The Open Stem Cell Journal




ISSN: 1876-8938 ― Volume 6, 2019
REVIEW ARTICLE

Exploring the Role of Mesenchymal Stem Cells During Normothermic Organ Perfusion: A New Paradigm to Enhance Outcome Following Allograft Transplantation



Mohamed Morsy1, *, Mohammad Ayaz Hossain2, Atul Bagul3
1 Consultant Transplant Surgeon, University Hospitals of Leicester/Leicester General Hospital, Leicester, LE5 4PW, UK
2 Specialty Registrar in Organ transplantation, Cambridge University Hospital NHS Trust, Hills Rd, Cambridge, UK
3 Head of Transplantation Services and Consultant Endocrine and Transplant surgeon, Leicester General Hospital, Leicester, LE5 4PW, UK

Abstract

Background:

Normothermic Machine Perfusion (NMP) has been established in the field of solid organ transplantation for both liver and kidney allografts. The ability to perfuse organs at body temperature enables viability assessment as well as optimisation prior to implantation.

Discussion:

A recent in vitro report of the use of Mesenchymal Stem Cells (MSCs) in the use of a normothermic lung perfusion circuit has raised the possibility of their use in solid organ transplantation. The aim of this short review is to outline the potential uses of bone marrow derived MSCs for their use in renal allograft ex vivo NMP. An overview is provided of current literature of NMP as well as theorised uses for MSCs.

Keywords: Mesenchymal stem cells, Normothermic perfusion, Transplantation, Outcomes, Allograft, EMP.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 5
First Page: 47
Last Page: 52
Publisher Id: TOSCJ-5-47
DOI: 10.2174/1876893801805010047

Article History:

Received Date: 27/6/2018
Revision Received Date: 19/10/2018
Acceptance Date: 2/11/2018
Electronic publication date: 30/11/2018
Collection year: 2018

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© 2018 Morsy et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Consultant Transplant Surgeon, University Hospitals of Leicester/Leicester General Hospital, Leicester, LE5 4PW, UK, E-mail: Mohamed.morsy@nhs.net




1. INTRODUCTION

Mesenchymal Stem Cells (MSCs) of bone marrow origin are a multipotent progenitor cells [1Friedenstein AJ. Stromal mechanisms of bone marrow: Cloning in vitro and retransplantation in vivo. Haematol Blood Transfus 1980; 25: 19-29.]. They express intermediate Class 1 MHC and express CD105, CD73 and CD90 while lack expression of both haematopiotic and endothelial lineage markers [2Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284(5411): 143-7.[http://dx.doi.org/10.1126/science.284.5411.143] ]. They have immunomodulatory and immune-evasive properties, making them suitable for cell based therapy [3Hass R, Kasper C, Böhm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Commu Signal CCS 2011; 9: 12.[http://dx.doi.org/10.1186/1478-811X-9-12] ]. These properties lend them to variable applications in the field of organ transplantation. Such applications include immunomodulation [4Pan GH, Chen Z, Xu L, et al. Low-dose tacrolimus combined with donor-derived mesenchymal stem cells after renal transplantation: A prospective, non-randomized study. Oncotarget 2016; 7(11): 12089-101.[http://dx.doi.org/10.18632/oncotarget.7725] ], post ischaemia reperfusion [5Yuzeng Q, Weiyang H, Xin G, Qingson Z, Youlin K, Ke R. Effects of transplantation with marrow-derived mesenchymal stem cells modified with survivin on renal ischemia-reperfusion injury in mice. Yonsei Med J 2014; 55(4): 1130-7.[http://dx.doi.org/10.3349/ymj.2014.55.4.1130] , 6Bagul A, Frost JH, Drage M. Stem cells and their role in ischaemia reperfusion injury. Am J Nephrol 2013; 37(1): 16-29.[http://dx.doi.org/10.1159/000345731] ] and more recently in the field of lung transplantation, during Extracorporeal Machine Perfusion (EMP) [7Mordant P, Nakajima D, Kalaf R, et al. Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation. J Heart Lung Transplant 2016; 35(10): 1245-54.[http://dx.doi.org/10.1016/j.healun.2016.04.017] ].

