Bài giảng Tế bào gốc - Bài 3: Cơ sở phân tử tính tự làm mới - Trần Hồng Diễm

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1. INSIGHT REVIEW NATURE|Vol 441|29 June 2006 a b Figure 5 | Stem cells can facultatively use both symmetric and asymmetric divisions. a, Division Symmetric Asymmetric in the plane of the epithelium generates two morphologically similar daughter cells that are both likely to be stem cells (orange). Grey line, basement membrane. b, Division perpendicular to the plane of the epithelium generates one stem cell and one c differentiated daughter (green). Such asymmetric divisions by stem cells are thought to predominate Symmetric Expansion during late fetal development and adulthood in the basal layer of epithelia7,61 and in the ventricular zone of the brain40,53. Although spindle orientation seems to correlate with cell fate in this manner in various systems, it is not an obligate relationship because current data on progenitor identity and daughter d cell fates are incomplete, and divisions in the plane Steady Asymmetric of the epithelium can sometimes yield progenitors 54 c, state that acquire different fates . During development, Phân bào đối xứng của tế bào mầmsymmetric C. divisions elegans expand the stem-cell pool. d, In healthy adults, divisions perpendicular to the epithelial plane typically maintain normal numbers trong giai đoạn phát triểofn stem cells and differentiated cells in the basal layer of epithelia and in the subventricular zone of e INSIGHT REVIEW the brain. e, In healthy adults, cells can be lost NATURE|Vol 441|29 June 2006 Injury Symmetric to injury (X). Symmetric divisions are proposed to regenerate additional stem cells, and asymmetric and asymmetric divisions to regenerate differentiated daughters. f, We speculate that defects in regulation of the INSIGHTswitch REVIEW between symmetric and asymmetric NATURE|Vol 441|29 June 2006 abdivisions can be deleterious. Left,that a defect seem favouring to be undifferentiated and lie side by side in the ventricular absymmetric divisions results in tumorigenesis. that seem to be undifferentiated and lie side by side in the ventricular Right, a defect favouring asymmetriczone divisions where stem cells are located. Similarly, cell divisions in the fetal f Chú thích: zone where stem cells are located. Similarly, cell divisions in the fetal Cancer epidermis seem to be largely symmetric, generating morphologically Reduced results in decreased capacity forepidermis tissue repair. Both seem to be largely symmetric, generating morphologically Defective Defective equivalent undifferentiated cells in the plane of the basal layer of the repair :Ttumorigenesisế bào chị andem poorbiệt wound hoá healing are typical 7 or epidermis where stem cells are present . It remains formally possible, of ageing animals, raising the questionequivalent of whether undifferentiated cells in the plane of the basal layer of the regulation regulation :Tế bào gốc (TBG) however, that morphologically and positionally equivalent7 progeny in defects in switch mechanisms accumulateepidermis with locations whereage. known stem to contain cells stem cellsare could present have different. develop-It remains formally possible, :Ổ tế bào gốc mental potentials. Thus, without direct information on developmental however, thatpotential morphologically or fate, inferences regarding symmetric and positionally versus asymmetric equivalent progeny in divisions of stem cells are based on incomplete criteria and should be 77,78 considered provisional. Stem-cell divisions and cancer is also frequentlyc deleted in cancer , andd deletionlocations of the corresponding known to contain stem cells could have different develop- The capacity for symmetric stem-cell self-renewal may confer devel- gene in mice leads to a loss of polarity and dysplasia in the central nervousSymmetric divisions can persist into adulthood 79Morrison SJ, Kimble J. (2006) Asymmetric and symmetric mentalstem-cell potentials. Thus, without direct information on developmental opmental plasticity, increased growth and enhanced regenerative systemdivisions. Loss in of development Numb may and becancer. involved Nature, in29;441(7097):1068-74. the hyperactivation of NotchSymmetric stem-cell divisions are common in developing tissues, but capacity; however, it may also confer an inherent risk of cancer. Nor- pathway signalling observed in breast cancers80,81. potentialAlthough these orthey gene fate, can also beinferences observed in adults, as