在胚胎發(fā)育期間,動(dòng)物產(chǎn)生很多不同類型的細(xì)胞,每種類型的細(xì)胞具有截然不同的功能和身份(identity).盡管這些細(xì)胞的身份在正常條件下保持穩(wěn)定,但是一些細(xì)胞通過(guò)重編程而能夠呈現(xiàn)出新的身份.研究人員之前就能夠在實(shí)驗(yàn)條件下重編程細(xì)胞,但是很少有人證實(shí)在體內(nèi),細(xì)胞能夠在正常生理?xiàng)l件下改變它們的身份,特別是在哺乳動(dòng)物體內(nèi),尤其如此.
在一項(xiàng)新的研究中,賓夕法尼亞大學(xué)佩雷爾曼醫(yī)學(xué)院胃腸科醫(yī)學(xué)助理教授Ben Stanger博士、博士生Kilangsungla Yanger,、Yiwei Zong博士和他們的同事們證實(shí)在小鼠的肝臟再生期間,肝細(xì)胞能夠自發(fā)轉(zhuǎn)化為膽管細(xì)胞.相關(guān)研究結(jié)果于2013年3月21日在線發(fā)表在Genes & Development期刊上,論文標(biāo)題為"Robust cellular reprogramming occurs spontaneously during liver regeneration".Stanger博士也是這篇論文的通信作者.
成年肝臟主要含有兩類細(xì)胞：肝實(shí)質(zhì)細(xì)胞(hepatocyte,也譯作肝上皮實(shí)質(zhì)細(xì)胞,也常譯作肝細(xì)胞)和膽管細(xì)胞(biliary cell),而且它們?cè)谛螒B(tài)和功能上存在顯著差別.肝實(shí)質(zhì)細(xì)胞是肝臟中主要的細(xì)胞類型,在那里,它們合成蛋白和其他大分子,并且讓毒性物質(zhì)去毒化.另一方面,膽管細(xì)胞位于膽管內(nèi)膜上,將膽汁從肝臟攜帶到小腸中從而有助于消化脂肪.
利用一種靈敏性的方法---使用黃色熒光蛋白(yellow fluorescent protein, YFP)---來(lái)標(biāo)記和追蹤細(xì)胞如何發(fā)育和分化,研究人員發(fā)現(xiàn)讓一種激活的Notch1基因條件性表達(dá)能夠?qū)⒏螌?shí)質(zhì)細(xì)胞轉(zhuǎn)化為膽管細(xì)胞.Notch是一種重要的受體,能夠傳遞告訴細(xì)胞如何發(fā)育的信號(hào).
更重要的是,當(dāng)研究人員利用多種毒素讓肝細(xì)胞遭受損傷以便激活傷口愈合之后,他們發(fā)現(xiàn)在兩到三周后,肝實(shí)質(zhì)細(xì)胞自我激活一種膽管細(xì)胞程序,從而獲得膽管細(xì)胞的形狀和功能.這些變化依賴于內(nèi)源性Notch信號(hào)的激活.
Stanger博士說(shuō),"這項(xiàng)發(fā)現(xiàn)直接證實(shí)在活動(dòng)物體內(nèi),細(xì)胞能夠從一種成熟細(xì)胞類型轉(zhuǎn)化為另一種成熟細(xì)胞類型.我們認(rèn)為,擴(kuò)大也已存在的細(xì)胞重編程關(guān)系可能是一種改造細(xì)胞的方法以便治療因沒有足夠的膽管而導(dǎo)致的疾病,如膽汁淤積(cholestasis)."（生物谷Bioon.com）
doi: 10.1101/gad.207803.112
PMC:
PMID:
Robust cellular reprogramming occurs spontaneously during liver regeneration
Kilangsungla Yanger1,2,6,Yiwei Zong1,2,6,Lara R. Maggs1,2,Suzanne N. Shapira1,2,Ravi Maddipati1,2,Nicole M. Aiello1,2,Swan N. Thung3,Rebecca G. Wells1,Linda E. Greenbaum4 andBen Z. Stanger1,2,5,7
Cellular reprogramming—the ability to interconvert distinct cell types with defined factors—is transforming the field of regenerative medicine. However, this phenomenon has rarely been observed in vivo without exogenous factors. Here, we report that activation of Notch, a signaling pathway that mediates lineage segregation during liver development, is sufficient to reprogram hepatocytes into biliary epithelial cells (BECs). Moreover, using lineage tracing, we show that hepatocytes undergo widespread hepatocyte-to-BEC reprogramming following injuries that provoke a biliary response, a process requiring Notch. These results provide direct evidence that mammalian regeneration prompts extensive and dramatic changes in cellular identity under injury conditions,。