Kidney transplantation remains the treatment of choice for End Stage Renal Disease (ESRD). Optimisation of renal transplant outcomes has been explored with recent developments in Normothermic Machine Perfusion (NMP). Monitoring and imaging of systemically delivered MSCs present a challenge in efficient cell seeding [8Hossain MA, Frampton AE, Bagul A. Challenges facing in vivo tracking of mesenchymal stem cells used for tissue regeneration. Expert Rev Med Devices 2014; 11(1): 9-13.[http://dx.doi.org/10.1586/17434440.2014.865306] ]. A closed ex-vivo NMP circuit therefore lends itself to overcome some of these challenges.

To date there is little in the way of clinical trials related to the use of MSCs in NMP kidney transplants.

This review provides an overview of potential applications of MSCs with NMP whilst theorising outcomes given the preclinical in vitro evidence to date.

1.1. Normothermic Machine Perfusion

Since the 1960s, static cold storage (a cold organ in a box of ice) has been the mainstay in preservation. The worldwide shortage of organs has driven research in to the use of machine perfusion pre-implantation to both assess as well as optimise function. Machine Perfusion (MP) can either be cold or warm. Warm perfusion, usually at body temperature, is termed normothermic (NMP). Several machines for liver, kidneys, lungs and hearts exist in the clinical practise [9Balfoussia D, Yerrakalva D, Hamaoui K, Papalois V. Advances in machine perfusion graft viability assessment in kidney, liver, pancreas, lung, and heart transplant. Exp Clin Transplant 2012; 10(2): 87-100.[http://dx.doi.org/10.6002/ect.2011.0167] ]. Continuous perfusion of the organ at body temperature ex-vivo, permits efficient oxygen delivery as well as essential nutrients in a closed circuit. The perfusate is renewed or filtered and in the case of renal ex-vivo NMP, the production of urine observed can be collected for analysis [10Hosgood SA. Renal transplantation after ex vivo normothermic perfusion: The first clinical study. Am J Transplant 2013; 13(5): 1246-52.]. Real time assessment of the organ during NMP can be made with clinical and biochemical parameters studied in order to “risk stratify” to outcome. Compared to static cold storage, a more sophisticated assessment can be made.

NMP devices have aided the expansion of Donation after Circulatory Death (DCD) organs that, due to the exposure of prolonged warm ischaemia, have conventionally been considered inferior to both living and brain dead donors [11Summers DM, Johnson RJ, Allen J, et al. Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: A cohort study. Lancet 2010; 376(9749): 1303-11.[http://dx.doi.org/10.1016/S0140-6736(10)60827-6] ]. The ability to machine perfuse under artificial physiological parameters, enables organ assessment prior to implantation.

Renal transplantation remains the treatment of choice for patients with End Stage Renal Disease (ESRD). DCD renal allografts have higher rates of Delayed Graft Function (DGF) as well as Primary Non Function (PNF) [11Summers DM, Johnson RJ, Allen J, et al. Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: A cohort study. Lancet 2010; 376(9749): 1303-11.[http://dx.doi.org/10.1016/S0140-6736(10)60827-6] ]. Early study into the use of ex-vivo NMP has been encouraging with significantly lower rates of DGF observed in machine perfused kidney allografts versus static cold storage [10Hosgood SA. Renal transplantation after ex vivo normothermic perfusion: The first clinical study. Am J Transplant 2013; 13(5): 1246-52.]. Long term survival outcomes from graft rejection as well as chronic allograft failure in the form of interstitial fibrosis lend the use of NMP towards stem cell therapy. To date there are no combined studies into the effect of renal allograft NMP and stem cell usage.