regardingexemplified by the adult symmetric Drosophila versus asymmetric 3 ovary. As described above, adult Drosophila germline stem cells nor- mally, Drosophila neuroblasts divide asymmetrically as a result of the products could inhibit tumorigenesis through variousdivisions mechanisms ofmally thatstem divide asymmetrically cells are55 (Fig. based 4a); however, on female incomplete germline stem criteria and should be asymmetric localization of cortical cell polarity determinants (such as are independent of their effects on cell polarity, the fact that these cellsgenes can be induced to divide symmetrically and to regenerate an addi- consideredtional provisional. stem cell after an experimental manipulation in which one stem Partner of Inscuteablec (PINS) and aPKC) and cell fate determinants dconsistently function as tumour suppressors suggests that asymmetriccell is removed from the niche (Fig 4b). Thus, adult Drosophila germline -> Ấ(foru example,trùng Numb nandở Prospero), ra t andừ regulatedtrứ ngalignment vớ ofi the chdivisionỉ 2 itselftế may bàoprotect againstgố cancer.c mầm duy stem cells are regulated to divide asymmetrically or symmetrically. mitotic spindle (Fig. 2). When the machinery that regulates asymmet- Further evidence for the link between symmetric cell divisions Recentand experiments further suggest that the daughters of Drosophila Symmetricgermline divisions stem cells have equivalentcan persist developmental into potential adulthood despite nhấtric, divisionsnhư isng disrupted, trong however, giaithese neuroblasts đoạ beginn dividingphát cancertri isể thenFigure observationấ 3 |u Symmetric trùng divisions that some in the developing genevề products C. eleganssau germ can, line. both inducetheir distinct cellular morphologies (Fig. 4c). In these experiments, symmetrically and form tumours42,70,71. symmetric a,cell C. elegans divisions germline and divisions function during development as oncogenes are symmetricSymmetric in with mammalian germline stem-cell stem cells were divisions induced to differentiate are common by altering specific in developing tissues, but 42,71 respect to size and morphology of daughter cells, cleavage plane and regulators: in the ovary, the bag-of-marbles activator of differentiation nhữngCell t clonesế bào lacking PINSmầ mare tumorigenicnày tă,ng and doublesinh mutant đ ể cells.t ạOneo examplepositionra46 . Continued iskho aPKC, mitotic ảtheng divisions atypical rely2000 onprotein signalling kinase fromt theế stem-cellthat normally was ectopically expressed by using a heat shock promoter52; in the tes- 5,46,87 they can also be observed in adults, as exemplified by the adult Drosophila niche . Stem cells are orange; differentiated cells are green; the stem- tis, the stat92E stem-cell activator was depleted by using a tempera- cells lacking both PINS and Lethal giant larvae (LGL) generate a localizes to the apical cortexb, of the neuroblast as part of the PAR–aPKC bào con trong tuyến sinh dục trưởng cellthành niche is red. Elimination gồ of onem or morecác germ cells ovary. by tlaserế ablation As describedture-sensitive mutant above,56. The former adult experiment Drosophila also required ectopic germline stem cells nor- brain composed largely of symmetrically dividing and self-renewing complex. Neural-specific(marked with a cross) expression during early (shown) of a constitutivelyor later larval development active variantexpression of of the DPP ligand in somatic ovarian cells. In both studies, 42 does not affect the ability to generate pools of stem cells and differentiated 42 55 bào neuroblastsmầm ch. Cellưa clones bi lackingệt thehoá cell fate và determinants các Numbtế or bàoaPKC concausescells a 5 .large Mitoticđang increase germ cells arebi in therefore symmetricallyệt developmentally hoá dividing equivalent mally neuroblasts dividegermline asymmetrically. stem cells located in the niche (Fig.lost their stem-cell4a); however,morphology female germline stem Prospero are tumorigenic and can be propagated after transplantation Consistent c,with Repositioning this tumorigenic the niche induces germlinepotential stem cellsin Drosophila at the new position, aPKC5. and has adopted cellular characteristics of a daughter fated to differentiate 71 d, Niche duplication results in duplication of the germlinecells stem-cell can pool. be82,83(Fig. induced 4c). When the to activities divide of the regulators symmetrically were reversed, however, and to regenerate an addi- into new hosts . Moreover, these