A Roadmap to Nonhematopoietic Stem Cell-Based Therapeutics From the Bench to the Clinic

515 Pages·2019·9.386 MB·English

by  Xiao-Dong Chen

A Roadmap to
Nonhematopoietic
Stem Cell-Based
Therapeutics
From the Bench to the Clinic
Edited by
Xiao-Dong Chen
Department of Comprehensive Dentistry and Chief,
Regenerative Medicine Program, School of Dentistry,
University of Texas Health Science Center, San Antonio, United States
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List of Contributors
Ashley E. Aaroe, Department of Neurology, Weill Cornell Medical College, New
York,NY,UnitedStates
TravisJ.Block,DepartmentofComprehensiveDentistry,UniversityofTexasHealth
Science Center at San Antonio, San Antonio, TX, United States; Department of
Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX,
UnitedStates
Gabriela Bortz, Institute of Science and Technology Studies, National University of
Quilmes, Buenos Aires, Argentina; National Council of Scientific and Technical
Research (CONICET),BuenosAires,Argentina
Rodney K. Chan, Q-SCARR(cid:1) (Quality Skin Collaborative for Advanced Recon-
struction and Regeneration) Research Program, US Army Institute of Surgical
Research, Joint Base San Antonio, TX, United States; Dental and Craniofacial
Trauma Research and Tissue Regeneration, US Army Institute of Surgical
Research, JointBaseSanAntonio,Ft.SamHouston,TX,UnitedStates
Xi Chen, State Key Laboratory of Military Stomatology and National Clinical
Research CenterforOralDiseasesandShaanxiKeyLaboratoryofOralDiseases,
Center for Tissue Engineering, Fourth Military Medical University, Xi’an, China;
NanjingStomatologicalHospital,MedicalSchoolofNanjingUniversity,Nanjing,
China
Xiao-DongChen,DepartmentofComprehensiveDentistry,UniversityofTexasHealth
Science Center at San Antonio, San Antonio, TX, United States; Department of
Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX,
UnitedStates;AudieMurphyVAMedicalCenter,SanAntonio,TX,UnitedStates;
Barshop Institute for Longevity and Aging Studies, University of Texas Health
ScienceCenteratSanAntonio,SanAntonio,TX,UnitedStates;ResearchService
andGeriatricResearch,Education,andClinicalCenter,AudieL.MurphyDivision,
South TexasVeteransHealth CareSystem,San Antonio,TX,UnitedStates
Robert J. Christy, Combat Trauma and Burn Injury Research, US Army Institute of
SurgicalResearch,JointBaseSan Antonio,Ft.SamHouston,TX,UnitedStates
C.S. Cox, Department of Pediatric Surgery, Regenerative Medicine Division,
McGovernMedicalSchool,UniversityofTexasHealthScienceCenteratHouston,
Houston,TX,UnitedStates
David D.Dean, Department of Comprehensive Dentistry, University of TexasHealth
Science Center at San Antonio, San Antonio, TX, United States; Department of
Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX,
UnitedStates
xvii
xviii ListofContributors
Alfonso Eirin, Division of Nephrology and Hypertension, Mayo Clinic, Rochester,
MN,UnitedStates
RobertoEsquivel,BioBridgeGlobal, SanAntonio,TX,UnitedStates
MichelleLynnFults,GenCure,San Antonio,TX,UnitedStates
Stan Gronthos, Adelaide Medical School, Faculty of Health and Medical Sciences,
TheUniversityofAdelaide,Adelaide,SA,Australia;SouthAustralianHealthand
MedicalResearch Institute,Adelaide,SA,Australia
Patrick J. Hanley, Program for Cell Enhancement and Technologies for Immuno-
therapy, Center for Cancer and Immunology Research, Sheikh Zayed Institute for
Pediatric Surgical Innovation, The George Washington University, Washington,
DC, United States; Division of Blood and Marrow Transplantation, Children’s
National Health System, The George Washington University, Washington, DC,
UnitedStates
