多能性诱导：从小鼠到人 & a+ z& x7 |; s4 p7 A) \. {8 j) m) }; ]. |( P' ]4 x$ n
Holm Zaehres and Hans R. Scholer; x* Q& C9 ~& L7 _' w! |8 r+ w/ Y/ J
9 F! `# P$ m c i& ^8 _$ h% XCell 131, 834 – 835, November 30, 20078 }7 V# i0 p @3 b( h( v
% b8 U1 w' r/ V/ _/ g: P4 [
8 R$ O0 L) I! f
2 S6 M& J$ [8 u1 z! @8 C5 y Takahashi等在本期Cell中把有关体细胞重新编程的重要工作从小鼠转移到了人。他们通过在成人成纤维细胞中超量表达4种转录因子，Oct4, Sox2, Klf4和c-Myc，成功地分离了在所有方面都类似于人胚胎干细胞的人多能干细胞。这是一个在细胞核重新编程研究中的重要突破，对制备供研究和治疗使用的患者专一性多能干细胞有重要意义。8 d0 I# @! [, D
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4 V* @5 h9 b$ C: y2 F+ p 10天之后在斯德哥尔摩今年的三位诺贝尔奖获得者，Martin Evans, Mario Capecchi和Oliver Smith将因发现DNA重组和小鼠胚胎干(ES)细胞技术的开发而获授颁奖。Martin Evans发现了怎样制备小鼠ES细胞，这将使任何遗传变化都可以转移到生殖细胞，进而转移到下一代。在这项突破之前，科研人员研究过从肿瘤衍生的小鼠胚胎癌细胞，这种细胞可以形成除了生殖细胞以外的任何一种细胞。DNA重组和小鼠ES细胞技术的结合使整个研究领域发生了革命，形成了研究和理解在胚胎发育、成体生理学、疾病和老化中各种基因作用的基础。至今已产生了500多种人类疾病的小鼠模型。现在发表在本期Cell上的Takahashi等人的研究是另一次重要革命。+ l7 s- a. A. W! e* m. b* d4 Q
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去年夏天，Takahashi和Yamanaka使用4个转录因子，Oct4, Sox2, Klf4和c-Myc，使小鼠体细胞成为诱导的多能干细胞(iPS)，他们的这项有关分子重新编程的研究震惊了科学界。他们进行的筛选参与小鼠成纤维细胞重新编程的各种因子的巧妙工作，从24个候选基因开始，最终成功地制备出与小鼠ES细胞在各方面都几乎无法区分的iPS细胞。和所有科学发现一样，这些重要发现必须进行重复。今年发表的几项研究通过严格的发育测定证实了小鼠iPS细胞的多能性和分化能力，这些研究不但证实了而且发展了Takahashi和Yamanaka的发现。- x. A" f+ A2 [" Z, W# ?$ y
; f: O' N: K4 u% Y! s Takahashi、Yamanaka及其同事在他们的新研究中，将在小鼠中得到的重要发现转移到人中。他们选择了来自不同人供体的成人皮肤成纤维细胞和另外两种人成纤维细胞群（来自润滑组织和新生儿包皮），作为从新编程靶细胞。然后用携带人Oct4, Sox2, Klf4和c-Myc转基因的逆转录病毒载体转导人成纤维细胞培养物，之后在人ES细胞培养条件下培养细胞。转导30天之后，类似人ES细胞的iPS克隆（在其他克隆之间）覆盖了培养皿，并可进一步扩增和扩大。在人iPS形成之后，逆转录病毒载体使4个转基因沉默（与在小鼠系统中的发现一样），这说明iPS细胞完全重新编程，不再依赖于转基因的表达。0 B7 u L$ l. A
8 c q2 \: |7 W j 与在小鼠中的研究不一样的是，该研究中产生的人iPS细胞完全没有任何遗传选择步骤。由于人ES细胞的有丝分裂指数较低，人iPS细胞的产生时间要比小鼠系统长很多是很正常的。Takahashi等对人iPS细胞进行了一系列测定，以便与人ES细胞比较。这些测定包括形态研究、表面标记表达、表观遗传状态、体外胚状体的形成、直接分化成神经细胞和跳动左心室肌细胞（根据人ES细胞分化的方法）以及在体内畸胎瘤的形成。DNA微阵列分析揭示了人iPS细胞和人ES细胞的整个基因表达谱极为相似。重要的是，基因组DNA分析和短串联重复分析证实，独立的人iPS克隆的遗传来源是其亲本成纤维细胞。 " }- X. j6 B) J2 a8 P o( E) Y- C9 @! y: v/ v& W1 i0 X+ X
作为多能干细胞最重要的标准是小鼠ES细胞和人ES细胞的衍生，在它们的衍生中必须注意小鼠与人ES细胞之间存在自我更新调节的不同。例如，人ES细胞必须依赖bFGF进行自我更新，而小鼠ES细胞的自我更新依赖于Lif/Stat3途径。BMP与小鼠ES细胞自我更新有关，但在人ES细胞中，BMP诱导分化。在小鼠和人中保持多能性的外部因子和信号有所不同。然而，小鼠和人使用相同的4个转录因子进行体细胞重新编程的翻译，这说明控制小鼠和人ES细胞自我更新的Oct4/Sox2转录因子网络的保守性。由于Klf4和c-Myc是慢性修饰物并能使细胞长久保存，这两个转录因子可能会由另外一些转录因子或小分子取代。在上述研究中，逆转录插入突变可能导致参与重新编程的其他基因活化，这为鉴定上述4个转录因子之外的其他新重新编程因子提供了机会。另外，大范围筛选人成纤维细胞重新编程的因子（如Takahashi和Yamanaka在小鼠研究中采用的方法），也可能找到其他重新编程因子的组合。: B6 Z& C! Y" h