tumour cells have been shown to been also identifiedNiche duplication as hasan been oncogene accomplished in by human alterations lungin either cancers the cell- the. We differentiating cells reverted to a stem-cell morphology and resumed become aneuploid within 40 days of adopting a symmetric mode of speculate thatcycle asymmetric machinery47,48,50 or divisionregulators of nichemay specification suppresstional49,51 carcinogenesis,. stema stem-cellcell in after fate. an experimental manipulation in which one stem division71. This finding indicates that invertebrate cells are capable of addition to its role in maintaining a balance between stem cells andThe simplest explanation is that asymmetric divisions of Drosophila Several lines of evidence show that C. elegans germcell cells divide is removed sym- germline from stem cells producethe niche daughters (Figof equivalent 4b). potential Thus, but place adult Drosophila germline rapid neoplastic transformation. An intriguing possibility is that the differentiatedmetrically progeny. during larval development. First, these divisions produce them in different positions with respect to signalling from the niche capacity to divide symmetrically may be a prerequisite for neoplastic Symmetricdaughters modes of ofequal division size and morphology,may not only and they promote stemare variable the cells with expansion are(Fig. 4d). regulated These equivalent to daughters divide then adoptasymmetrically distinct identities or symmetrically. respect to both plane of cleavage and daughter cell position46. Second, depending on the presence or absence of signalling from the niche transformation and that cancer may reflect, at least in part, the capacity of stem-cell onenumbers, or more germ but cells also can be be permissiveremoved by laser for ablation secondary withoutRecent elimi- events experiments(Fig. lead- 4d). This idea could further have been tested suggest more directly, that either the by daughters of Drosophila to adopt a symmetric mode of cell division. ing to aneuploidy.nating the Consistent capacity of the stem with cells this for both possibility, self-renewal the and generationmachinery reversing that the positions of the two daughter cells with respect to the of gametes5 (Fig. 3b). Third, experimental repositioninggermline of the stem- stemniche to seecells whether have their fates equivalent could be reversed, or developmental by removing the potential despite The machinery that promotes asymmetric cell divisions has an evolu- controls asymmetriccell niche during division early development also regulates — a time the when orientation all germ cells areof mitoticstem cell by laser ablation to determine whether its differentiating sister 2,72 29,41,42 tionarily conserved role in tumour suppression . The adenomatous poly- spindles proliferating. A potential — results source in maintenance of aneuploidy of the stem-cell in symmetrically fate by whatever divid-could enter the niche and adopt the stem-cell fate. However, such physi- Figure 3 | Symmetric divisions in the developing C. elegans germ line. their5 distinct cellular morphologies (Fig. 4c). In these experiments, posis coli (APC) gene is required for the asymmetric division of Drosophila ing fly neuroblastsgerm cells happenis a defective to be located centrosome near the new niche — position either (Fig. duplicated 3c). cal manipulations or are technically challenging in this system. a, C. elegans29 germline divisions during developmentLast, are duplication symmetric of the niche resultswith in duplication ofgermline germline stem- stemSymmetric cells stem-cell were divisions induced are also common to in the differentiate adult C. elegans by altering specific spermatogonial stem cells and is an important tumour suppressor in abnormal incell shape pools47–51 — (Fig. that 3d). presumably Thus, during the leads expansion to errors phase ofin germline chromosome germ line. Although individual germline stem cells in the adult gonad the mammalian intestinalrespect epithelium to size73–75 and. It ismorphology not known whether of daughter APC segregation cells, cleavagedevelopment,71. The regulation plane C. elegans andgerm of centrosome cells generate daughters functionregulators: with byequivalent tumour have insup- not the been identifiedovary, by lineagethe tracing,bag-of-marbles a region of mitotically divid- activator of differentiation 46 developmental potential, and these daughter cells ultimately acquire ing germ cells called