Claire Henchcliffe, Department of Neurology, Weill Cornell Medical College, New
York,NY,UnitedStates
LaTonya J. Hickson, Division of Nephrology and Hypertension, Mayo Clinic,
Rochester,MN,UnitedStates
JamieHoover,ProgramforCellEnhancementandTechnologiesforImmunotherapy,
CenterforCancerandImmunologyResearch,SheikhZayedInstituteforPediatric
SurgicalInnovation,TheGeorgeWashingtonUniversity,Washington,DC,United
States
MariaV.Irazabal,DivisionofNephrologyandHypertension,MayoClinic,Rochester,
MN,UnitedStates
YanJin,StateKeyLaboratoryofMilitaryStomatologyandNationalClinicalResearch
CenterforOralDiseasesandShaanxiKeyLaboratoryofOralDiseases,Centerfor
TissueEngineering, FourthMilitaryMedicalUniversity,Xi’an,China
Christian Jorgensen, IRMB, INSERM, University of Montpellier, Montpellier,
France; Clinical Immunology and Osteoarticular Diseases Therapeutic Unit,
HoˆpitalLapeyronie,Montpellier,France
NoorHayatyAbuKasim,DepartmentofRestorativeDentistry,FacultyofDentistry,
UniversityofMalaya,KualaLumpur,Malaysia
Joseph W. Kim, Department of Medicine, School of Medicine, Boston University,
Boston,MA, UnitedStates
Maciej Kurpisz, Institute of Human Genetics, Polish Academy of Sciences, Poznan,
Poland
BeiLi,StateKeyLaboratoryofMilitaryStomatologyandNationalClinicalResearch
CenterforOralDiseasesandShaanxiKeyLaboratoryofOralDiseases,Centerfor
TissueEngineering, FourthMilitaryMedicalUniversity,Xi’an,China
JohnZ.Q.Luo,InsureHealth,Inc.,Warwick,RI,UnitedStates
Luguang Luo, Department of Medicine, School of Medicine, Boston University,
Boston, MA, United States; The Center for Natural Healing Rhode Island, Paw-
tucket,RI,UnitedStates
ListofContributors xix
ShivaprasadManjappa,DepartmentofMedicine,WashingtonUniversityinSt.Louis,
St.Louis,MO, UnitedStates
Milos Marinkovic, Department of Comprehensive Dentistry, University of Texas
HealthScienceCenteratSanAntonio,SanAntonio,TX,UnitedStates;Department
ofBiomedicalEngineering,UniversityofTexasatSanAntonio,SanAntonio,TX,
UnitedStates
Marie Maumus,IRMB,INSERM,UniversityofMontpellier,Montpellier,France
ShanmugasundaramNatesan,CombatTraumaandBurnInjuryResearch,USArmy
Institute of Surgical Research, Joint Base San Antonio, Ft. Sam Houston, TX,
UnitedStates
Danie`le Noe¨l, IRMB, INSERM, University of Montpellier, Montpellier, France;
Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Hoˆpital
Lapeyronie,Montpellier,France
S.D. Olson, Department of Pediatric Surgery, Regenerative Medicine Division,
McGovernMedicalSchool,UniversityofTexasHealthScienceCenteratHouston,
Houston,TX,UnitedStates
ArminRashidi,DivisionofHematology,Oncology,andTransplantation,Universityof
Minnesota, Minneapolis,MN,UnitedStates
Rizwan Romee, Clinical Director of Haploidentical Transplant Program, Division of
Oncology,DepartmentofMedicine,WashingtonUniversityinSt.Louis,St.Louis,
MO, UnitedStates
Achim Rosemann, Department of Sociology, University of Exeter, Exeter, United
Kingdom; Centre for Bionetworking, School of Global Studies, University of
Sussex,Brighton,UnitedKingdom
Natalia Rozwadowska, Institute of Human Genetics, Polish Academy of Sciences,
Poznan,Poland
Maxime Ruiz,IRMB,INSERM,UniversityofMontpellier,Montpellier,France
K.A. Ruppert, Department of Pediatric Surgery, Regenerative Medicine Division,
McGovernMedicalSchool,UniversityofTexasHealthScienceCenteratHouston,
Houston,TX,UnitedStates
ThekkeparambilChandraboseSrijaya,DepartmentofRestorativeDentistry,Faculty
ofDentistry,UniversityofMalaya,KualaLumpur,Malaysia
AnandSrinivasan,GenCure,SanAntonio,TX,UnitedStates;BioBridgeGlobal,San
Antonio,TX,UnitedStates
Sandhya Sriram, Fat Metabolism and Stem Cell Group (FMSCG), Singapore Bio-