5 U7 I' S* j/ ]' s! A 体细胞直接重新编程成为多能状态，使发育的时间方向逆转，被某些人奉为干细胞研究的“圣杯”。一旦人类细胞中的研究成果被证实，就能利用这些成果创造患者专一性干细胞系，在实验室研究不同疾病的机制。这些细胞模型也可极大增加药物开发效率，并可为毒理测试提供重要工具。此外，这种重新编程系统可以创造更多更经济更理想的患者客户化专一性筛选和治疗。最后，这项工作将对有关ES细胞研究的道德、宗教、政治等方面的激烈辩论有重大影响。然而，认为人ES细胞已过时是一个重大错误。在我们完全理解多能性和有能用于治疗的人iPS 之前，还有许多障碍有待克服。例如，由于c-Myc逆转录病毒的反应，与从ES细胞产生的小鼠（一般是正常鼠）相比，从iPS细胞产生的小鼠有很大比例会产生肿瘤。目前正在寻找不使用逆转录病毒使体细胞重新编程的方法，甚至是使用一组小分子的方法。考虑到这一点，必须注意人ES细胞研究比过去更重要，因为这种研究将指出iPS如何能最好地保持多能性，如何被诱导分化成所需要的细胞系。细胞核重新编程的领域已走过了漫长的路，包括50年前开始的在蛙类中的细胞核移植研究，一直到第一个从成体体细胞克隆的哺乳动物多莉的诞生，再到几年前装配式人细胞核转移实验的完成，然后是现在Takahashi、Yamanaka及其同事先在小鼠、再在人中进行的里程碑式的研究。. Z! z& a! o% g" T! M" I& t
Induction of Pluripotency: . F: X3 O6 d0 @1 e" ^4 ZFrom Mouse to Human . F) J! c! n4 U$ m* j& H7 w% m' H- THolm Zaehres1 $ |; R+ e- F, X/ n and Hans R. Schöler1,6 w- s8 U; F f9 ^& r7 h6 M y
* ! c, E9 c$ d! W, Z* ~* |1$ T; g& t; ]& c; P# Y k7 i4 P6 {
Max Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, Münster, NRW 48149, Germany 4 b6 ?) A) u! c6 D- _- j*Correspondence: schoeler@mpi-muenster.mpg.de 5 ]& H& c% I4 F0 L. x; W4 q; Z( ADOI 10.1016/j.cell.2007.11.020# K. y1 I* c# o, u4 E* i
In this issue of Cell, Takahashi et al. (2007) transfer their seminal work on somatic cell & t5 {: `# E6 v$ ~ d6 o, sreprogramming from the mouse to human. By overexpressing the transcription factor 6 w# J# e! y# P! T; m
quartet of Oct4, Sox2, Klf4, and c-Myc in adult human fbroblasts, they successfully : G$ ~7 e* J7 }) e, a$ ?0 \' k
isolate human pluripotent stem cells that resemble human embryonic stem cells by all " X7 V& P$ y) {" r# ?( }
measured criteria. This is a signifcant turning point in nuclear reprogramming research & B5 }2 z2 b) [; ~
with broad implications for generating patient-specifc pluripotent stem cells for research $ A# {9 O" o" F$ \" n6 h0 K
and therapeutic applications.6 x* d, x: [8 o
This year’s three Physiology or Medi-2 }: R# v+ r+ g" m- F
cine Nobel Laureates—Martin Evans, 2 S9 a! O* o! \( I6 [- q1 ^Mario Capecchi, and Oliver Smithies—, r t8 S1 V6 R9 y5 l1 R
will be honored in Stockholm in 10 3 G, h" ^, ]* }3 s4 ~: w s
days time for their discovery of DNA 9 e. t2 Q) `8 W, z( `9 Erecombination and the development , \; ?5 \3 |1 b# ~! uof mouse embryonic stem (ES) cell % \' w' ?- V+ d. w4 t2 F
technology. It was Martin Evans who / n5 ^8 r/ W3 Y( P: z4 L+ J
discovered how to make mouse ES 4 p4 v8 O+ D" m2 J' u
cells, enabling any genetic alteration ! e4 s' G8 s0 z5 N- ^: Q: zto be transferred to the germline and 2 S; l, S2 ]9 H7 i0 _3 lhence to the next generation (Evans ! w; |3 r1 g+ D! J7 l% Y& N* G
and Kaufman, 1981; Martin, 1981). 9 M) t/ X& C! B; FBefore this breakthrough, researchers 0 r5 B0 Q* T3 F) [. ]3 i! _
studied mouse embryonal carcinoma & \: y+ a2 w* `' y0 }) }
cells derived from tumors, which $ v5 } Y' D w9 V4 t$ q
could form every mouse cell lineage ( _- t5 `4 X, u4 t9 \: Eexcept the germline. Combining DNA , f; k5 l% ?7 ^* v1 Y$ Lrecombination and mouse ES cell * V3 G9 Z; `9 @" K
