Stem Cells in the Lung: Development, Repair and Regeneration

366 Pages·2015·6.585 MB·English

by  Ivan Bertoncello (eds.)

Stem Cell Biology and Regenerative Medicine
Ivan Bertoncello E ditor
Stem Cells
in the Lung
Development, Repair and Regeneration
Stem Cell Biology and Regenerative Medicine
SeriesEditor
KursadTurksen,Ph.D.
[email protected]
More information about this series at http://www.springer.com/series/7896
Ivan Bertoncello
Editor
Stem Cells in the Lung
Development, Repair and Regeneration
Editor
IvanBertoncello
LungHealthResearchCentre,
DepartmentofPharmacologyandTherapeutics
UniversityofMelbourne
Melbourne,Victoria
Australia
ISSN2196-8985 ISSN2196-8993 (electronic)
StemCellBiologyandRegenerativeMedicine
ISBN978-3-319-21081-0 ISBN978-3-319-21082-7 (eBook)
DOI10.1007/978-3-319-21082-7
LibraryofCongressControlNumber:2015950860
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Preface
The last decade has witnessed significant progress in understanding the organiza-
tion and regulation of regenerative cells in the adult lung. The development and
refinement of multiparameter flow cytometric cell sorting protocols and in vitro
clonogenicassayshasenabledtheidentification,prospectiveisolation,andcharac-
terizationofcandidateadultlungstemandprogenitorcells.Powerfulgenelabelling
technologies, cell lineage tracing andcell fate mapping protocols,andgenetically
engineered mouse models have revealed critical regulatory molecules, mecha-
nisms, pathways, and cellular interactions important in building the lung during
fetal development; and in maintaining lung function and rebuilding the lung in
adulthood.Thisinturnhasadvancedtheunderstandingofthepathophysiologyof
lungdiseases;andhowendogenouslungstemandprogenitorcells,exogenousstem
cells, and bioengineering technologies might be harnessed to attenuate or reverse
intractable,life-threateningrespiratorydiseases.
This is the more remarkable considering that until relatively recently the lung
was generally considered a conditionally renewing organ with limited growth
potentialandregenerativecapacityinadultlife[1,2].Whythisparadigmremained
so entrenched for so long is puzzling given compelling lung cell kinetic analysis
that showed that lung epitheliumwas continuously replaced, albeit at a very slow
rateoverall,thatcouldonlybeexplainedbycontinuousrenewal[3,4]ofpostulated
subsets of cells with much higher rates ofturnover than the average for the organ
[5].Thisfailuretofullyappreciatethattheextremelyslowturnoverofcellsinthe
adultlungwasnotinconsistentwiththeexistenceofcontinuouslyrenewingendog-
enous lung stem and progenitor cells able to replace senescent cells in the steady
state,andregeneratefunctionallungcelllineageslifelongfollowinginsultorinjury
“blinded”thefieldtothepotentialofstemcellsastherapeutictargetsforadultlung
regenerationandrepair.Rather,researchpredominantlyfocusedonunderstanding
the pathophysiology of intractable lung diseases, and on the development of
essentially palliative pharmacologic interventions to resolve inflammation and
attenuate fibrotic responses induced by infectious agents, toxicants, or injury.
This bias is patently obvious on interrogation of the Pubmed database as of May
v
vi Preface
7,2015.Whereas185,890publicationswereretrievedusingthesearchterm“lung
inflammation OR lung fibrosis,” only 6688 publications were retrieved using the
search term “lung stem cell OR lung progenitor cell,” and 3228 using the search
term “lung regeneration.” Comparison with an archetypal continuously renewing
stemcellhierarchyisalsoillustrativeinthiscontext,showingthat87,492publica-
tionswereretrievedinthesameperiodusingthesearchterm“hematopoieticstem
cellORhematopoieticprogenitorcell.”
Interest in the potential of stem cell-based therapies in lung regenerative med-
icinewasinitiallymotivatedbystudiesintheearly2000spurportingtoshowthat
various adult and embryonic stem cell populations could be respecified or
reprogrammed to express lung epithelial cell lineage markers when cultured in
defined media, or engrafted in the lung. Concurrently, various research groups
intensifiedtheir effortsto develop best-practicetools, assays, and models to iden-
tify, isolate, and characterize endogenous adult lung stem and progenitor cells,
determine their spatial location(s) in the airway, and assess their regenerative
potential.Inparticular,thesestudiesaimed todeterminewhethertheorganization
andregulationoftheseputativestemandprogenitorcellcompartmentsconformed
with, or deviated from, the organization of classical continuously renewing stem
cellhierarchies[6].
The reductionist approach was predominantly concerned with determining and
defining the intrinsic properties of adult lung epithelial stem and progenitor cells.
