Screening for regulators of human embryonic axis elongation in vitro

人胚胎轴伸长调控因子的体外筛选

• 批准号: BB/P000444/1
• 负责人: Anestis Tsakiridis
• 金额: $ 53.19万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP000444%2F1
• 关键词: Screening; regulators; human; embryonic; axis

Directing pluripotent stem cells (PSCs) to generate ("differentiate") various cell types in the petri dish is an attractive tool for understanding how embryos develop and a promising route towards therapies. However, our ability to produce cell types corresponding to the lower spinal cord (the thoracic, lumbar and sacral regions) and skeletal muscle is currently very limited. This is because conventional PSC differentiation methods fail to produce the common embryonic precursor of these cell types known as neuromesodermal progenitors (NMPs). We have recently succeeded in devising a protocol for converting efficiently human PSCs into NMPs (hNMPs). These in vitro generated NMPs appear to be a promising starting material for producing lower spinal cord and skeletal muscle cells. However, we still do not know much about the signals and the molecular mechanisms driving the generation of these cell types from hNMPs. The experiments proposed here will test various chemicals in order to identify the best "recipes" for pushing human NMPs to become exclusively either lower spinal cord or skeletal muscle cells. We will also examine how the binding of certain proteins known as transcription factors to the DNA of NMPs influences their decision to remain NMPs or differentiate into spinal cord/skeletal muscle cells. This work will lead to a better understanding of NMP biology and pave the way for the use of their differentiation products in the clinic.

引导多能干细胞(PSCs)在培养皿中产生(“分化”)各种类型的细胞是了解胚胎发育过程的一个有吸引力的工具，也是一条很有希望的治疗途径。然而，我们目前产生与下脊髓(胸、腰和骶骨区域)和骨骼肌相对应的细胞类型的能力非常有限。这是因为传统的PSC分化方法不能产生这些细胞类型的共同胚胎前体细胞，即神经中胚层前体细胞(NMP)。我们最近成功地设计了一种有效地将人PSCs转换为NMP(HNMP)的协议。这些体外产生的NMPs似乎是生产下段脊髓和骨骼肌细胞的一种有前途的起始材料。然而，我们仍然不太清楚hNMP产生这些细胞类型的信号和分子机制。这里提出的实验将测试各种化学物质，以确定推动人类NMP专门成为下脊髓或骨骼肌细胞的最佳“配方”。我们还将研究某些被称为转录因子的蛋白质与NMP的DNA的结合如何影响它们决定保留NMP或分化为脊髓/骨骼肌细胞。这一工作将有助于更好地了解NMP的生物学特性，为其分化产物在临床上的应用奠定基础。

项目成果

Shaping axial identity during human pluripotent stem cell differentiation to neural crest cells.

• DOI: 10.1042/bst20211152
• 发表时间: 2022-02-28
• 期刊: Biochemical Society transactions
• 影响因子: 3.9

Human axial progenitors generate trunk neural crest cells in vitro.

• DOI: 10.7554/elife.35786
• 发表时间: 2018-08-10
• 期刊: eLife
• 影响因子: 7.7
• 作者: Frith TJ;Granata I;Wind M;Stout E;Thompson O;Neumann K;Stavish D;Heath PR;Ortmann D;Hackland JO;Anastassiadis K;Gouti M;Briscoe J;Wilson V;Johnson SL;Placzek M;Guarracino MR;Andrews PW;Tsakiridis A
• 通讯作者: Tsakiridis A

Early anteroposterior regionalisation of human neural crest is shaped by a pro-mesodermal factor.

• DOI: 10.7554/elife.74263
• 发表时间: 2022-09-26
• 期刊: eLife
• 影响因子: 7.7
• 作者: Gogolou A;Souilhol C;Granata I;Wymeersch FJ;Manipur I;Wind M;Frith TJR;Guarini M;Bertero A;Bock C;Halbritter F;Takasato M;Guarracino MR;Tsakiridis A
• 通讯作者: Tsakiridis A