technology revolutionized an entire 4 U6 c* s" @2 ^, cfeld of research, forming the basis for & c3 k' V( O6 v$ B# H( I4 e" v: ostudying and understanding the roles ' ?" x* v$ d! Xof numerous genes in embryonic # {# U u. Y* h' t+ _7 Ndevelopment, adult physiology, dis- 5 G d% J& w4 @/ l6 `ease, and aging. To date, more than 8 D6 h* j/ i" z* x8 J5 `500 mouse models of human disor-8 g6 }( N- u# a, Q% ~1 R
ders have been generated. Now, with ) u5 a& o5 e$ {! R; Mthe study by Takahashi et al. (2007) " a1 ?1 M7 x" c: f6 ?5 K$ d6 S' ypublished in this issue of Cell, another # |( t/ o: [2 C* c7 U
important revolution is taking place. 9 t; |; I+ Y, p0 Y$ T5 GLast summer, Takahashi and 8 ~/ y C1 ~- e& f9 h, t% z
Yamanaka (2006) stunned the scientifc 0 ?5 F! \* X, B6 Hcommunity with their study showing 9 E$ Z) q) I; `* k2 A% cmolecular reprogramming of mouse % p9 c' @2 r2 M U9 U: W. a1 Msomatic cells into induced pluripotent 7 @: @4 t& J7 q. Gstem (iPS) cells using just four factors: - @7 Z0 q3 ` s+ U# n7 K7 _: Y8 g6 I
Oct4, Sox2, Klf4, and c-Myc. Their Z# f4 U1 c( {+ n3 Pelegant but demanding approach of - y" j/ q0 |# u5 z7 Cscreening for a cocktail of factors that 4 j( X0 o& B _: y
could reprogram mouse fbroblasts $ k" }+ S9 a7 r1 L2 _7 e
starting from 24 candidate genes paid 3 b$ _9 H/ L1 W) y4 L
off with their detailed description of iPS # ~4 }3 | i: v, m4 X: H0 w+ ~' o+ E
cells, which are almost indistinguish-" ]5 o Q& |9 x, c: I* X
able from mouse ES cells. As with all ( m/ a! ]6 A5 e
scientifc discoveries, these exciting ; C3 u# h, U! i" O8 l6 m$ ?% @' J6 I2 _2 U
fndings had to be reproduced. Sev-. B" y4 s' R( R/ \# q& X
eral studies published this year not $ }; G/ T/ P8 S4 N4 o. a6 |- m+ z
only reproduced but also extended 4 D/ T% V6 X6 D- v) Jthe Takahashi and Yamanaka fndings P$ I: ]. P# ?by demonstrating the pluripotency and 1 O' y- i, b$ W( `& idifferentiation potential of mouse iPS * c! P9 X' U; h+ {+ H. Ocells in rigorous developmental assays * }: f- s! ^- c- b% _
(Maherali et al., 2007; Okita et al., 2007; : F6 `! V& e$ y* YWernig et al., 2007). 3 t- N. U* j* z$ ]In their new study, Takahashi, " o% { v8 e" B9 qYamanaka, and their colleagues 4 [* Y3 r( }* J- \' U2 k
(Takahashi et al., 2007) now translate . m2 m# X$ ~: O2 U8 e9 n
their remarkable fndings from mouse 7 `) B: F- B2 _. j0 s) C( Wto human (see Figure 1). They selected 4 M. h6 R: s/ E6 R) |$ b a P4 Madult human dermal fbroblasts and 2 u# m/ ~0 u' W; gtwo other human fbroblast popula-( x8 N2 _+ e& b6 _
tions (from synovial tissue and neo- % O* T- g) q/ nnatal foreskin) from different human $ U* n9 g, Z) C% U$ \
donors as their reprogramming target * w7 C5 u2 V/ |9 _. C6 Ucell populations. They then trans-: Y6 |) k X. ?
