引言
转分化代表了直接的谱系转换;然而,对这一过程的描述不足阻碍了其潜在的应用。
2024年3月19日,山东大学刘峰团队(张一帆及康志鑫为论文的共同第一)在
Developmental Cell
在线发表题为“
Single-cell omics identifies inflammatory signaling as a trans-differentiation trigger in mouse embryos”的研究论文,该研究利用单细胞组学鉴定炎症信号作为小鼠胚胎的
转分化触发器。
为了探索
转分化的潜在普遍原理,该研究在小鼠胚胎中进行了内皮到造血转化(EHT)、内皮到间充质转化和上皮到间充质转化的单细胞转录组分析。应用熵、细胞型特征转录因子表达和关键过渡信号三个评分指标来显示支持过渡状态命运可塑性的共同特征。
跨模型比较确定了炎症特征的过渡状态和白细胞介素-33在促进命运转换中的共同触发作用。多模式分析(整合转录组学和染色质可及性分析)证明了造血规范的炎症调节。此外,多模态组学和命运定位分析表明,内皮特异性Spi1作为炎症效应因子,控制着适当的染色质可及性和转录程序,以保护EHT。总的来说,该研究使用单细胞组学来识别关键的过渡状态/信号以及炎症信号在发育应激诱导的命运转换中的常见触发作用。
Waddington的表观遗传景观一直被认为是描述细胞从全能性状态到终末分化状态的一个隐喻该景观具有三个基本要素,即细胞类型/状态、分化路径和基因调控网络(GRN)后来,
细胞重编程
的成就补充了Wadding的景观。
细胞重编程对再生医学至关重要。从一个成熟谱系到另一个成熟谱系的
转分化是细胞重编程的主要途径通过操纵确定的因素成功的
转分化表明,稳定的细胞状态在Waddington的表观遗传景观可以克服障碍,直接改变他们的命运。
虽然获得具有明确功能的终末细胞是成功的
转分化的标志,但对过渡状态、动态过渡路径和复杂GRN的全面理解仍然是
转分化领域的重大挑战。
在脊椎动物的最终造血干细胞和祖细胞(HSPC)生成过程中,内皮到造血转化(EHT)是一个被充分研究的
转分化范式。
在小鼠中,主动脉-性腺-中肾(AGM)中的扁平动脉内皮细胞(AECs)首先特化为具有内皮-造血双重电位的造血内皮细胞(HECs)然后,HECs萌发形成主动脉内造血集群(IAHCs),其中包含造血祖细胞(HPCs)和造血干细胞(HSCs)的未成熟前体(1型[T1]和2型[T2]前造血干细胞)。此外,内皮-间充质转化(
EndoMT
)和上皮-间充质转化(EMT)也是两种典型的
转分化模式,在组织发育、再生和肿瘤发生中起着至关重要的作用。与EHT类似,EndoMT和EMT也有一系列的过渡状态。
尽管现有的研究为
转分化提供了丰富的组学和实验数据资源,但要获得指导其广泛应用的通用原理仍然是一个巨大的挑战。
模式图(Credit:
Developmental Cell)
体内细胞命运的转变通常由输入刺激介导,如发育线索或损伤诱导的应激炎症信号在感染或炎症期间负责防御病原体和维持机体稳态,也调节着自然或应激条件下的命运转变。
在最终的HSPC出现时,toll样受体4下游的炎症信号或被干扰素、肿瘤坏死因子α和白细胞介素激活,指示EHT。内皮功能障碍时,炎症反应诱导EndoMT,进一步导致血管系统缺陷当在小鼠成纤维细胞中强制转录因子(TF) Etv2过表达以实现内皮细胞重编程时,在重编程成纤维细胞中存在激活的炎症信号通路。
此外,逆转录病毒介导的多能重编程或成纤维细胞到内皮细胞(EC)的
转分化导致先天免疫反应和炎症信号的激活,这有助于有效的细胞命运重编程。这些研究促使人们重新审视炎症信号在细胞命运转变中的特定作用。
该研究进行了单细胞组学分析和功能分析,以揭示小鼠胚胎中EHT、EndoMT和EMT的潜在共同分子特征和机制。
研究发现由炎症信号和下游效应TF介导的发育应激负责天然
转分化。激活免疫/炎症信号的富集是EHT、EndoMT和EMT过渡状态的共同特征;同时,已知的EndoMT/ EMT调节剂促炎白细胞介素-33 (IL-33)通过其受体抑制致瘤性2 (ST2)触发EHT。
该研究基于目前可用的单细胞转录组数据集和实验验证,提供了一个框架来表征反式分化的过渡状态和信号触发因素。将该框架应用于疾病相关数据集还可以帮助解码疾病进展过程中的关键转变,例如正常细胞向肿瘤细胞的转化。
https://doi.org/10.1016/j.devcel.2024.02.010
|探索君
排版|探索君
文章来源|“iNature”
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#259c5c;--weui-FG: #fff;--weui-BG: #000;--weui-TAG-TEXT-RED: rgba(250, 81, 81, .6);--weui-TAG-BACKGROUND-RED: rgba(250, 81, 81, .1);--weui-TAG-TEXT-ORANGE: rgba(250, 157, 59, .6);--weui-TAG-BACKGROUND-ORANGE: rgba(250, 157, 59, .1);--weui-TAG-TEXT-GREEN: rgba(6, 174, 86, .6);--weui-TAG-BACKGROUND-GREEN: rgba(6, 174, 86, .1);--weui-TAG-TEXT-BLUE: rgba(16, 174, 255, .6);--weui-TAG-BACKGROUND-BLUE: rgba(16, 174, 255, .1);--weui-TAG-TEXT-BLACK: rgba(255, 255, 255, .5);--weui-TAG-BACKGROUND-BLACK: rgba(255, 255, 255, .05)}}@media screen and (min-width:1024px) and (prefers-color-scheme:dark){body:not(.pages_skin_pc) .wx-root:not([data-weui-theme=light]),body:not(.pages_skin_pc) body:not([data-weui-theme=light]){--appmsgExtra-BG: #121212}}@media(prefers-color-scheme:dark){body:not([data-weui-theme=light]).my_comment_empty_data{background-color:#111}}body,.wx-root{--weui-BG-6: rgba(0, 0, 0, .05);--weui-ACTIVE-MASK: rgba(0, 0, 0, .05)}body,.wx-root{--weui-REDORANGE: #ff6146;--weui-BG-0: 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