But, according to the niche hypothesis first articulated by Schofield in 1978 [7],
“stemness”isdeterminedbyanchorageofthestemcelltoacomplexandmalleable
anatomical niche comprising a matrix scaffold, adhesion molecules, soluble and
insoluble factors, and contiguous fixed and circulating cells which engage in
crosstalk with the stem cell to specify its fate and constrain its proliferation and
differentiation. The importance of these critical niche interactions, and
mesenchymal–epithelial crosstalk in particular, have long been appreciated in
lungdevelopmentalbiology,andarelikelyrecapitulatedinregenerationandrepair
oftheadultlung[8].Theanalysisofmesenchymal–epithelialinteractionshasalso
long been a major focus of research in the pathogenesis of fibrosis and airway
remodeling in intractable lung diseases such as allergy and asthma [9]. However,
the lung is a complex organ comprising as many as 60 cell lineages and less is
knownabouttheroleofinteractionsofmanyofthesediversecelllineageswithlung
epithelialstemandprogenitorcells,andwitheachother,inregulatinglungdevel-
opment and in maintaining, regenerating, and repairing the lung in adulthood.
Significant advances have recently been made in understanding the process of
vasculogenesisandangiogenesisinthelung,andinthecrosstalkwithlungepithe-
lial cells. In comparison, the important role of neuronal cells in the regulation of
lungdevelopment,andinlungregenerationandrepairislesswelldeterminedanda
worthyandfertilesubjectoffurtherstudy.
Thismonographpresentsacomprehensiveoverviewofthecurrentunderstand-
ingoftheorganizationandregulationofendogenouslungstemandprogenitorcell
compartments during fetal and perinatal lung development, and in the adult and
ageinglung.Thechaptersonfetallungdevelopmentaimtoelucidatetheintegrated
Preface vii
role of epithelial, stromal, vascular, and neural cell elements in building a func-
tional lung. These chapters provide a basis for identifying critical factors and
pathways regulating lifelong lung regeneration and repair, and understanding the
fetal and neonatal origin of lung disease. The chapters on adult lung regeneration
describe the organization and properties of epithelial stem and progenitor cell
compartments distributed along the proximal–distal axis of the airway tree and
how they are affected with age. The chapters on lung regeneration and repair
describetheroleofcrosstalkbetweenregenerativecellsandcellularandbiomatrix
elementsoftheirnicheintheadultlunginmaintainingorganintegrityinthesteady
state,andregulatinglungregeneration.
The chapters on cellular therapies for lung disease provide an overview of
emerging therapies utilizing exogenous mesenchymal stromal cells, and vascular
endothelial cells to repair the diseased lung; and also review studies in animal
models exploring the potential of pluripotent stem cells in lung regenerative
medicine. The monograph concludes with an overview of recent progress in lung
bioengineering describing the challenges in engineering acellular biomatrix scaf-
folds to replace damaged or diseased airways, or reconstruct a functional lung
exvivo.
Itremainsformetothankthemanyauthorsatthecutting-edgeofthefieldwho
enthusiastically contributed the lucid and authoritative chapters in this volume. I
alsothankKursadTurksen(SeriesEditor)fortheinvitationtoeditthisvolume;and
acknowledge BrianHalm andAletaKalksteinandtheir team at Springer fortheir
adviceandassistanceindevelopingandpreparingthisvolumeforpublication.
Melbourne,VIC,Australia IvanBertoncello
References
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Contents
PartI FetalLungDevelopment
1 TheRegulationofBranchingMorphogenesisinthe
DevelopingLung. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
JichaoChen
2 Epithelial–MesenchymalCrosstalkinLungDevelopment. . . . . . . 17
DavidWarburton
3 LungVasculogenesisandAngiogenesis. . . . . . . . . . . . . . . . . . . . . . 25
BernardThe´baudandMervinC.Yoder
4 NeuralRegulationofLungDevelopment. . . . . . . . . . . . . . . . . . . . 43
AlanJ.Burns,LucyJ.Freem,andJean-MarieDelalande
5 FetalandNeonatalOriginsofLungDisease. . . . . . . . . . . . . . . . . . 63
FoulaSozo,MeganO’Reilly,andRichardHarding
PartII AdultLungStemandProgenitorCells
6 StemandProgenitorCellsoftheTracheaand
ProximalAirways. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
AhmedE.Hegab,TomokoBetsuyaku,andBrigitteN.Gomperts
7 StemCellsoftheDistalBronchiolarAirways. . . . . . . . . . . . . . . . . 113
RobertE.HyndsandAdamGiangreco
8 RegenerativeCellsintheAgeingLung. . . . . . . . . . . . . . . . . . . . . . 127
AndrewM.Hoffman
PartIII RegulationofLungRegenerationandRepair
9 StromalRegulationofLungRegenerationandRepair. . . . . . . . . . 149
JonathanL.McQualter
ix