duced the human fbroblast cultures . Y8 d5 w, U8 x8 I2 Y5 h
with retroviral vectors carrying trans- 8 b& Z/ [% g/ o0 @( Rgenes for the human versions of Oct4, ( }& H6 v" M! ], [+ G0 h
Sox2, Klf4, and c-Myc and cultured : l* s K0 W7 J; o
the cells under human ES cell culture * I" R- ~ t# y% b/ E
conditions. Thirty days after transduc- & `, }3 ]' ~% C6 t7 F' Ttion, the culture plates were covered 6 r0 w6 E. N6 |. K; r4 ?4 d
with human ES cell-like iPS colonies # j. k/ v" r# I: G5 c8 g(among other colonies), which could 2 `6 S. [& |- fbe further propagated and expanded. 7 i* ]# @0 T. s( N E8 P" H
The retroviral vectors enabled silenc- 8 j) D- ?. B6 M6 e+ y; Jing of all four transgenes after human z: K' c( z/ g( r1 MiPS formation (as found in the mouse Q1 |5 j5 S8 f% J
system) indicating that the iPS cells & Q# l& y k+ M Sare fully reprogrammed and no longer 6 ~7 F' O# [9 k" |2 J( W0 s3 _
depend on transgene expression.( w W: ]% @ ~ P& _
Unlike the mouse study, human 2 m& Q* ?6 ^* x! b" o
iPS cells were generated without any & i- Q4 W: x- C1 M) ?" s4 P6 j- z
genetic selection procedures. Given " B+ `& q2 B- `
the lower mitotic index of human ES 7 b u p. t, w7 ]cells, it is not surprising that the gen- 8 Y- z4 z- q& xeration of human iPS cells takes nota- 9 R9 N+ Q9 M- B' w% F' pbly longer than in the mouse system. ( ^5 e+ a9 i* f7 a) r
The authors subjected their human # i! ]5 j2 ?: e; h- ]0 O
iPS cells to a panel of assays to com- ' h& [5 I0 `* epare them with human ES cells. These - E* _; M0 Q: N- P* K
assays included morphological stud-- p% q% N, m! H$ u' I
ies, surface-marker expression, epi-8 h; h+ A4 b" J0 T% S+ X @
genetic status, formation of embryoid 6 r$ ]" Q) L: W5 O% Bbodies in vitro, directed differentia- 7 c2 N; j& [: H; stion into neural cells and beating car- $ [) z0 U" T5 l' m+ G* _" \diomyocytes (according to human % N# G; o+ M- z+ j+ h
ES cell differentiation protocols), and ) f0 M @4 ^+ m9 T+ ?* {
fnally teratoma formation in vivo. - F; ?3 O5 |* {- QDNA microarray analysis revealed + a/ z0 X( H( W
the remarkable degree of similar-6 H3 z m% X- B+ d7 n% X( Q
ity between the global gene expres- & s! e9 O; v4 usion patterns of human iPS cells and 9 j# k4 g5 |' g/ J [/ p% Xhuman ES cells. Notably, genomic 1 e+ y- L7 e6 {* |, ]1 D$ s! ~3 X9 L. uDNA analysis as well as analysis of ( u: o$ f) ^) x5 E$ e4 S
short tandem repeats demonstrated & U8 d7 v1 ?0 Jthe genetic origin of independent + o0 {' T0 W1 R* e1 Q/ F
human iPS clones from their parental 1 Y+ @; Z% p) U* ~+ P4 Efbroblast populations.5 J0 x1 K' Z" H8 B3 `8 e' @2 N