the ‘mitotic region’ is responsible for both self- 52 regulates asymmetricposition division by. stemContinued cells in the mitotic intestinal divisions epithelium, relypressors on signalling is alsodistinct important fates from depending to the avoid on thestem-cell positiongenomic and numberinstability of niche in cells. mammalian A renewal and replenishment of germ cells57,58 (Fig. 4e). Unlike Drosophila 84 was ectopically expressed by using a heat shock promoter ; in the tes- but it is intriguing that, except5,46,87 for their unregulated proliferation, color- cells . Indeed,similar centrosomes phenomenon of symmetricand mitotic germ cellspindles divisions seem during tolarval be tightlygermline stem-cell divisions, which are reproducibly oriented with niche . Stem cells are orange; differentiated cellsdevelopment are green; has recently the been stem- documented in Drosophila52. respect to the niche29,55, C. elegans germ cells do not divide along any ectal cancer cells have properties that are strikingly similar to those of regulated in asymmetrically dividing cells to ensuretis, that the daughter stat92E cells stem-cell58 activator was depleted by using a tempera- cell niche76 is red. b, Elimination of one or more germ cellsMammalian by stem laser cells alsoablation seem to undergo largely symmetric divi- particular axis (Fig. 4f,56 g). Indeed, about one-fifth of the germline stem- intestinal epithelial stem cells . The human homologue of Lgl, HUGL-1, adopt differentsions tofates. expand It stem-cellis tempting pools during to speculate embryonic orthatture-sensitive early tightly fetal devel- regulatedcell divisions mutant maintain both. daughtersThe former in the niche (Fig. experiment 4e), whereas the also required ectopic (marked with a cross) during early (shown) or later opment.larval For development example, mouse haematopoietic stem (HS) cells double in other four-fifths place daughter cells in variable positions with respect 1072 number every day during mid-gestation6, implying expressionthat a substantial to of the nichethe (Fig. DPP 4f). ligand in somatic ovarian cells. In both studies, does not affect the ability to generate© 2006 Na poolsture Pub lofish istemng Gro ucellsfractionp andof these differentiated stem cells must undergo symmetric self-renewing A key unresolved issue is whether C. elegans germline stem cells divide 5 divisions. However, direct imaging of these stem-cellgermline divisions has not stemasymmetrically cells with located respect to their in developmental the niche potential. lost However, their stem-cell morphology cells . Mitotic germ cells are therefore developmentallybeen possible. equivalent. By contrast, it has been possible to image both the divi- given the symmetric germline divisions in the early larval C. elegans sions of undifferentiated neural progenitors5 in culturedand slices adopted of the germ cellular line5,46, and evidence characteristics that Drosophila germline stem-cellof a daughter daughters fated to differentiate MMorrison.inddorrison.indd 11072072 c, Repositioning the niche induces germline stem cellsdeveloping at the rodent new cerebral position cortex40,53,54 and. cell divisions in the basal are116/6/066 equivalent/6/06 33:15:17:1 5in:1 developmental7 pmpm potential52,56, it seems likely that adult d, layer of the fetal epidermis7. During embryonic development(Fig. 4c). of the WhenC. elegans germline the activities stem-cell divisions of are alsothe symmetric, regulators and that dif- were reversed, however, Niche duplication results in duplication of the germlinecerebral cortex stem-cell and epidermis, thepool. pool of undifferentiated progenitors ferentiation results in daughters that become displaced from the niche. Niche duplication has been accomplished by alterationsinitially expandsin either in number the before cell- significant amountsthe of differentiated differentiating Consistent with cells this idea, reverted molecular regulators to promotinga stem-cell the differenti- morphology and resumed 47,48,50 cells are generated.49,51 During this expansion, cell divisions in the cortical ated state are expressed in germline daughter cells located outside the cycle machinery or regulators of niche specificationventricular zone. generate two morphologically identicala stem-cell daughter cells niche fate. at a point about halfway through the mitotic region59,60 (Fig. 4e). 