1.2. Mesenchymal Stem cells and Immunomodulation

Mesenchymal stem cells are multipotent progenitors, which in current clinical practise are usually derived from Bone Marrow (BM). They have immunomodulatory and immune-evasive properties, making them suitable for cell based therapy. MSCs are known to activate T and B regulatory cells and interfere with maturation and activation of Antigen Presenting Cells (APCs) [2Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284(5411): 143-7.[http://dx.doi.org/10.1126/science.284.5411.143] , 12Cho D-I, Kim MR, Jeong H-Y, et al. Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages. Exp Mol Med 2014; 46(1): e470.[http://dx.doi.org/10.1038/emm.2013.135] , 13Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 2006; 24(1): 74-85.[http://dx.doi.org/10.1634/stemcells.2004-0359] ]. The potential use of MSCs is not solely limited to cellular repair and regeneration. Preclinical studies elucidated their immunoregulatory potential; however their clinical use still remains to be explored. Accumulated evidence showed MSC helps the development of tolerance through the induction of T and B regulatory cells and its inhibitory and modulatory effect on various immune effector cells including APCs, macrophages, neutrophils, mast cells, T and B cells also enhance the anti-inflammatory pathways and supress the cytotoxic activities of NK cells [2Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284(5411): 143-7.[http://dx.doi.org/10.1126/science.284.5411.143] , 12Cho D-I, Kim MR, Jeong H-Y, et al. Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages. Exp Mol Med 2014; 46(1): e470.[http://dx.doi.org/10.1038/emm.2013.135] , 13Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 2006; 24(1): 74-85.[http://dx.doi.org/10.1634/stemcells.2004-0359] ]. They produce wide range of Th2, anti-inflammatory [14Kyurkchiev D, Bochev I, Ivanova-Todorova E, et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells 2014; 6(5): 552-70.[http://dx.doi.org/10.4252/wjsc.v6.i5.552] ] and ant apoptotic [15Galleu A, Riffo-Vasquez Y. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci Transl Med 2017; 9(416) pii: eaam 7828.[http://dx.doi.org/10.1126/scitranslmed.aam7828] ] effectors including TGF-B, HGF, NO, HO-1, IDO, TNF-TRAIL and PD-L1.

Preclinical studies established their safety and their effect on enhancing graft survival, diminishing rejection rate and lymphocyte proliferation [16Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002; 30(1): 42-8.[http://dx.doi.org/10.1016/S0301-472X(01)00769-X] -18Inoue S, Popp FC, Koehl GE, et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation 2006; 81(11): 1589-95.[http://dx.doi.org/10.1097/01.tp.0000209919.90630.7b] ]. However, early clinical study reports didn’t show similar potential yet due to various reasons including their use in conjunction with immunosuppression medications that already supress various function, the influence of microenvironments and the immunogenicity when allogenic - MSC used [18Inoue S, Popp FC, Koehl GE, et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation 2006; 81(11): 1589-95.[http://dx.doi.org/10.1097/01.tp.0000209919.90630.7b] -21Giai Via A, Frizziero A, Oliva F. Biological properties of mesenchymal stem cells from different sources. Muscles Ligaments Tendons J 2012; 2(3): 154-62.].

A recent study by Pan et al, demonstrated similar 2 year survival outcomes of patients given low dose Calcineurin Inhibitor (CNI) with donor derived BM-MSCs compared with standard CNI use alone [4Pan GH, Chen Z, Xu L, et al. Low-dose tacrolimus combined with donor-derived mesenchymal stem cells after renal transplantation: A prospective, non-randomized study. Oncotarget 2016; 7(11): 12089-101.[http://dx.doi.org/10.18632/oncotarget.7725] ]. The authors do not give a formal explanation for the mechanism of action and the method of MSC immunosuppression is not completely understood. Early in vitro work has suggested that autologous T-cell proliferation is inhibited by MSCs through the secretion of both transforming growth factor-β [22Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99(10): 3838-43.[http://dx.doi.org/10.1182/blood.V99.10.3838] ]. Indeed some authors have suggested that because of the production of extracellular vesicles, such as exosomes, as well as cytokines and growth factors, MSC immunomodulation is related to the trophic and stimulatory function over the cellular differentiation aspect [23Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: Immune evasive, not immune privileged. Nat Biotechnol 2014; 32(3): 252-60.[http://dx.doi.org/10.1038/nbt.2816] ]. Both low levels of Major Histocompatibility Complex (MHC) class I & II as well as CD-40 expression further support this hypothesis [23Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: Immune evasive, not immune privileged. Nat Biotechnol 2014; 32(3): 252-60.[http://dx.doi.org/10.1038/nbt.2816] ]. This is, however, contradictory to previously held belief that BM-MSCs do not express MHC class II or their co-stimulatory molecules including CD-40 [24Ryan JM, Barry FP, Murphy JM, Mahon BP. Mesenchymal stem cells avoid allogeneic rejection. J Inflamm (Lond) 2005; 2: 8.[http://dx.doi.org/10.1186/1476-9255-2-8] ].

