Biagi, Ettore

Henschler, Reinhard

Kuçi, Selim

Meisel, Roland

Müller, Ingo

English

PubMed

Selim Kuçi

Reinhard Henschler

Ingo Müller

Ettore Biagi

Roland Meisel

Crossref

Hindawi Publishing CorporationStem Cells InternationalVolume 2012, Article ID 185943, 3 pagesdoi:10.1155/2012/185943EditorialBasic Biology and Clinical Application of MultipotentMesenchymal Stromal Cells: From Bench to BedsideSelim Kuc¸i,1 Reinhard Henschler,2 Ingo Mu¨ller,3 Ettore Biagi,4 and Roland Meisel51Departments of Hematology and Oncology, University Children’s Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany2 Institute for Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig Maximilians University Munich,Marchioninistrasse 15, 81377 Munich, Germany3Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52,20246 Hamburg, Germany4Laboratory of Cell Therapy “Stefano Verri,” Pediatric Department, University of Milano-Bicocca, San Gerardo Hospital,20900 Monza, Italy5Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty,Heinrich-Heine University Du¨sseldorf, 40225 Du¨sseldorf, GermanyCorrespondence should be addressed to Selim Kuc¸i, selim.kuci@kgu.deReceived 8 August 2012; Accepted 8 August 2012Copyright © 2012 Selim Kuc¸i et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Since their discovery in the end of the 1960s and thebeginning of the 1970s by Alexander Friedenstein, mesenchy-mal stromal cells (MSCs) have attracted the interest of thescientific community because of their ubiquitous presence inthe organism, the ease of their procurement, and potentialto diﬀerentiate into other tissues. As a nonhematopoieticcell population, first described in the bone marrow, MSCscomprise a pool of progenitor cells with diﬀerent prolifera-tive, diﬀerentiation, immunosuppressive, and hematopoieticengraftment-promoting potential. To bring more insightsinto cellular and molecular mechanisms of action of MSCsand their potential for clinical use, stem cells internationalset out to launch and publish a special Issue on this topic.In this issue, distinguished researchers from all over theworld contributed with their experience and knowledge tohighlight the latest developments in this emerging field ofresearch.The conundrum of the MSC origin remains unresolveddue to the lack of a specific cell surface marker. Identificationof such markers could undoubtedly help the scientists todevelop new methodologies for prospective isolation andexpansion of MSCs in their “native” state (undiﬀerentiated)for clinical application.S. A. E. Boxall and Jones in the UK (in “Markers for char-acterization of bone marrow multipotential stromal cells”)have focused on description of the most important markers,which have been reported so far for the characterization andprospective isolation of progenitor cells for MSCs. In thefirst part of this paper, the authors discussed surface andmolecular markers that were proposed as the indicators ofMSC potency, in terms of their proliferative potential or theability to diﬀerentiate into desired lineages. In the secondpart of this paper, the authors discussed critically surfacemarkers of uncultured (i.e., native) bone marrow-(BM-)derived MSCs. Although no formal consensus has yet beenreached on which markers may be best suited for prospectiveBM-MSC isolation, the authors suggest that markers thatcross-react with MSCs of animal models (such as CD271 andW8-B2/MSCA-1) may have the strongest translational value.As the number of progenitor cells for MSCs in BMand other organs is pretty low, MSCs should be ex vivoexpanded in order to achieve a suﬃcient number for clinicalapplication. Historically, large-scale clinical expansions ofMSCs have been performed by using a basal medium sup-plemented with fetal bovine serum (FBS). Because of the ill-defined nature of FBS (presence of xenogeneic components)and lot-to-lot inconsistency of performance, developmentof a more defined serum-free MSC culture medium hasbecome absolutely necessary. Therefore, S. Jung et al. inCanada (in “Ex vivo expansion of human mesenchymalstem