imaging Consortium (SBIC), A*STAR Research Entities, Biopolis Way, Helios,
Singapore
RandolphStone,II,CombatTraumaandBurnInjuryResearch,USArmyInstituteof
SurgicalResearch,JointBaseSan Antonio,Ft.SamHouston,TX,UnitedStates
xx ListofContributors
ShigekiSugii,FatMetabolismandStemCellGroup(FMSCG),SingaporeBioimaging
Consortium(SBIC),A*STARResearchEntities,BiopolisWay,Helios,Singapore;
Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School,
CollegeRoad,Singapore
Lingyun Sun, Department of Rheumatology and Immunology, The Affiliated Drum
TowerHospital,NanjingUniversityMedical School,Nanjing,China
PeterSupronowicz,GenCure, SanAntonio,TX,UnitedStates
Olivia N. Tran, Department of Comprehensive Dentistry, University of TexasHealth
Science Center at San Antonio, San Antonio, TX, United States; Department of
Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX,
UnitedStates
Federico Vasen, National Council of Scientific and Technical Research (CONICET),
BuenosAires,Argentina;InstitutodeInvestigacionesenCienciasdelaEducacio´n,
UniversidaddeBuenosAires,BuenosAires,Argentina
DandanWang,Department ofRheumatologyandImmunology,The AffiliatedDrum
TowerHospital,NanjingUniversityMedical School,Nanjing,China
HanzhouWang,DepartmentofComprehensiveDentistry,UniversityofTexasHealth
ScienceCenteratSanAntonio,SanAntonio,TX,UnitedStates
Chih-Ko Yeh, Department of Comprehensive Dentistry, University of Texas Health
Science Center at San Antonio, San Antonio, TX, United States; Geriatric
Research,Education,andClinicalCenter,AudieL.MurphyDivision,SouthTexas
VeteransHealthCareSystem,SanAntonio,TX,UnitedStates
RogelioZamilpa,GenCure,SanAntonio,TX,UnitedStates
Preface
WHY THE BOOK IS NEEDED
Since 1993, I have been studying nonhematopoietic stem cells (so called
“mesenchymalstemcells”).Asapostdoctoralfellow,Iwasactivelyinvolvedin
identifying a group of specific cell surface antigens that were associated with
mesenchymal stem cell (MSC) maturation. During that time, the term “stem
cell” was typically used to refer to hematopoietic stem cells (HSCs). Indeed,
MSCs were far less characterized and understood than HSCs. Over the last
25years,thefieldofMSCbiologyhasdevelopedintooneofthemostexciting
and rapidly advancing areas of scientific endeavor. Although MSCs were
originallyidentifiedinbonemarrow,theyhavebeendiscoveredinalmostevery
tissue of the body, including those that were previously thought to be
“non-regenerative,”aswellasothermoreunusualsources(e.g.,umbilicalcord
blood, umbilical cord tissue [Wharton jelly], amniotic fluid, dental pulp, and
periodontal ligament). Furthermore, the technology for preparing embryonic
stemcells(ESCs)isnowwell-establishedandevenartificialESCs(i.e.,induc-
iblepluripotentstemcells[iPSCs])canbecreatedinthelab.Theboominstem
cellresearchandassociatedindustrieshasled totheestablishmentofregener-
ative medicine as a major treatment for repairing damaged tissues caused by
traumaor,morefrequently,age-relateddiseases.However,thisrapidgrowthin
information has also created much confusion and controversy, which has
negatively impacted the translation of basic research on MSCs to clinical
applications.Sincemycareerhasspannedmuchofthetimeduringwhichthis
boom occurred, I have witnessed and contributed to many of these new
developments.Thus,ithasmotivatedmetoassemblethetopicscoveredinthis
text and express my thoughts, as well as share my personal experiences, with
othersinthefield.Myhopeisthatthisbookwillhelpgeneratediscussionaimed
at addressing many of the critical questions in the field today and lead to the
identification of new solutions for navigating the roadblocks that obstruct
translationofstemcellresearchtonewtherapeutics.
