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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >In vivo reprogramming of Sox9~+ cells in the liver to insulin-secreting ducts
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In vivo reprogramming of Sox9~+ cells in the liver to insulin-secreting ducts

机译：体内将Sox9〜+细胞在肝脏中重编程为胰岛素分泌管

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摘要

In embryonic development, the pancreas and liver share developmental history up to the stage of bud formation. Therefore, we postulated that direct reprogramming of liver to pancreatic cells can occur when suitable transcription factors are overexpressed. Using a polycistronic vector we misexpress Pdx1, Ngn3, and MafA in the livers of NOD-SCID mice rendered diabetic by treatment with streptozotocin (STZ). The diabetes is relieved long term. Many ectopic duct-like structures appear that express a variety of p-cell markers, including dense core granules visible by electron microscopy (EM). Use of a vector also expressing GFP shows that the ducts persist long after the viral gene expression has ceased, indicating that this is a true irreversible cell reprogramming event. We have recovered the insulin~+ cells by cell sorting and shown that they display glucose-sensitive insulin secretion. The early formed insulin'1' cells can be seen to coexpress SOX9 and are also labeled in mice lineage labeled for Sox9 expression. SOX9~+ cells are normally found associated with small bile ducts in the periportal region, indicating that the duct-like structures arise from this source. This work confirms that developmentally related cells can be reprog-rammed by suitable transcription factors and also suggests a unique therapy for diabetes.
机译：在胚胎发育中，直到芽形成阶段，胰腺和肝脏都具有发育史。因此，我们推测当适当的转录因子过表达时，可能发生肝脏直接重编程为胰腺细胞。使用多顺反子载体，我们在通过链脲佐菌素（STZ）治疗而成为糖尿病的NOD-SCID小鼠的肝脏中错误表达Pdx1，Ngn3和MafA。糖尿病可以长期缓解。出现许多表达各种p细胞标记的异位导管样结构，包括通过电子显微镜（EM）可见的致密核心颗粒。使用还表达GFP的载体表明，病毒基因表达停止后，导管仍然存在很长时间，这表明这是真正的不可逆的细胞重编程事件。我们已经通过细胞分选恢复了胰岛素+细胞，并显示它们显示出葡萄糖敏感的胰岛素分泌。可以看到早期形成的胰岛素'1'细胞共表达SOX9，并且还在标记有Sox9表达的小鼠谱系中被标记。通常发现SOX9〜+细胞与周围区域的小胆管有关，表明这种来源的管状结构。这项工作证实了与发育相关的细胞可以通过合适的转录因子进行重组，并且还提出了一种针对糖尿病的独特疗法。

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    Anannya Banga; Ersin Akinci; Lucas V. Greder; James R. Dutton; Jonathan M. W. Slack;

  • 作者单位

    Stem Cell Institute, McGuire Translatlonal Research Facility, University of Minnesota, Minneapolis, MN 55455;

    Stem Cell Institute, McGuire Translatlonal Research Facility, University of Minnesota, Minneapolis, MN 55455;

    Stem Cell Institute, McGuire Translatlonal Research Facility, University of Minnesota, Minneapolis, MN 55455;

    Stem Cell Institute, McGuire Translatlonal Research Facility, University of Minnesota, Minneapolis, MN 55455;

    Stem Cell Institute, McGuire Translatlonal Research Facility, University of Minnesota, Minneapolis, MN 55455;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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