cells in defined serum-free media”) reviewed hereincurrent cell culture media for hMSCs and discussed medium2 Stem Cells Internationaldevelopment strategies. In addition to the serum-containingand serum-free MSC-culture medium supplemented withplatelet lysates the authors compared properties of a serum-free, chemically defined MSC-culture medium (PPRF-msc6)developed in their laboratory with the commercially availableserum-free media.MSCs after their in vivo administration show their anti-inflammatory and regenerative eﬀects either by secretionof long-distance acting soluble molecules or by migratingand homing to the damaged tissues. S. k. Kang et al. inSouth Korea in their review (in “Journey of mesenchymalstem cells for homing: strategies to enhance eﬃcacy and safetyof stem cell therapy”) outline the current understanding ofMSC migration and discuss strategies for enhancing boththe environmental and cellular conditions that give rise toeﬀective homing ofMSCs. According to the authors, this mayallow MSCs to quickly find and migrate to injured tissues,where they may best exert clinical benefits resulting fromimproved homing and the presence of increased numbers ofMSCs.Extensive experimental research during the past decadesprofoundly influenced the understanding of the mechanismof MSC-action and consequently its potential use in regen-erative medicine. P. Babei et al. in Iran (in “Transplantedbone marrow mesenchymal stem cells improve memory in ratmodels of alzheimer’s disease”) demonstrated in the rat modelthat MSC treatment significantly increased learning abilityand memory in both age-induced and chemically inducedmemory impairment.In addition, stem cell-based therapy represents a rapidlygrowing alternative for cardiovascular diseases as the leadingcause of death worldwide. M. T. Elnakish et al. in USA (in“Mesenchymal stem cells for cardiac regeneration: translationto bedside reality”) focussed on therapeutic applications ofMSCs and their transition from experimental bench side toclinical bedside. Based on the reports published so far, theyconclude that in addition to embryonic stem cells, inducedpluripotent stem cells (iPSCs), endothelial progenitor cells,hematopoietic stem cells, and skeletal myoblasts that wereused in the treatment of ischemic heart disease and myocar-dial infarction, MSCs due to their distinctive propertiesrepresent an innovative approach for cardiac regeneration.In line with this, N. A. Kouris et al. in USA (in “Directedfusion of mesenchymal stem cells with cardiomyocytes viaVSV-G facilitates stem cell programming”) in their originalarticle demonstrated that expression of the fusogen ofthe vesicular stomatitis virus (VSV-G) in human MSCs(vMSCs) increased their fusion capacity with cardiomyocytes(CMs). The fused cells adopted a CM-like phenotype andmorphology in vitro. Furthermore, the authors found thatthe vMSCs delivered to the damaged mouse myocardium,via a collagen patch, were able to home to the myocardiumand fuse to cells within the infarct and peri-infarct region ofthe myocardium and exerted functional benefit via multiplemechanisms.H. Thaker and A. K. Sharma in USA (in “Engaging stemcells for customized tendon regeneration”) outlined in theirreview the use of MSCs together with poly(1,8-octanediolco-citrate) scaﬀolds (POCs) to develop a fibroelastic networkguided by cytokines and growth factors in order to be used asa consistent therapeutic approach to tendon injury repair.R. Nuzzi et al. in Italy (in “Eﬀect of in vitro exposure ofcorticosteroid drugs, conventionally used in AMD treatment,on mesenchymal stem cells”) in their research article foundthat steroid drugs, often used to treat age-related maculardegeneration (AMD), demonstrate a negative eﬀect onMSCsas a potential candidate for treatment of AMD. This eﬀectwas reduced in the presence of supernatant of a humanretinal pigment epithelial cell line (ARPE-19).As MSCs exert a very potent immunomodulatory eﬀect,they are often used clinically to suppress the adverse eﬀectsof graft versus host disease (GvHD) after