1070 The© 2006 Nsimplestature Publishing G rexplanationoup is that asymmetric divisions of Drosophila Several lines of evidence show that C. elegans germ cells divide sym- germline stem cells produce daughters of equivalent potential but place MMorrison.inddorrison.indd 11070070 116/6/066/6/06 33:15:10:15:10 pmpm metrically during larval development. First, these divisions produce them in different positions with respect to signalling from the niche daughters of equal size and morphology, and they are variable with (Fig. 4d). These equivalent daughters then adopt distinct identities respect to both plane of cleavage and daughter cell position46. Second, depending on the presence or absence of signalling from the niche one or more germ cells can be removed by laser ablation without elimi- (Fig. 4d). This idea could have been tested more directly, either by nating the capacity of the stem cells for both self-renewal and generation reversing the positions of the two daughter cells with respect to the of gametes5 (Fig. 3b). Third, experimental repositioning of the stem- niche to see whether their fates could be reversed, or by removing the cell niche during early development — a time when all germ cells are stem cell by laser ablation to determine whether its differentiating sister proliferating — results in maintenance of the stem-cell fate by whatever could enter the niche and adopt the stem-cell fate. However, such physi- germ cells happen to be located near the new niche position5 (Fig. 3c). cal manipulations are technically challenging in this system. Last, duplication of the niche results in duplication of germline stem- Symmetric stem-cell divisions are also common in the adult C. elegans cell pools47–51 (Fig. 3d). Thus, during the expansion phase of germline germ line. Although individual germline stem cells in the adult gonad development, C. elegans germ cells generate daughters with equivalent have not been identified by lineage tracing, a region of mitotically divid- developmental potential, and these daughter cells ultimately acquire ing germ cells called the ‘mitotic region’ is responsible for both self- distinct fates depending on the position and number of niche cells. A renewal and replenishment of germ cells57,58 (Fig. 4e). Unlike Drosophila similar phenomenon of symmetric germ cell divisions during larval germline stem-cell divisions, which are reproducibly oriented with development has recently been documented in Drosophila52. respect to the niche29,55, C. elegans germ cells do not divide along any Mammalian stem cells also seem to undergo largely symmetric divi- particular axis58 (Fig. 4f, g). Indeed, about one-fifth of the germline stem- sions to expand stem-cell pools during embryonic or early fetal devel- cell divisions maintain both daughters in the niche (Fig. 4e), whereas the opment. For example, mouse haematopoietic stem (HS) cells double in other four-fifths place daughter cells in variable positions with respect number every day during mid-gestation6, implying that a substantial to the niche (Fig. 4f). fraction of these stem cells must undergo symmetric self-renewing A key unresolved issue is whether C. elegans germline stem cells divide divisions. However, direct imaging of these stem-cell divisions has not asymmetrically with respect to their developmental potential. However, been possible. By contrast, it has been possible to image both the divi- given the symmetric germline divisions in the early larval C. elegans sions of undifferentiated neural progenitors in cultured slices of the germ line5,46, and evidence that Drosophila germline stem-cell daughters developing rodent cerebral cortex40,53,54 and cell divisions in the basal are equivalent in developmental potential52,56, it seems likely that adult layer of the fetal epidermis7. During embryonic development of the C. elegans germline stem-cell divisions are also symmetric, and that dif- cerebral cortex and epidermis, the pool of undifferentiated progenitors ferentiation results in daughters that become displaced from the niche. initially expands in number before significant amounts of differentiated Consistent with this idea, molecular regulators promoting the differenti- cells are generated. During this expansion, cell divisions in the cortical ated state are expressed in germline daughter cells located outside the ventricular zone generate two morphologically identical daughter cells niche at a point about halfway through the mitotic region59,60 (Fig. 4e). 1070 © 2006 Nature Publishing Group MMorrison.inddorrison.indd 11070070 116/6/066/6/06 33:15:10:15:10 pmpm