1、From totipotency of zygotes to pluripotency in the blas-tomere and multipotency,oligopotency or unipotency in mature tissues,self-renewing stem cells(SCs)become increasingly restricted in their cell fate options.In adult humans,the 5070 billion cells lost daily in tissues from wear and tear are repl
2、enished through the action of lineage-restricted,resident SCs,which act as guardians of their designated lineages throughout life(BOX1).This process of steady-state tissue maintenance is known as homeostasis and is one of the most crucial roles of a tissueSC.In addition,tissue SCs must be equipped t
3、o rapidly bolster their regenerative response and restore tissue integrity when wounded,a process vital for the organ-ism.Even though regenerative capacity varies markedly across different tissues for example,the skin and the heart represent the two extremes of high and low regen-eration ability,res
4、pectively their sense of urgency to repair wounds is conserved and has captured the molecular resourcefulness of nature.The outcome is a broadening of regenerative powers and lineage options compared with those seen under normal homeostasis.By enabling SCs to embark upon behaviours that are distinct
5、 from their normal patterns under homeostasis,a phenomenon termed cell plasticity,the SCs closest to a wound can participate in repairing it,thereby height-ening the chances of tissue restoration and organism survival.However,as an essential survival mechanism during wound repair,plasticity is often
6、 hijacked by can-cer,bypassing the need for actual injury in the presence of accumulating oncogenic mutations.Many parallels exist between wounds and cancer,with a few features distinguishing the two phenomena.This Review discusses SC plasticity in the context of normal tissues as SCs transition fro
7、m homeostasis to wound repair and tackles plasticity in malignant pro-gression,a wound-healing process gone amok.We aim to contrast SC behaviours under steady state to those that are under stress.Meanwhile,we draw analogies across diverse stress conditions,including wounding,transplantation,culture
8、and cancer,to illustrate how SC plasticity is conserved in certain aspects and distinct in others.We focus on plasticity in the context of SCs;however,the ability to remodel behaviour in response to changing environments may go beyond SCs,par-ticularly in the context of cancer.Whenever suitable,we t
9、ouch upon plasticity in other cells,including the fate-committed progenies and SC niches1,micro-environments whose various constituents provide the instructive cues that have an impact on SC behaviour and fate decision.Our discussions centre on recent studies of three different mammalian tissues the
10、 haema topoietic system,skin epithelium and intestinal epithelium for which we know most about not only their SCs but also their niches.Whenever suitable,other SC models and species are introduced to further illus-trate principles of SC behaviour and plasticity.We tackle several questions:how are SC
11、s spatially and temporally coordinated within their niches?What is the molecu-lar basis of the crosstalk between SCs and their niche Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development,Howard Hughes Medical Institute,The Rockefeller University,New York,NY,USA.*e-mail:fuchslbr
12、ockefeller.edudoi:10.1038/nrg.2018.9Published online 26 Feb 2018TotipotencyThe ability of a zygote to give rise to all the lineages of the embryo and extra-embryonic tissues.It differs from the ability of embryonic stem cells to generate all lineages of the embryo(pluripotency)and the ability of adu
13、lt stem cells to reconstitute multiple(multipotency),a few selective(oligopotency)or a single lineage(unipotency)of a tissue.Stretching the limits:from homeostasis to stem cell plasticity in wound healing and cancerYejing Ge and Elaine Fuchs*Abstract|Stem cells(SCs)govern tissue homeostasis and woun
14、d repair.They reside within niches,the special microenvironments within tissues that control SC lineage outputs.Upon injury or stress,new signals emanating from damaged tissue can divert nearby cells into adopting behaviours that are not part of their homeostatic repertoire.This behaviour,known as S
15、C plasticity,typically resolves as wounds heal.However,in cancer,it can endure.Recent studies have yielded insights into the orchestrators of maintenance and lineage commitment for SCs belonging to three mammalian tissues:the haematopoietic system,the skin epithelium and the intestinal epithelium.We
16、 delineate the multifactorial determinants and general principles underlying the remarkable facets of SC plasticity,which lend promise for regenerative medicine and cancer therapeutics.REVIEWSNATURE REVIEWS|GENETICS VOLUME 19|MAY 2018|311 2018 Macmillan Publishers Limited,part of Springer Nature.All
17、 rights reserved.PlasticityIn this Review,any process that is distinct from homeostasis.For example,the increased differentiation of haematopoietic stem cells(HSCs)into cells of all blood lineages upon injury is in sharp contrast to their homeostatic behaviour,where HSCs contribute minimally;therefo
