学术报告
题 目: Chemical reprogramming of human somatic cells to pluripotent stem cells
北京大学博雅讲席教授、北京大学干细胞研究中心主任，北大-清华生命科学联合中心高级研究员
地 点: 吕志和B101
主持人: 韩敬东 教授
摘 要:
Cellular reprogramming can manipulate the identity of cells to generate the desired cell types. The use of cell intrinsic components, including oocyte cytoplasm and transcription factors, can enforce somatic cell reprogramming to pluripotent stem cells. By contrast, chemical stimulation by exposure to small molecules offers an alternative approach that can manipulate cell fate in a simple and highly controllable manner. However, human somatic cells are refractory to chemical stimulation owing to their stable epigenome and reduced plasticity; it is therefore challenging to induce human pluripotent stem cells by chemical reprogramming. Here we demonstrate, by creating an intermediate plastic state, the chemical reprogramming of human somatic cells to human chemically induced pluripotent stem cells that exhibit key features of embryonic stem cells. The whole chemical reprogramming trajectory analysis delineated the induction of the intermediate plastic state at the early stage, during which chemical-induced dedifferentiation occurred, and this process was similar to the dedifferentiation process that occurs in axolotl limb regeneration. Moreover, we identified the JNK pathway as a major barrier to chemical reprogramming, the inhibition of which was indispensable for inducing cell plasticity and a regeneration-like program by suppressing pro-inflammatory pathways. Our chemical approach provides a platform for the generation and application of human pluripotent stem cells in biomedicine. This study lays foundations for developing regenerative therapeutic strategies that use well-defined chemicals to change cell fates in humans.
参考文献: Jingyang Guan, et al., Chemical reprogramming of human somatic cells to pluripotent stem cells. Nature volume 605, pages325–331 (2022)
邓宏魁，北京大学博雅讲席教授、长江学者特聘教授，北京大学干细胞研究中心主任，北大-清华生命科学联合中心高级研究员，国家杰出青年科学基金获得者，973项目和国家重点研发计划首席科学家。课题组长期以来致力于开发调控细胞命运的新方法和建立多潜能干细胞制备的全新底层技术，累计发表论文160余篇，被引用16,000余次，尤其在小分子化合物诱导细胞命运转变方面做出了一系列开拓性工作：1）首次实现完全使用小分子化合物逆转“发育时钟”，让小鼠体细胞重新获得多潜能性（Science, 2013），在后续的研究工作中揭示了化学重编程全新的分子机制（Cell, 2015; Cell Stem Cell, 2018），一系列成果开创了全新的体细胞重编程体系；2) 首次实现完全使用小分子化合物诱导人类体细胞转变为多潜能干细胞（hCiPS细胞）（Nature, 2022），是我国从源头上独创的新一代多潜能干细胞制备技术；3）利用小分子化合物建立了一种全新的具有全能性特征的干细胞（EPS细胞）（Cell, 2017），从小鼠2细胞胚胎建立了新型全能性干细胞（TPS细胞）（Cell Res, 2022）；4）利用小分子化合物实现功能成熟细胞在体外的长期维持（Science, 2019），从多潜能干细胞诱导制备功能成熟的肝细胞，在急性肝衰猪模型上成功完成了人工肝治疗的动物实验；从多潜能干细胞高效分化制备功能成熟的胰岛细胞，在糖尿病小鼠和猴模型上验证了有效性和安全性（Nature Medicine, 2022）；5）实现小分子化合物诱导小鼠体细胞成为功能性神经元（Cell Stem Cell, 2015），并实现了在成年小鼠大脑中将体细胞原位转变神经元的体内重编程（Cell Discov, 2021）。