1.3. Ischaemia Reperfusion

Ischaemia Reperfusion Injury (IRI), is the development of organ dysfunction following arterial clamp release and subsequent perfusion of the allograft. Reactive oxygen species’ (ROS) development at the time of IRI is a leading contributor DCD renal allograft dysfunction [25Waller HL, Harper SJF, Hosgood SA, et al. Biomarkers of oxidative damage to predict ischaemia-reperfusion injury in an isolated organ perfusion model of the transplanted kidney. Free Radic Res 2006; 40(11): 1218-25.[http://dx.doi.org/10.1080/10715760600907368] ]. The role of MSCs in ameliorating IRI, remains unclear. Casiraghi et al have studied the topic in-vivo and in-vitro. The group postulated that the presence of MSCs engraft during the reperfusion process, induces complement activation as well as expression of pro-inflammatory cytokines, which contribute to the subsequent organ dysfunction [26Casiraghi F, Azzollini N, Todeschini M, et al. Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation. Am J Transplant 2012; 12(9): 2373-83.[http://dx.doi.org/10.1111/j.1600-6143.2012.04115.x] ]. They hypothesized that MSCs could be directed towards acquisition of pro-inflammatory functions when exposed to specific mediators of inflammation such as ROS during renal IRI. This non NMP work, however, contrasts that found in the only clinical study of note in MSC use with an NMP circuit.

Both vascular endothelial growth factor and IL-8 are key mediators in IRI. In their ex-vivo NMP porcine lung model which perfused human-umbilical cord derived MSCs, Mordant and associates, observed elevated VEGF concentrations in the lung perfusate as well as suppression of IL-8 [7Mordant P, Nakajima D, Kalaf R, et al. Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation. J Heart Lung Transplant 2016; 35(10): 1245-54.[http://dx.doi.org/10.1016/j.healun.2016.04.017] ]. It may be possible that with the use of both a ROS species and lymphocyte scavenger within the circuit, the pro-inflammatory induction of MSCs theorised by Caseraghi’s group is potentially overcome, therefore permitting favourable cellular expression of VEGF. Mordants work supports the use of ex-vivo NMP to pre condition the allograft for MSC acceptance by creating an environment for beneficial cellular MSC expression. The groups’ machine, however, is still at its infancy.

1.4. Outcome Measures of MSCs in NMP

Delivery of MSCs in Mordants’ group was either endotracheally or intra-arterially in 18 animals [7Mordant P, Nakajima D, Kalaf R, et al. Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation. J Heart Lung Transplant 2016; 35(10): 1245-54.[http://dx.doi.org/10.1016/j.healun.2016.04.017] ]. After a cold storage period of 18 hours, ex-vivo lung perfusion (EVLP) was sustained for 12 hours with administration of human umbilical cord MSCs after one hour. One of the main observations of the model was the retention of the cells during the first few minutes after retention. Measurement of CD73+ cells as biomarkers of MSCs concentration, revealed high perfusate retention (83%) after the first 2 minutes followed by 100% depletion by 30 minutes. The converse elevated concentrations of CD73+ in the leucocyte scavenger of the machine highlighted a critical limitation. Intravascular administration albeit more effective than endobronchial, produce high losses through the scavenger mechanism. The resultant demonstration of human DNA in the lung parenchyma after 12 hours by the group using PCR, confirms the action of the MSCs. The aforementioned expression of IL-8 in the perfusate validated the function of the MSCs during this period. A clear limitation of the NMP model reported is the duration of the CS time along with the machine perfusion. Eighteen hours of cold storage followed by 12 hours of NMP would be considered extreme for solid organ use. In lung transplantation, current clinical practise is to ex vivo perfuse for upto four hours. Even though the authors’ have not commented, with further optimization, it may be possible that MSCs infusion of the circuit would enable longer perfusion and storage times in order to establish VEGF expression and in turn initiate IR repair mechanisms prior to implantation. It is not clear from this model or report alone, the dose effect relationship of the delivered human umbilcal cord MSCs on IR and inflammatory repair on immunomodulation. A potential target for renal allograft NMP would be to examine the expression of interleukin factors within the NMP circuit at time intervals as well and stratify this against outcome in an experimental large animal model.