hematopoietic stemcell transplantation. Because of a broad immunosuppression,the patients are at risk of bacterial and viral infections. G.Lucchini et al. in Italy (in “Mesenchymal stromal cells do notincrease the risk of viral reactivation nor the severity of viralevents in recipients of allogeneic stem cell transplantation”)in their clinical study analyzed viral reactivation episodesby a whole blood PCR in 24 patients receiving MSCs forthe treatment of GvHD. In their cohort of patients, viralreactivation after MSC infusion occurred in 45% of thecases, which did not significantly diﬀer from the incidencein a historical cohort of patients aﬀected by steroid-resistantGvHD and treated with conventional immunosuppression.In addition to the bone marrow, during the last decadethe adipose tissue is being recognized not only as an energyreservoir, but also as a rich source of multipotent cells. P.C. Baer and H. Geiger in Germany (in “Adipose-derivedmesenchymal stromal/stem cells: tissue localization, character-ization, and heterogeneity”) and H. Orbay et al. in Japan(in “Mesenchymal stem cells isolated from adipose and othertissues: basic biological properties and clinical applications”)in their review articles made an overview about the sourcesand methods of isolation, phenotype as well as the potentialof adipose tissue-derived MSCs to give rise to the tissuesof three germ layers. In line with this, R. k. Chan et al.in USA (in “Development of a vascularized skin constructusing adipose-derived stem cells from debrided burned skin”)have exploited autologous stem cells from the adipose layerof surgically debrided burned skin (dsASC) to generate invitro an epithelial layer, a vascularised dermal layer, and ahypodermal layer. The authors conclude that this techniquemay provide an alternative approach for cutaneous coverageafter extensive burn injuries.Regulatory issues concerning the safety of clinical use ofMSCs are strongly required for their broad clinical appli-cation. Y. Wang et al. in China (in “Safety of mesenchymalstem cells for clinical application”) in their review focussedon safety issues of MSCs, in particular their genetic stabilityin long-term in vitro expansion, their cryopreservation,banking, and the role of serum in the preparation ofMSCs. Based on hundreds of clinical trials using MSCsthat have been registered, the authors conclude that theproduction of safe cell products requires an entire process ofsupervision in order to assure that the cells maintain overallphenotype, functional potential, and to ensure that culturedcells remain untransformed and without microbiologicalcontaminations.Stem Cells International 3In summary, we hope that the reader of this special issuewill gain more insights into the advancements and challengesfaced by this rapidly expanding field of medicine.Selim Kuc¸iReinhard HenschlerIngo Mu¨llerEttore BiagiRoland MeiselSubmit your manuscripts athttp://www.hindawi.comHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014 Anatomy Research InternationalPeptidesInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporation http://www.hindawi.com International Journal ofVolume 2014ZoologyHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Molecular Biology International GenomicsInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014BioinformaticsAdvances inMarine BiologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Signal TransductionJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014BioMed Research InternationalEvolutionary BiologyInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Biochemistry Research InternationalArchaeaHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Genetics Research InternationalHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Advances inVirolog yHindawi Publishing Corporationhttp://www.hindawi.comNucleic AcidsJournal ofVolume 2014Stem CellsInternationalHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Enzyme ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014International Journal ofMicrobiology