AUDIENCE FOR THIS BOOK
In this book, many important clinically relevant concepts, as well as research
philosophy, are reviewed as a background in MSC biology for college and
graduatelevelbiologicalsciencestudentsandpostdoctoralfellows.Inaddition,
xxi
xxii Preface
theprinciplesofMSCtherapeuticsforanumberofcommonage-relateddiseases
arediscussedforphysicians/surgeons/dentistsandresearchscientists/engineers
in the regenerative medicine field. For a future perspective, regulation of
MSC-basedtherapies,thepotentialofMSC-relatedproductsanddrugs,anduse
of MSCs in antiaging are also discussed. These topics will be of interest to a
broad audience, including nonresearchers or researchers in other fields (e.g.,
sociologists, politicians). Finally, another important goal that I hope this book
willachieveistogaintheattentionofpolicymakersand/orregulatoryofficials.
Atpresent,regulationsoftenignoretherealityofMSCbiology(e.g.,MSCsare
frequentlyobtainedfromtissuesinsmallnumbersandmustbeexpandedbefore
useintherapeuticapplicationswhichpresentsanimpossiblehurdletoovercome
the requirement that cells be “minimally” manipulated), which dramatically
slowstheapproval/translationofcell-basedtherapiestotheclinic.Inthefuture,
regulationsneedtobestructuredsothattranslationcantakeplaceinbothasafe
and timely manner to provide valuable new therapies for large numbers of
elderlypatientswithage-relateddiseases.
STRUCTURE OF THIS BOOK
Thebookisdividedintothreesections.Inthefirstsection,weprovidearationale
forthebookandbrieflyintroduceanumberofissues/questionsforthereaderto
considerwhilereadingthetext.Thefollowingchaptersinthissectionthenfocus
onthefeaturesofMSCsfromvarioussourcesanddescribetherelativeadvan-
tagesanddisadvantagesofeachofthecell-basedtherapies,currentissuesrelated
to the preparation of stem cells, and the establishment of standardized high-
quality stem cell banks. In Section 2, we focus on the use of MSCs for treat-
ingvarioustypesofdiseases.Thecurrentstatusofeachofthefollowingdiseases
isreviewedbyexpertsinthefield:autoimmunediseases,osteoarthritis,neuro-
logical disorders, cardiovascular diseases, chronic kidney disease, diabetes,
wound healing, spinal cord injury, and dental/oral diseases. In Section 3, we
focus on future perspectives and review the development of stem cellebased
products,aswellasbiologicaldrugs,anddiscussanewparadigmfortheuseof
MSCsasanantiagingstrategy.Inaddition,expertscomparepathwaysleadingto
theapprovalofstemcellebasedtherapiesintheUS,UK,andothercountriesand
address a number of critical issues/questions commonly encountered in
developingthisclassofdrugs/therapeuticagents.
UNIQUENESS OF THIS BOOK
Thecontentofthisbookisdifferentfromotherregulartexts.Weonlyfocuson
addressingthemostcriticalissuesthatmayblockthetranslationofMSCsfrom
thelaboratorytotheclinic.Inordertoprovidefirst-handinformation,allofthe
contributingauthorsareworldwideexpertsfromthefrontline.Theybringtheir
ownexperienceandexpertisetomakethebookunique.
