2015年2月9日 訊 /生物谷BIOON/ -- 荷蘭烏德勒支大學醫學中心分子遺傳學教授Hans Clevers現為荷蘭皇家科學院院士，歐洲分子生物學組織EMBO會士。是Wnt信號轉導通路、腸發育和相關癌症方面研究領域的頂尖專家。近日其帶領的研究組連續在Cell、Neuron和Cell Stem Cell雜誌上發表了4篇論文，公布了關於癌症幹細胞研究的最新成果。
2月5日，Cell子刊《Cell Stem Cell》雜誌發表的一篇題為"Ascl2 Acts as an R-spondin/Wnt-Responsive Switch to Control Stemness in Intestinal Crypts"文章指出，Wnt信號通路的一個靶基因、腸幹細胞身份的主調控因子--Ascl2，是在一個直接的自動活化環中被調控的，從而導致明顯不同的開/關表達模式，Wnt/R脊椎蛋白可以激活這個調控環。這一機制可解釋腸隱窩中的Wnt水平，並將連續的Wnt信號翻譯為一個不連續的Ascl2"開"或"關"決定。反過來，Ascl2連同β-catenin/Tcf，可激活對幹細胞狀態很重要的基因。
1月21日在Cell子刊《Neuron》發表的題為"Microbiota Controls the Homeostasis of Glial Cells in the Gut Lamina Propria"論文中，Clevers研究小組發現，在正常條件下，腸道黏膜膠質細胞固有層的定植開始於出生後早期階段，但是在斷奶後達到穩態水平。採用遺傳譜系追蹤，研究小組提供證據表明，在成年小鼠中，黏膜EGCs網絡通過腸壁叢起源的傳入膠質細胞得以不斷更新。此外，研究人員還證明，腸黏膜中膠質細胞的最初定植和穩態是由腸道固有菌群所調節。
另外，該研究小組在2015年1月15號《Cell》雜誌同期發表兩篇論文："Organoid Models of Human and Mouse Ductal Pancreatic Cancer"和"Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver"。在前一篇論文中，他們與冷泉港實驗室合作，描述了一種胰腺癌三維"類器官"培養系統，這種方法不僅可以培養來自實驗室小鼠模型的胰腺組織，還可培養來自人類患者的胰腺組織，由此提供了一條未來通向個體化療法的路徑。而後一篇論文中，該研究小組構建了一種長期的人類肝臟類器官培養物，發現人類肝臟幹細胞在長期擴增後仍保持遺傳穩定性，肝臟類器官培養物可在體內和體外分化成為功能性肝細胞。
作為時下最熱門學科之一，幹細胞領域的研究工作可謂越來越多，相關的研究成果也是層出不窮，其轉化與應用也越來越值得期待。Susan Solomon也致力於幹細胞研究，是罕見病及個體化用藥的專家。她在以"幹細胞研究所承諾的未來"為題的演講中，對幹細胞的未來發展方向進行了展望，並表明未來存在以人體細胞來進行藥物測試，並成為標準的研究流程的可能性。(生物谷Bioon.com)
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生物谷推薦的原文：
Ascl2 Acts as an R-spondin/Wnt-Responsive Switch to Control Stemness in Intestinal Crypts
doi: 10.1016/j.stem.2014.12.006
Schuijers J1, Junker JP1, Mokry M2, Hatzis P3, Koo BK4, Sasselli V1, van der Flier LG5, Cuppen E1, van Oudenaarden A1, Clevers H6.
Abstract
The Wnt signaling pathway controls stem cell identity in the intestinal epithelium and in many other adult organs. The transcription factor Ascl2 (a Wnt target gene) is a master regulator of intestinal stem cell identity. It is unclear how the continuous Wnt gradient along the crypt axis is translated into discrete expression of Ascl2 and discrete specification of stem cells at crypt bottoms. We show that (1) Ascl2 is regulated in a direct autoactivatory loop, leading to a distinct on/off expression pattern, and (2) Wnt/R-spondin can activate this regulatory loop. This mechanism interprets the Wnt levels in the intestinal crypt and translates the continuous Wnt signal into a discrete Ascl2 "on" or "off" decision. In turn, Ascl2, together with β-catenin/Tcf, activates the genes fundamental to the stem cell state. In this manner, Ascl2 forms a transcriptional switch that is both Wnt responsive and Wnt dependent to define stem cell identity.
Microbiota Controls the Homeostasis of Glial Cells in the Gut Lamina Propria
doi: 10.1016/j.neuron.2014.12.037
Kabouridis PS1, Lasrado R2, McCallum S2, Chng SH3, Snippert HJ4, Clevers H4, Pettersson S3, Pachnis V5.
Abstract
The intrinsic neural networks of the gastrointestinal tract are derived from dedicated neural crest progenitors that colonize the gut during embryogenesis and give rise to enteric neurons and glia. Here, we study how an essential subpopulation of enteric glial cells (EGCs) residing within the intestinal mucosa is integrated into the dynamic microenvironment of the alimentary tract. We find that under normal conditions colonization of thelamina propria by glial cells commences during early postnatal stages but reaches steady-state levels after weaning. By employing genetic lineage tracing, we provide evidence that in adult mice the network of mucosal EGCs is continuously renewed by incoming glial cells originating in the plexi of the gut wall. Finally, we demonstrate that both the initial colonization and homeostasis of glial cells in the intestinal mucosa are regulated by the indigenous gut microbiota.
Organoid Models of Human and Mouse Ductal Pancreatic Cancer
doi: 10.1016/j.cell.2014.12.021
Boj SF1, Hwang CI2, Baker LA2, Chio II2, Engle DD2, Corbo V2, Jager M3, Ponz-Sarvise M2, Tiriac H2, Spector MS2, Gracanin A1, Oni T4, Yu KH5, van Boxtel R3, Huch M3, Rivera KD6, Wilson JP6, Feigin ME2, Öhlund D2, Handly-Santana A7, Ardito-Abraham CM2, Ludwig M2, Elyada E2, Alagesan B8, Biffi G2,Yordanov GN7, Delcuze B2, Creighton B2, Wright K2, Park Y2, Morsink FH9, Molenaar IQ10, Borel Rinkes IH10, Cuppen E3, Hao Y6, Jin Y6, Nijman IJ3,Iacobuzio-Donahue C11, Leach SD11, Pappin DJ6, Hammell M6, Klimstra DS12, Basturk O12, Hruban RH13, Offerhaus GJ9, Vries RG1, Clevers H14, Tuveson DA15.
Abstract
Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreaticorganoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.
Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver
doi: 10.1016/j.cell.2014.11.050
Huch M1, Gehart H2, van Boxtel R2, Hamer K2, Blokzijl F2, Verstegen MM3, Ellis E4, van Wenum M5, Fuchs SA6, de Ligt J2, van de Wetering M7, Sasaki N2,Boers SJ6, Kemperman H8, de Jonge J3, Ijzermans JN3, Nieuwenhuis EE6, Hoekstra R5, Strom S9, Vries RR7, van der Laan LJ3, Cuppen E2, Clevers H10.
Abstract
Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derivedbipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from α1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy.
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