18、re,we consider such behaviour to be plastic.Plasticity is not restricted to stem cells,although this Review focuses primarily on stem cell plasticity.StemnessThe unique ability of stem cells to undergo long-term self-renewal and multilineage ponents?What are the molecular components of a wound respo
19、nse that coax SCs to adopt new regenerative and differentiation routes that are closed to SCs in their native microenvironment?What are the boundaries of SC plasticity in an injury response,and how does the tis-sue return to normal homeostasis?Finally,what are the parallels between wound healing and
20、 cancer,and what are the molecular steps that lead to the derailment of SC behaviour during malignancy?Heterogeneity under homeostasisAdult SCs not only intimately associate with a diverse array of niche cell types within a given tissue but are also dynamically regulated by their niche signals.There
21、fore,heterogeneity of SCs needs to be considered in the con-text of both spatial differences and temporal changes.Below,we use three relatively well-characterized mam-malian adult SC models to elaborate this idea of SC heterogeneity in space and time.Haematopoietic stem cells and their niche.The cha
22、se after Till and McCullochs famous spleen colony-forming units2 led to one of the most important discoveries in the SC field:the identification of self-renewing haemato-poietic SCs(HSCs),which at near single-cell level are able to reconstitute the haematopoietic system of lethally irradiated mice35
23、(BOX1).Probing deeper,fluorescence-activated cell sorting(FACS)was used to systemati-cally purify and molecularly characterize bone marrow cells,which identified a long-term,repopulating subset of HSCs that could reconstitute all blood lineages6,7.Downstream of HSCs,haematopoiesis progresses via a s
24、tereotypic path to multipotent progenitors,common lymphoid progenitors and common myeloid progenitors and finally to all differentiated lymphoid and myeloid lin-eages810.It has been estimated that each HSC divides only about five times during the entire lifetime of a mouse1113.Given that 30 billion
25、haematopoietic cells per day are needed just to maintain human haemato poietic homeo stasis,the majority of daily blood production has often been attributed to the fast-cycling multipotent progenitors rather than to their HSC parents1418.To preserve their stemness,HSCs,similar to other tis-sue SCs,a
26、re intimately associated with and functionally dependent on their SC niche.For many years,it was sur-mised that the HSC niche was the endosteal surface19,the cellular lining that separates bone from bone marrow and is composed of different cell types,including osteoblasts,osteoclasts and stromal fib
27、roblasts.Live imaging showed that engrafted HSCs seem to home to the bone surface and were in close proximity to osteoblasts enmeshed in microvessels20,21.In recent years,however,attention has shifted to the sinusoidal22 and arteriolar23 endothelium as the niches for HSCs(FIG.1a).Indeed,endothelial
28、cells are crucial for HSC maintenance and formation2427.Closely associated with the sinusoids,perivascular stro-mal cells express leptin receptor(LEPR)and C-X-C motif chemokine 12(CXCL12;also known as SDF1)and are required for HSC maintenance and retention2831.Upon activation,these stromal cells pro
29、mote adipogenesis and HSC regeneration32,33.On the arterioles side,a group of perivascular cells expressing chondroitin sulfate proteo-glycan 4(CSPG4;also known as NG2)have been found to be essential for maintaining HSCs23.In addition,a population of stromal cells expressing nestin(NES)that is disti
30、nct from the LEPR-positive cells seems cru-cial for HSC maintenance34.The heterogeneity in niche cells,for example,the perivascular cells and the factors they secrete,suggests that distinct vascular niches exist within the bone marrow35.This finding is consistent with an earlier observation that HSC
31、s and early lymphoid progenitors occupy distinct bone marrow niches25.As the HSC niche within the bone marrow continues to take shape,these studies along with recent multi-colour and invivo barcoding lineage tracing16,18,36,37 collectively point to the view that molecular diversity in bone marrow ni
32、ches may have an impact on the behav-iour of its HSC residents,which could bias them towards distinct lineages before they enter the circulation(BOX2).A number of questions remain to be addressed.What are the spatial and temporal relationships between the two niches?Does each niche know the status o
33、f the other,and if so,how is such crosstalk achieved?If molecular heterogeneity in HSCs exists and is compartmentalized in niches,then how does it affect functional lineage output?Box 1|Stem cell:gold standard versus common propertiesInitially referred to by German biologist Ernst Haeckel as Stammze