Preface xxiii
ACKNOWLEDGMENTS
I wouldlike tosincerely thankeach oftheauthors fordevoting theirtime and
effort towards this book. It would not have been possible to accomplish this
projectwithouttheirenthusiasticparticipation.Iamparticularlygratefultomy
colleague,Dr.DavidD.Dean,whohasworkedcloselywithmethroughoutthe
preparationofthistext,carefullyeditedeachchapter,andprovidedwiseadvice
aboutitsorganizationandcontent.
Iwouldalsoliketothanktwoveryspecialpeople,myfatherandmylovely
wife,whohavebothhadmajorimpactsonmylife.Myfatheralwaysprovided
strongsupportwhileIwasgrowingupsothatIcouldobtainthebesteducation
possibleduringsomeverytoughyearsinChina.Ireallybelievethatnomatter
howmuchIachieve,itwouldneverbeenoughtoexceedhisexpectations.Even
now,ourweeklyphoneconversationsalwaysbeginwithhimaskingme“What’s
thegoodnews?”Thisbookwillbeaveryspecialgiftforhimashecelebrateshis
90thbirthdaythisyear.Andtomywife,Lily,whohassacrificedherowncareer
anddreamssoIcouldhavethefreedomtopursuemyown.Icanneverrepayher
foreverythingshehasgivenup.Therefore,Idedicatethisbooktoherandour
upcoming 25th anniversary. I am deeply grateful for her continued compan-
ionship and I thank her for all the encouragement and moral support over the
years!
Finally, I would like to thank all of the people andorganizationsthat have
supportedmeduringmyresearchcareer.Iamespeciallygratefulforthefinancial
support provided by the National Institutes of Health, Department of Veterans
Affairs(VAMeritReview),andtheOwensMedicalResearchFoundation.
Chapter 1
What Can We Learn From This
Book?
Travis J. Block1,2, David D. Dean1,2, Xiao-Dong Chen1,2,3,4
1DepartmentofComprehensiveDentistry,UniversityofTexasHealthScienceCenterat
SanAntonio,SanAntonio,TX,UnitedStates;2DepartmentofBiomedicalEngineering,University
ofTexasatSanAntonio,SanAntonio,TX,UnitedStates;3AudieMurphyVAMedicalCenter,
SanAntonio,TX,UnitedStates;4BarshopInstituteforLongevityandAgingStudies,Universityof
TexasHealthScienceCenteratSanAntonio,SanAntonio,TX,UnitedStates
1. INTRODUCTION
Duringthe21stcentury,stemcelltherapywillplayanincreasinglyimportant
role in treating many previously incurable diseases. More importantly, stem
cellsarelikelytoholdthe keytodelayingthe agingprocessandsignificantly
improvehuman longevity and healthspan. This is due to the unique ability of
stem cells to serve as: (1) “a cell reservoir” that can continually replace aged
and/or damaged cells over a lifetime and (2) “a drug store” that can imme-
diately respond to pathological processes by rapidly secreting trophic factors
torepairdamagedtissuesandrestorehomeostasis.Moreover,stemcellebased
therapies are often able to simultaneously and precisely target multiple
signaling pathways resulting in a systemic treatment for diseases with fewer
sideeffects.Thismultiprongedtherapeuticapproachstandsinstrikingcontrast
to traditional pharmaceutical agents that usually target a single metabolic
pathwaybyeitherblockingorcatalyzingaspecificbiologicalprocessresulting
in regional treatment with more side effects.
In the early 1970s, Friedenstein et al. were the first to identify bone
marrow-derived nonhematopoietic stem cells (now called “mesenchymal
stem cells” [MSCs]) that are capable of differentiating into osteoblasts,
chondrocytes, and adipocytes [1e3]. These cells have been found in almost
every tissue or organ, including tissues that were previously thought to be
“nonregenerative” (e.g., central nervous system, myocardium, skeletal
muscle, and fat), as well as other more unusual sources (e.g., umbilical cord
blood,umbilicalcordtissue[Whartonjelly],amnioticfluid,dentalpulp,and
ARoadmaptoNonhematopoieticStemCell-BasedTherapeutics.https://doi.org/10.1016/B978-0-12-811920-4.00001-X
Copyright©2019ElsevierInc.Allrightsreserved. 3