Stem Cells International

Basic Biology and Clinical Application of Multipotent Mesenchymal Stromal Cells: From Bench to Bedside

Kuci, Selim

Mueller, Ingo

Universität München: Elektronischen Publikationen

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Hindawi Publishing CorporationStem Cells InternationalVolume 2012, Article ID 185943, 3 pagesdoi:10.1155/2012/185943EditorialBasic Biology and Clinical Application of MultipotentMesenchymalStromal Cells: From Bench to BedsideSelimKuc ¸i,1 Reinhard Henschler,2 Ingo M¨ uller,3 Ettore Biagi,4 andRolandMeisel51Departments of Hematology and Oncology, University Children’s Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany2Institute for Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig Maximilians University Munich,Marchioninistrasse 15, 81377 Munich, Germany3Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52,20246 Hamburg, Germany4Laboratory of Cell Therapy “Stefano Verri,” Pediatric Department, University of Milano-Bicocca, San Gerardo Hospital,20900 Monza, Italy5Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty,Heinrich-Heine University D¨ usseldorf, 40225 D¨ usseldorf, GermanyCorrespondence should be addressed to Selim Kuc ¸i,selim.kuci@kgu.deReceived 8 August 2012; Accepted 8 August 2012Copyright © 2012 Selim Kuc ¸i et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Since their discovery in the end of the 1960s and thebeginningofthe1970sbyAlexanderFriedenstein,mesenchy-mal stromal cells (MSCs) have attracted the interest of thescientiﬁc community because of their ubiquitous presence inthe organism, the ease of their procurement, and potentialto diﬀerentiate into other tissues. As a nonhematopoieticcell population, ﬁrst described in the bone marrow, MSCscomprise a pool of progenitor cells with diﬀerent prolifera-tive, diﬀerentiation, immunosuppressive, and hematopoieticengraftment-promoting potential. To bring more insightsinto cellular and molecular mechanisms of action of MSCsand their potential for clinical use, stem cells internationalset out to launch and publish a special Issue on this topic.In this issue, distinguished researchers from all over theworld contributed with their experience and knowledge tohighlight the latest developments in this emerging ﬁeld ofresearch.The conundrum of the MSC origin remains unresolveddue to the lack of a speciﬁc cell surface marker. Identiﬁcationof such markers could undoubtedly help the scientists todevelop new methodologies for prospective isolation andexpansion of MSCs in their “native” state (undiﬀerentiated)for clinical application.S. A. E. Boxall and Jones in the UK (in “Markers for char-acterization of bone marrow multipotential stromal cells”)have focused on description of the most important markers,which have been reported so far for the characterization andprospective isolation of progenitor cells for MSCs. In theﬁrst part of this paper, the authors discussed surface andmolecular markers that were proposed as the indicators ofMSC potency, in terms of their proliferative potential or theability to diﬀerentiate into desired lineages. In the secondpart of this paper, the authors discussed critically surfacemarkers of uncultured (i.e., native) bone marrow-(BM-)derived MSCs. Although no formal consensus has yet beenreached on which markers may be best suited for prospectiveBM-MSC isolation, the authors suggest that markers thatcross-react with MSCs of animal models (such as CD271 andW8-B2/MSCA-1) may have the strongest translational value.As the number of progenitor cells for MSCs in BMand other organs is pretty low, MSCs should be ex vivoexpanded in order to achieve a suﬃcient number for clinicalapplication. Historically, large-scale clinical expansions ofMSCs have been performed by using a basal medium sup-plemented with fetal bovine serum (FBS). Because of the ill-deﬁned nature of FBS (presence of xenogeneic components)and lot-to-lot inconsistency of performance, developmentof a more deﬁned serum-free MSC culture medium hasbecome absolutely necessary. Therefore, S. Jung et al. inCanada (in “Ex vivo expansion of human mesenchymalstem cells in deﬁned serum-free media”) reviewed hereincurrent cell culture media for hMSCs and discussed medium2 Stem Cells Internationaldevelopment strategies. In addition to the serum-containingand serum-free MSC-culture medium supplemented withplatelet lysates the authors compared properties of a serum-free, chemically deﬁned MSC-culture medium (PPRF-msc6)developedintheirlaboratorywiththecommerciallyavailableserum-free media.MSCs after their in vivo administration show their anti-inﬂammatory and regenerative eﬀects either by secretionof long-distance acting soluble molecules or by migratingand homing to the damaged tissues. S. k. Kang et al. inSouth Korea in their review (in “Journey of mesenchymalstem cells for homing: strategies to enhance eﬃcacy and safetyof stem cell therapy”) outline the current understanding ofMSC migration and discuss strategies for enhancing boththe environmental and cellular conditions that give rise toeﬀectivehomingofMSCs.Accordingtotheauthors,thismayallow MSCs to quickly ﬁnd and migrate to injured tissues,where they may best exert clinical beneﬁts resulting fromimproved homing and the presence of increased numbers ofMSCs.Extensive experimental research during the past decadesprofoundly inﬂuenced the understanding of the mechanismof MSC-action and consequently its potential use in regen-erative medicine. P. Babei et al. in Iran (in “Transplantedbone marrow mesenchymal stem cells improve memory in ratmodels of alzheimer’s disease”) demonstrated in the rat modelthat MSC treatment signiﬁcantly increased learning abilityand memory in both age-induced and chemically inducedmemory impairment.In addition, stem cell-based therapy represents a rapidlygrowing alternative for cardiovascular diseases as the leadingcause of death worldwide. M. T. Elnakish et al. in USA (in“Mesenchymal stem cells for cardiac regeneration: translationto bedside reality”) focussed on therapeutic applications ofMSCs and their transition from experimental bench side toclinical bedside. Based on the reports published so far, theyconclude that in addition to embryonic stem cells, inducedpluripotent stem cells (iPSCs), endothelial progenitor cells,hematopoietic stem cells, and skeletal myoblasts that wereused in the treatment of ischemic heart disease and myocar-dial infarction, MSCs due to their distinctive propertiesrepresent an innovative approach for cardiac regeneration.In line with this, N. A. Kouris et al. in USA (in “Directedfusion of mesenchymal stem cells with cardiomyocytes viaVSV-G facilitates stem cell programming”) in their originalarticle demonstrated that expression of the fusogen ofthe vesicular stomatitis virus (VSV-G) in human MSCs(vMSCs)increasedtheirfusioncapacitywithcardiomyocytes(CMs). The fused cells adopted a CM-like phenotype andmorphology in vitro. Furthermore, the authors found thatthe vMSCs delivered to the damaged mouse myocardium,via a collagen patch, were able to home to the myocardiumand fuse to cells within the infarct and peri-infarct region ofthe myocardium and exerted functional beneﬁt via multiplemechanisms.H. Thaker and A. K. Sharma in USA (in “Engaging stemcells for customized tendon regeneration”) outlined in theirreview the use of MSCs together with poly(1,8-octanediolco-citrate) scaﬀolds(POCs)todevelopaﬁbroelasticnetworkguided bycytokines and growth factorsin order to be used asa consistent therapeutic approach to tendon injury repair.R. Nuzzi et al. in Italy (in “Eﬀect of in vitro exposure ofcorticosteroid drugs, conventionally used in AMD treatment,on mesenchymal stem cells”) in their research article foundthat steroid drugs, often used to treat age-related maculardegeneration(AMD),demonstrateanegativeeﬀectonMSCsas a potential candidate for treatment of AMD. This eﬀectwas reduced in the presence of supernatant of a humanretinal pigment epithelial cell line (ARPE-19).As MSCs exert a very potent immunomodulatory eﬀect,they are often used clinically to suppress the adverse eﬀectsof graftversus host disease (GvHD)afterhematopoietic stemcelltransplantation.Becauseofabroadimmunosuppression,the patients are at risk of bacterial and viral infections. G.Lucchini et al. in Italy (in “Mesenchymal stromal cells do notincrease the risk of viral reactivation nor the severity of viralevents in recipients of allogeneic stem cell transplantation”)in their clinical study analyzed viral reactivation episodesby a whole blood PCR in 24 patients receiving MSCs forthe treatment of GvHD. In their cohort of patients, viralreactivation after MSC infusion occurred in 45% of thecases, which did not signiﬁcantly diﬀer from the incidencein a historical cohort of patients aﬀected by steroid-resistantGvHD and treated with conventional immunosuppression.In addition to the bone marrow, during the last decadethe adipose tissue is being recognized not only as an energyreservoir, but also as a rich source of multipotent cells. P.C. Baer and H. Geiger in Germany (in “Adipose-derivedmesenchymal stromal/stem cells: tissue localization, character-ization, and heterogeneity”) and H. Orbay et al. in Japan(in “Mesenchymal stem cells isolated from adipose and othertissues: basic biological properties and clinical applications”)in their review articles made an overview about the sourcesand methods of isolation, phenotype as well as the potentialof adipose tissue-derived MSCs to give rise to the tissuesof three germ layers. In line with this, R. k. Chan et al.in USA (in “Development of a vascularized skin constructusing adipose-derived stem cells from debrided burned skin”)have exploited autologous stem cells from the adipose layerof surgically debrided burned skin (dsASC) to generate invitro an epithelial layer, a vascularised dermal layer, and ahypodermal layer. The authors conclude that this techniquemay provide an alternative approach for cutaneous coverageafter extensive burn injuries.Regulatory issues concerning the safety of clinical use ofMSCs are strongly required for their broad clinical appli-cation. Y. Wang et al. in China (in “Safety of mesenchymalstem cells for clinical application”) in their review focussedon safety issues of MSCs, in particular their genetic stabilityin long-term in vitro expansion, their cryopreservation,banking, and the role of serum in the preparation ofMSCs. Based on hundreds of clinical trials using MSCsthat have been registered, the authors conclude that theproduction of safe cell products requires an entire process ofsupervision in order to assure that the cells maintain overallphenotype, functional potential, and to ensure that culturedcells remain untransformed and without microbiologicalcontaminations.Stem Cells International 3In summary, we hope that the reader of this special issuewillgainmoreinsightsintotheadvancementsandchallengesfaced by this rapidly expanding ﬁeld of medicine.Selim Kuc ¸iReinhard HenschlerIngo M¨ ullerEttore BiagiRoland Meisel