1.5. Future Proposals

Preclinical studies confirmed the safe use of MSC with promising results that demonstrated the immunomodulatory potential of MSC and their possible role in anti-rejection and immunosuppression maintenance protocols in organ transplantation. However, early clinical studies struggled to show this optimism. This was explained by various reasons including the in vitro microenvironment, type and donor age, Isolation techniques and site of isolation [27Kaundal U, Bagai U, Rakha A. Immunomodulatory plasticity of mesenchymal stem cells: A potential key to successful solid organ transplantation. J Transl Med 2018; 16(1): 31.[http://dx.doi.org/10.1186/s12967-018-1403-0] ]. A surge of trials is underway tackling these challenges including proposals [27Kaundal U, Bagai U, Rakha A. Immunomodulatory plasticity of mesenchymal stem cells: A potential key to successful solid organ transplantation. J Transl Med 2018; 16(1): 31.[http://dx.doi.org/10.1186/s12967-018-1403-0] ] utilising genetic modifications and targeted delivery systems with P-Selectin Glycoprotien Ligand-1 [28Liao W, Pham V, Liu L, et al. Mesenchymal stem cells engineered to express selectin ligands and IL-10 exert enhanced therapeutic efficacy in murine experimental autoimmune encephalomyelitis. Biomaterials 2016; 77: 87-97.[http://dx.doi.org/10.1016/j.biomaterials.2015.11.005] ] or Etanercept [29Park N, Rim YA, Jung H, et al. Etanercept-synthesising mesenchymal stem cells efficiently ameliorate collagen-induced arthritis. Sci Rep 2017; 7: 39593.[http://dx.doi.org/10.1038/srep39593] ]. We propose a novel technique in using MSC during ex-vivo normothermic kidney perfusion utilising the plasticity of MSC in organ optimisation and minimising the effect of reperfusion injury through their anti-apoptotic and anti-inflammatory functions.

CONCLUSION

There are no reports demonstrating the use of BM-MSCs during an ex vivo NMP of renal allografts either clinically or experimentally. As such, we have reviewed one study utilising human umbilical cord isolated MSCs to determine the potential challenges facing future use in solid organ transplantation. The benefit of MSC use in a closed circuit is the ability of the cell clone to home to the organ and differentiate providing potential immunomodulation as well an IR inflammation repair post reperfusion. However, delivery of the MSC within the circuit has been shown to have some limitations as summarised in Fig. (1). The dose optimisation of the MSC clone will be a priority in retention of the cells within the circuit. Confirmation of homing will need to be demonstrated through expression markers, although this process has been difficult using conventional imaging [8Hossain MA, Frampton AE, Bagul A. Challenges facing in vivo tracking of mesenchymal stem cells used for tissue regeneration. Expert Rev Med Devices 2014; 11(1): 9-13.[http://dx.doi.org/10.1586/17434440.2014.865306] ]. Collection of urinary and venous sampling will also determine percentage uptake, although this is only a theory at present as there are no current experimental data to prove MSC or marker positivity in these samples from an ex vivo circuit. Nonetheless, the use of cells taken from the leucocyte scavenger in the circuit may determine the retention of the MSC population. Regular sampling from the scavenger may determine the necessary duration of perfusion. Mordants group acknowledges that 18 hours of cold ischaemia with 12 hours of warm perfusion is beyond the clinical application of an NMP circuit [7Mordant P, Nakajima D, Kalaf R, et al. Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation. J Heart Lung Transplant 2016; 35(10): 1245-54.[http://dx.doi.org/10.1016/j.healun.2016.04.017] ]. This period should be considerably shorter to align with current NMP kidney models and it is unclear whether 2 to 4 hours of perfusion would satisfy an adequate MSC effect.

Fig. (1)
Considerations for the use of MSCs in NMP.


We acknowledge the limitations of this short review, whilst highlighting the need for further in vitro experimental reports of BM-MSCs in NMP circuits. Challenges have been demonstrated on the paucity of current literature and we look forward to reporting on future studies.

Schematic representation of a conventional renal allograft ex-vivo NMP circuit. Sites of potential experimental considerations for MSCs are listed as 1. MSC dose delivery optimisation, 2. Ensuring retention of MSCs during the period of NMP as well as monitoring homing, 3. Collection of samples from venous and urine effluent to assay expression markers e.g interleukins and Vascular Endothelial Growth Factor (VEGF), CD+ve cells, 4. Limiting loss of MSCs in the leucocyte scavenger and or utilizing the scavenger to assess retention 5. Histological efficacy of MSC cellular differentiation within the parenchyma.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

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Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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