The derivation of mouse and then ( g+ k' K: g8 h, c3 w' p. R: Z Yhuman ES cells (Thomson et al., 1998) + v4 |/ ~: P3 E; ?0 D: n/ L( ras the gold standard of pluripotent , K9 `3 x1 o: a. H0 Tstem cell populations has necessarily 5 m p7 @) o/ Z3 C, H/ T
led to emphasis on differences in the ; m, L& w) |% Zregulation of self-renewal between 5 z! ]$ n! `# l- w' x8 u5 H
mouse and human ES cells. For 5 S$ e8 D9 N- F* \# u9 x2 @% P
example, human ES cells depend on 9 [5 ?# L* y* O; i$ \
bFGF for self-renewal, whereas their ) ` Y1 `4 m; \9 jmouse counterparts depend on the " E. X& s7 m2 {* N2 A$ z
Lif/Stat3 pathway; BMP is involved in 0 q, X9 Y0 c. f% @ a
mouse ES cell self-renewal, whereas : Q7 r' y; g5 j8 fin human ES cells it induces differen- n( ~# T m* v/ R4 P. d. qtiation. Extrinsic factors and signals 7 r* O1 w$ ?' y, t, ^
for maintaining pluripotency may dif-* R# O- a+ d p' {: f
fer between mouse and human. How-! Q- A" ~0 E8 @+ b" Z0 a1 W
ever, the ability to translate somatic ) m8 f) {+ X4 ]1 J0 V6 ^cell reprogramming from mouse to ?! ]5 ^% o. h2 a- z
human using the same transcription # O7 X7 G9 o& U. _" D; L! dfactor quartet further emphasizes the 8 `" n4 I' Q. E2 o/ Aconserved nature of the Oct4/Sox2 ; I& Q) n# M; w% Y$ q E
transcription factor network that + S+ p/ Y b l1 o) |controls self-renewal of mouse and / B! h' @" O3 k) V9 s
human ES cells (Boyer et al., 2005). $ D m$ l3 d* F
Given that Klf4 and c-Myc are chro- , M8 ]8 p: h9 P; n1 Jmatin modifers and can immortal- 9 X X/ j4 w7 H% _$ W, x: B7 Zize cells, one might be able to fnd " a5 z6 }$ @5 R" @other factors or small molecules that / z! _( E" l# f5 l1 C4 S- ]# P
could replace these two factors in the . ^6 `* F" I; k2 K h( f& b
cocktail (Yamanaka, 2007). In these ( D! |6 Y1 o: @1 }, ]1 R Z9 p$ hstudies, the possibility of retroviral 7 [' } ]* Q) ^+ ^3 u
insertional mutagenesis, resulting " v+ E8 \% |+ c; g
in the activation of other genes con-# @ |) }/ n5 w) C( @3 G5 p
tributing to reprogramming, cannot $ a \! X$ ?! }3 ebe excluded, providing an opportu-& h: g9 a) P% ~+ @& [
nity to potentially identify new repro- 1 K; {, T& }* X Ugramming factors beyond the cur-: H: K, ?# x; b L k) d
rent quartet. Also, taking a broader 1 c; R/ C/ g& \9 ^* d pscreening approach for reprogram-9 l1 @* e$ S0 M8 Y- i) z- D& w0 M
ming human fbroblasts (as Takahashi 2 F2 J0 v" I4 X, t' q' n) Gand Yamanaka did for their mouse 4 K# j4 V4 @& R# m) w
study) might yield other combinations ?7 V$ {$ ]0 H, ]+ W% Y! t7 N9 aof reprogramming factors. 5 a# X5 g4 E, }) K! S& ODirect reprogramming of somatic ) s( t |( m7 O' Q# Gcells to a pluripotent state, thus revers-1 c- K, B M- {6 m
ing the developmental arrow of time, # p! R2 U& F2 |+ p8 A. {, E0 L! _is considered by some to be the “holy 9 d1 A3 b$ G; y% R! ?/ ?grail” of stem cell research. Once the ' w. J) o z F9 v: F