Basic biology and clinical application of multipotent mesenchymal stromal cells : from bench to bedside

Open Access LMU ( Ludwig-Maximilians-Univ. München)

Hindawi Publishing CorporationStem Cells InternationalVolume 2012, Article ID 185943, 3 pagesdoi:10.1155/2012/185943EditorialBasic Biology and Clinical Application of MultipotentMesenchymal Stromal Cells: From Bench to BedsideSelim Kuçi,1 Reinhard Henschler,2 Ingo Müller,3 Ettore Biagi,4 and Roland Meisel51 Departments of Hematology and Oncology, University Children’s Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany2 Institute for Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig Maximilians University Munich,Marchioninistrasse 15, 81377 Munich, Germany3 Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52,20246 Hamburg, Germany4 Laboratory of Cell Therapy “Stefano Verri,” Pediatric Department, University of Milano-Bicocca, San Gerardo Hospital,20900 Monza, Italy5 Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty,Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, GermanyCorrespondence should be addressed to Selim Kuçi, selim.kuci@kgu.deReceived 8 August 2012; Accepted 8 August 2012Copyright © 2012 Selim Kuçi et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Since their discovery in the end of the 1960s and thebeginning of the 1970s by Alexander Friedenstein, mesenchy-mal stromal cells (MSCs) have attracted the interest of thescientific community because of their ubiquitous presence inthe organism, the ease of their procurement, and potentialto differentiate into other tissues. As a nonhematopoieticcell population, first described in the bone marrow, MSCscomprise a pool of progenitor cells with different prolifera-tive, differentiation, immunosuppressive, and hematopoieticengraftment-promoting potential. To bring more insightsinto cellular and molecular mechanisms of action of MSCsand their potential for clinical use, stem cells internationalset out to launch and publish a special Issue on this topic.In this issue, distinguished researchers from all over theworld contributed with their experience and knowledge tohighlight the latest developments in this emerging field ofresearch.The conundrum of the MSC origin remains unresolveddue to the lack of a specific cell surface marker. Identificationof such markers could undoubtedly help the scientists todevelop new methodologies for prospective isolation andexpansion of MSCs in their “native” state (undifferentiated)for clinical application.S. A. E. Boxall and Jones in the UK (in “Markers for char-acterization of bone marrow multipotential stromal cells”)have focused on description of the most important markers,which have been reported so far for the characterization andprospective isolation of progenitor cells for MSCs. In thefirst part of this paper, the authors discussed surface andmolecular markers that were proposed as the indicators ofMSC potency, in terms of their proliferative potential or theability to differentiate into desired lineages. In the secondpart of this paper, the authors discussed critically surfacemarkers of uncultured (i.e., native) bone marrow-(BM-)derived MSCs. Although no formal consensus has yet beenreached on which markers may be best suited for prospectiveBM-MSC isolation, the authors suggest that markers thatcross-react with MSCs of animal models (such as CD271 andW8-B2/MSCA-1) may have the strongest translational value.As the number of progenitor cells for MSCs in BMand other organs is pretty low, MSCs should be ex vivoexpanded in order to achieve a sufficient number for clinicalapplication. Historically, large-scale clinical expansions ofMSCs have been performed by using a basal medium sup-plemented with fetal bovine serum (FBS). Because of the ill-defined nature of FBS (presence of xenogeneic components)and lot-to-lot inconsistency of performance, developmentof a more defined serum-free MSC culture medium hasbecome absolutely necessary. Therefore, S. Jung et al. inCanada (in “Ex vivo expansion of human mesenchymalstem cells in defined serum-free media”) reviewed hereincurrent cell culture media for hMSCs and