34、lle in 1868,the term stem cell(SC)was coined by Theodor Boveri and Valentin Haecker,who used it to describe cells giving rise to the germline,and by Artur Pappenheim and others,who used it to describe a common progenitor of the blood system(see commentary in REF.193).In their 1961 seminal experiment
35、,Till and McCulloch showed the existence of clonogenic bone marrow precursors,referred to as spleen colony-forming units(CFUS),that gave rise to macroscopic spleen colonies 1114days after injection into irradiated recipient mice2.The authors then proposed the defining property of SCs194:that at the
36、single-cell level,an SC is capable of long-term self-renewal and multilineage differentiation,which has become the enduring definition of SCs that we use today.In contrast to the two gold standard features,there are several empirically observed characteristics frequently associated with SCs.First,gi
37、ven the importance of the SC niche,many fields began the search for SCs with defined anatomic locations,such as hair follicle SCs(HFSCs)in the bulge,intestinal SCs(ISCs)in the crypt,and muscle SCs(MuSC,the so-called satellite cells)under the basal lamina of myofibres.However,niche locations are not
38、static,nor are their residents.For example,trans-tissue migration is a common feature of many developing SCs,such as primordial germ cells,MuSCs and haematopoietic SCs(HSCs).Adult HSCs and their progenitors continue to travel among adult tissues195197,and ectopic niches can be induced via various ph
39、ysiological stimuli,wounding or forced expression of stemness factors198,199.Second,the ability to retain cellular labels has been used to search for SCs200202,which are often quiescent.While quiescence has been intimately linked to SC niche retention151,203205 and stemness13,15,206,207,it is neithe
40、r mandatory74,208210 nor sufficient12,140 to define SCs.Third,asymmetric cell divisions are characteristic of many SC types58,211216,but not all SC types exhibit such behaviour125,126.Among the cellular constituents that have been observed to partition asymmetrically,certain SCs are found to prefere
41、ntially retain their old chromosome(the immortal strand hypothesis)217219,whereas in many other cases such a phenotype has not been observed208,220.Finally,cell-surface markers are useful to prospectively enrich for SCs;however,these markers are insufficient to define SCs.Rather than being exclusive
42、 to SCs,many SC genes are in fact expressed in a gradient by SCs and multipotent progenitors57,139,221 and can sometimes be found in committed cells222.In addition,marker expression can often be misleading for the identification of putative SCs,particularly considering the widely observed plasticity
43、 under stress conditions,including cancer112,174,185,223227.REVIEWS312|MAY 2018|VOLUME 19 2018 Macmillan Publishers Limited,part of Springer Nature.All rights reserved.Intriguingly,progenies of HSCs themselves,such as regulatory Tcells38,macrophages3941 and megakaryo-cytes42,43,have been implicated
44、in providing feedback and regulating HSC behaviours.These feedback loops could also contribute to spatial and temporal HSC heterogeneity and downstream lineagebias.Skin epithelial stem cells.In the skin epithelium,niche diversity clearly has an impact on both SC gene expres-sion and functional outpu
45、t(reviewed in REF.44).The stratified epidermis(often referred to as interfollicular epidermis)possesses an inner layer of proliferative basal SCs(keratinocytes),which is separated from the under-lying dermis by a basement membrane.When basal cells detach(delaminate),they cease proliferating and emba
46、rk upon an upward path of differentiation,generating the skin barrier that excludes harmful microorganisms and retains body fluids.In transit,the differentiating cells undergo a programmed series of molecular changes that culminate in the production of dead squames,which are sloughed from the skin s
47、urface.In mice,this pro-cess takes approximately 2weeks,resulting in constant rejuvenation of the skin barrier.Contiguous with the epidermis are hair follicles(FIG.1b),which are encased by the basement membrane that demarks the epithelialmesenchymal border.The upper portion of the hair follicle,whic
48、h includes the orifice and sebaceous glands,undergoes frequent turnover governed by multiple resident SC pools,each responsible for maintaining homeostasis of their nearby territory4549.SCs of the interfollicular epidermis and upper hair follicle above the sebaceous glands have been recently reviewe
49、d elsewhere44,50,51.Below the sebaceous glands is an anatomical struc-ture known as the bulge,which consists of a single layer of SCs attached to the basement membrane and an inner layer of cells able to adhere to the hair during the rest-ing phase of the follicle.Confirming their location and SC st
50、atus,an individual colony can be cultured from a single bulge cell that expresses high levels of integrins and can be passaged long-term.Most importantly,upon engraftment,the cells from such a colony can generate hair follicles,epidermis and sebaceous glands upon engraftment52,53.Comparative lineage