results in human cells are confrmed, # S1 q: Q2 O8 u. O* X
these advances will enable the cre-- m4 V" b0 X& w: Y- x
ation of patient-specifc stem cell lines & Y& u! ~* w V0 l$ e
to study different disease mechanisms ' ?& ~+ t0 q5 Q X
in the laboratory. Such cellular models " U8 _8 r) Q: L4 \9 a& v! a& K! C
also have the potential to dramatically 7 h" {/ `5 i2 n* I
increase the effciency of drug discov-; o. M k) r' W* r
ery and to provide valuable tools for 5 b8 o8 [0 ?& m3 D, x5 m
toxicology testing. Furthermore, this * x# `4 b) a& J) l! O0 _reprogramming system could make " g2 x. a- i2 n6 Qthe idea of customized patient-specifc ! O! o' U" T Y7 Z) K3 bscreening and therapy both possible 3 o4 Z7 h1 U+ V* E
and economically feasible. Finally, the 5 _( }3 k0 c9 A# i3 X8 m: b, L
work will have a powerful impact on 2 z+ S# \" v; [
the intense debate regarding the moral, 3 r8 k* l. ?/ N. }) dreligious, and political aspects of ES cell - _5 G, v3 E; b2 B3 W4 |1 ^
research. However, a big mistake now % W- {8 r2 d& `: M& [
would be to consider human ES cells $ {" ?: V" u2 T6 o$ @
obsolete. There are still many hurdles , B' q! q3 q- A" S$ T. g. C- k7 ^to overcome before we ful ly understand , g" J0 _6 F- n3 f" W' _$ hpluripotency and before we have human & c5 @. t; Y- C+ piPS cells in hand that are suitable for ( y1 W+ {' O, q9 Ttherapeutic application. For example, 2 ~# _8 g) c* `, W" I% i1 l, k' |a signifcant proportion of mice derived 8 Q$ S+ D) z2 t5 y4 _
from mouse iPS cells develop tumors " I V' @. I: B( V9 c( \
due to reactivation of the c-Myc retro-$ ]8 d6 D5 c8 h2 @2 q. I
virus (Okita et al., 2007) compared to - u* B% O9 z9 X/ q8 w$ k! B6 `
mice derived from ES cells, which are 6 ]$ V) n+ I4 G9 i$ c# W/ {8 _normal. The search is now on to fnd a 9 P5 h0 } j/ }: N* L. ~% _
way to reprogram somatic cells without a% a* i, m0 P1 W- Yretroviruses and maybe even using a 8 L4 }' V! M, S z
cocktail of small molecules. Given this, 9 k$ [6 D8 `2 H; I2 @! _# o2 _$ ?it should be emphasized that human 7 e& v) `8 R4 tES cell research is more important than ! g& P3 x' B$ V2 d+ }& v
ever for it will shed light on how iPS - N8 n7 g# r% }( w# Ncells can best be maintained in their 4 b9 W- @/ Z* x' _8 W/ e8 l
pluripotent state and how they can be % l1 D. T2 E" a+ ?8 O8 N5 |
induced to differentiate into the cell % j9 _# n5 {" ulineage of interest. The feld of nuclear " y5 L" c0 G3 ireprogramming has come a long way 1 U- W' [* V5 d& I, D2 x- _& mfrom the initial nuclear transplantation 6 n" y8 @- x" Z8 `9 \6 _( O
studies in frogs 50 years ago, to the * {" V4 G ^% c* ~
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