discussed medium2 Stem Cells Internationaldevelopment strategies. In addition to the serum-containingand serum-free MSC-culture medium supplemented withplatelet lysates the authors compared properties of a serum-free, chemically defined MSC-culture medium (PPRF-msc6)developed in their laboratory with the commercially availableserum-free media.MSCs after their in vivo administration show their anti-inflammatory and regenerative effects either by secretionof long-distance acting soluble molecules or by migratingand homing to the damaged tissues. S. k. Kang et al. inSouth Korea in their review (in “Journey of mesenchymalstem cells for homing: strategies to enhance efficacy and safetyof stem cell therapy”) outline the current understanding ofMSC migration and discuss strategies for enhancing boththe environmental and cellular conditions that give rise toeffective homing of MSCs. According to the authors, this mayallow MSCs to quickly find and migrate to injured tissues,where they may best exert clinical benefits resulting fromimproved homing and the presence of increased numbers ofMSCs.Extensive experimental research during the past decadesprofoundly influenced the understanding of the mechanismof MSC-action and consequently its potential use in regen-erative medicine. P. Babei et al. in Iran (in “Transplantedbone marrow mesenchymal stem cells improve memory in ratmodels of alzheimer’s disease”) demonstrated in the rat modelthat MSC treatment significantly increased learning abilityand memory in both age-induced and chemically inducedmemory impairment.In addition, stem cell-based therapy represents a rapidlygrowing alternative for cardiovascular diseases as the leadingcause of death worldwide. M. T. Elnakish et al. in USA (in“Mesenchymal stem cells for cardiac regeneration: translationto bedside reality”) focussed on therapeutic applications ofMSCs and their transition from experimental bench side toclinical bedside. Based on the reports published so far, theyconclude that in addition to embryonic stem cells, inducedpluripotent stem cells (iPSCs), endothelial progenitor cells,hematopoietic stem cells, and skeletal myoblasts that wereused in the treatment of ischemic heart disease and myocar-dial infarction, MSCs due to their distinctive propertiesrepresent an innovative approach for cardiac regeneration.In line with this, N. A. Kouris et al. in USA (in “Directedfusion of mesenchymal stem cells with cardiomyocytes viaVSV-G facilitates stem cell programming”) in their originalarticle demonstrated that expression of the fusogen ofthe vesicular stomatitis virus (VSV-G) in human MSCs(vMSCs) increased their fusion capacity with cardiomyocytes(CMs). The fused cells adopted a CM-like phenotype andmorphology in vitro. Furthermore, the authors found thatthe vMSCs delivered to the damaged mouse myocardium,via a collagen patch, were able to home to the myocardiumand fuse to cells within the infarct and peri-infarct region ofthe myocardium and exerted functional benefit via multiplemechanisms.H. Thaker and A. K. Sharma in USA (in “Engaging stemcells for customized tendon regeneration”) outlined in theirreview the use of MSCs together with poly(1,8-octanediolco-citrate) scaffolds (POCs) to develop a fibroelastic networkguided by cytokines and growth factors in order to be used asa consistent therapeutic approach to tendon injury repair.R. Nuzzi et al. in Italy (in “Effect of in vitro exposure ofcorticosteroid drugs, conventionally used in AMD treatment,on mesenchymal stem cells”) in their research article foundthat steroid drugs, often used to treat age-related maculardegeneration (AMD), demonstrate a negative effect on MSCsas a potential candidate for treatment of AMD. This effectwas reduced in the presence of supernatant of a humanretinal pigment epithelial cell line (ARPE-19).As MSCs exert a very potent immunomodulatory effect,they are often used clinically to suppress the adverse effectsof graft versus host disease (GvHD) after hematopoietic stemcell transplantation. Because of a broad immunosuppression,the patients are at risk of bacterial and viral infections. G.Lucchini et al. in