex coronary artery for 90 min. During reperfusion, 60,000 CellBeads (n = 11), control beads (n = 4), or lactated Ringers’ (n = 6) were infused. Animals were sacrificed after 2 or 7 days, and the hearts were excised for histological analyses. Intracoronary infusion did not permanently affect coronary flow in any of the groups. Histological analysis revealed CellBeads containing viable MSCs up to 7 days. Viability and activity of the MSCs was confirmed by qPCR analysis that showed expression of recombinant GLP-1 and human genes after 2 and 7 days. CellBeads reduced inflammatory infiltration by 29% (p = 0.001). In addition, they decreased the extent of apoptosis by 25% (p = 0.001) after 2 days. We show that intracoronary infusion of 5 million encapsulated MSCs is safe and feasible. Also, several parameters indicate that the cells have paracrine effects, suggesting a potential therapeutic benefit of this new approach.

Key words: Glucagon-like peptide-1 (GLP-1); Mesenchymal stem cells (MSCs); Acute myocardial infarction (AMI); Cell therapy; GLP-1 CellBeads; Coronary intervention

Received March 31, 2011; final acceptance December 20, 2011. Online prepub date: April 10, 2012.
Address correspondence to Henricus J. Duckers, M.D., Ph.D., FESC, FACC, Department of Cardiology, Heidelberglaan 100, 3584 CX, Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. Tel: +31 (88) 75 555 55; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 545-562, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368912X636777
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Safety and Efficacy of Autologous Cell Therapy in Critical Limb Ischemia: A Systematic Review

Eric Benoit,* Thomas F. O’Donnell, Jr.,† and Amit N. Patel‡

*Department of Surgery, Tufts Medical Center, Boston, MA, USA
†The CardioVascular Center, Tufts Medical Center, Boston, MA, USA
‡Division of Cardiothoracic Surgery, University of Utah, Salt Lake City, UT, USA

Researchers have accumulated a decade of experience with autologous cell therapy in the treatment of critical limb ischemia (CLI). We conducted a systematic review of clinical trials in the literature to determine the safety and efficacy of cell therapy in CLI. We searched the literature for clinical trials of autologous cell therapy in CLI, including observational series of five or more patients to accrue a large pool of patients for safety analysis. Safety analysis included evaluation of death, cancer, unregulated angiogenesis, and procedural adverse events such as bleeding. Efficacy analysis included the clinical endpoints amputation and death as well as functional and surrogate endpoints. We identified 45 clinical trials, including seven RCTs, and 1,272 patients who received cell therapy. The overall adverse event rate was low (4.2%). Cell therapy patients did not have a higher mortality rate than control patients and demonstrated no increase in cancer incidence when analyzed against population rates. With regard to efficacy, cell therapy patients had a significantly lower amputation rate than control patients (OR 0.36, p = 0.0004). Cell therapy also demonstrated efficacy in a variety of functional and surrogate outcomes. Clinical trials differed in the proportion of patients with risk factors for clinical outcomes, and these influenced rates of amputation and death. Cell therapy presents a favorable safety profile with a low adverse event rate and no increase in severe events such as mortality and cancer and treatment with cell therapy decreases the risk of amputation. Cell therapy has a positive benefit-to-risk ratio in CLI and may be a valuable treatment option, particularly for those challenging patients who cannot undergo arterial reconstruction.

Key words: Critical limb ischemia (CLI); Autologous cell therapy; Bone marrow mononuclear cells (BMMNCs); Peripheral blood mononuclear cells (PBMNCs); Granulocyte-colony stimulating factor (G-CSF); Systematic review

Received March 16, 2012; final acceptance March 16, 2012. Online prepub date: March 28, 2012.
Address correspondence to Amit N. Patel, M.D., M.S., Director of Clinical Regenerative Medicine, Associate Professor of Surgery, University of Utah, 30 N. 1900 E. SOM 3C127, Salt Lake City, UT 84132, USA. Tel: +1 801-587-7946; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 22, pp. 563-568, 2013
0963-6897/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368911X627570
E-ISSN 1555-3892
Copyright © 2013 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Experience From Experimental Cell Transplantation Therapy of Myocardial Infarction: What Have We Learned?

Wangde Dai, Gregory L. Kay, Aarne J. Jyrala, and Robert A. Kloner

The Heart Institute of Good Samaritan Hospital and Division of Cardiovascular Medicine of the Keck School of Medicine, University of Southern California, Los Angeles, California, USA

During the past 15 years, our research group has transplanted fetal/neonatal cardiomyocytes, mesenchymal stem cells, and embryonic stem cell-derived cardiomyocytes into infarcted myocardium in a rat myocardial infarction model. Our experimental data demonstrated that cell transplantation therapy provides a potential approach for the treatment of injured myocardium after myocardial infarction based on the reported positive effects upon histological appearance and left ventricular function. However, the underlying mechanisms of the benefits from cell transplantation therapy remain unclear and may involve replacement of scar tissue by transplanted cells, induced neoangiogenesis and paracrine effects of factors released by the transplanted cells. In this review, we summarize our experiences from experimental cell transplantation therapy in a rat myocardial infarction model and discuss the controversies and questions that need to be addressed in future studies.

Key words: Cell transplantation therapy; Fetal/neonatal cardiomyocyte; Mesenchymal stem cell (MSC); Embryonic stem cell-derived cardiomyocyte (hESC-CM); Myocardial infarction

Received March 16, 2011; final acceptance October 18, 2011. Online prepub date: March 27, 2012.
Address correspondence to Wangde Dai, M.D., The Heart Institute of Good Samaritan Hospital, 1225 Wilshire Boulevard, Los Angeles, CA 90017, USA. Tel.: +1-213-977-4050; Fax: +1-213-977-4107; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it