Italy (in “Mesenchymal stromal cells do notincrease the risk of viral reactivation nor the severity of viralevents in recipients of allogeneic stem cell transplantation”)in their clinical study analyzed viral reactivation episodesby a whole blood PCR in 24 patients receiving MSCs forthe treatment of GvHD. In their cohort of patients, viralreactivation after MSC infusion occurred in 45% of thecases, which did not significantly differ from the incidencein a historical cohort of patients affected by steroid-resistantGvHD and treated with conventional immunosuppression.In addition to the bone marrow, during the last decadethe adipose tissue is being recognized not only as an energyreservoir, but also as a rich source of multipotent cells. P.C. Baer and H. Geiger in Germany (in “Adipose-derivedmesenchymal stromal/stem cells: tissue localization, character-ization, and heterogeneity”) and H. Orbay et al. in Japan(in “Mesenchymal stem cells isolated from adipose and othertissues: basic biological properties and clinical applications”)in their review articles made an overview about the sourcesand methods of isolation, phenotype as well as the potentialof adipose tissue-derived MSCs to give rise to the tissuesof three germ layers. In line with this, R. k. Chan et al.in USA (in “Development of a vascularized skin constructusing adipose-derived stem cells from debrided burned skin”)have exploited autologous stem cells from the adipose layerof surgically debrided burned skin (dsASC) to generate invitro an epithelial layer, a vascularised dermal layer, and ahypodermal layer. The authors conclude that this techniquemay provide an alternative approach for cutaneous coverageafter extensive burn injuries.Regulatory issues concerning the safety of clinical use ofMSCs are strongly required for their broad clinical appli-cation. Y. Wang et al. in China (in “Safety of mesenchymalstem cells for clinical application”) in their review focussedon safety issues of MSCs, in particular their genetic stabilityin long-term in vitro expansion, their cryopreservation,banking, and the role of serum in the preparation ofMSCs. Based on hundreds of clinical trials using MSCsthat have been registered, the authors conclude that theproduction of safe cell products requires an entire process ofsupervision in order to assure that the cells maintain overallphenotype, functional potential, and to ensure that culturedcells remain untransformed and without microbiologicalcontaminations.Stem Cells International 3In summary, we hope that the reader of this special issuewill gain more insights into the advancements and challengesfaced by this rapidly expanding field of medicine.Selim KuçiReinhard HenschlerIngo MüllerEttore BiagiRoland MeiselSubmit your manuscripts athttp://www.hindawi.comHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014 Anatomy Research InternationalPeptidesInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporation http://www.hindawi.com International Journal ofVolume 2014ZoologyHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Molecular Biology International GenomicsInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014BioinformaticsAdvances inMarine BiologyJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Signal TransductionJournal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014BioMed Research InternationalEvolutionary BiologyInternational Journal ofHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Biochemistry Research InternationalArchaeaHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Genetics Research InternationalHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Advances inVirolog yHindawi Publishing Corporationhttp://www.hindawi.comNucleic AcidsJournal ofVolume 2014Stem CellsInternationalHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014Enzyme ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014International Journal ofMicrobiology

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Basic biology and clinical application of multipotent mesenchymal stromal cells : from bench to bedside

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