TRANSLATING HUMAN EMBRYONIC STEM CELL-DERIVED ENDOTHELIAL CELL THERAPY TO THE CLINIC

将人类胚胎干细胞衍生的内皮细胞疗法转化为临床

• 批准号: MR/K00719X/1
• 负责人: Andrew Baker
• 金额: $ 152.33万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK00719X%2F1
• 关键词: TRANSLATING; HUMAN; EMBRYONIC; STEM; CELL

Human embryonic stem (hES) cells and induced pluripotent stem cells (iPS) hold broad potential in regenerative medicine. Such cells can generate all cell types upon stimulation to differentiate along defined cell commitment pathways. We are interested in the mechanisms that govern stimulation of these cells into vascular endothelial cells and their subsequent application to regenerative medicine. These cells line all blood vessels and have the capacity to induce blood vessel growth upon injection into the body. We have recently published a study that shows the potential of human endothelial cells derived from human embryonic stem cells (Kane et al., ATVB, 2010). We showed a very efficient production of endothelial cells in just 10 days following initiation of differentiation from the original hES cells. This rapid system induced robust changes, i.e. very effective reduction in pluripotency markers and induction of endothelial selective markers. We also defined the "therapeutic" potential of these cells in cell cultures and in animal models by demonstrating the induction of new blood vessel growth leading to better blood flow in the muscle that was damaged. The induction of this phenotype suggests that these cells and this differentiation system may be useful clinically in the treatment of ischemic conditions in patients with cardiovascular disease. In previous funding that ended recently, we were able to produce endothelial cells from hES cells at clinical grade thus showing proof of concept that these cells can be produced at the quality and quantity required for potential clinical use. This is a powerful approach that has not been tested in man yet. This is our aim for the present grant application.In this proposal we will address a very important issue that now is required for further development of this product towards a first application in man. We require this grant funding to complete development of the cells at a grade acceptable for clinical use. We will further refine the protocol for production, fully test the cells produced in cell culture and by detailed analysis. We will then test the safety the cells and how good they are at inducing blood vessel growth in two important animal models, in mouse and rabbit. Finally, we will assess where the cells go after injection looking at retention in the tissue, dissemination to other tissues and organs and how long they stay there. These are important issues that will allow us to gain regulatory approval if the grant is successful.

人胚胎干细胞(HES)和诱导多能干细胞(IPS)在再生医学中具有广阔的应用前景。这样的细胞可以在刺激下产生所有类型的细胞，沿着确定的细胞承诺途径分化。我们感兴趣的是这些细胞刺激成血管内皮细胞的机制，以及它们随后在再生医学中的应用。这些细胞排列在所有血管中，并在注射到体内后具有诱导血管生长的能力。我们最近发表了一项研究，显示了从人类胚胎干细胞衍生的人内皮细胞的潜力(Kane等人，ATVB，2010)。我们展示了在从原始的HES细胞开始分化后的短短10天内非常有效地产生内皮细胞。这一快速系统导致了强劲的变化，即非常有效地减少了多能性标志物和诱导了内皮选择性标志物。我们还定义了这些细胞在细胞培养和动物模型中的“治疗”潜力，通过证明诱导新的血管生长导致受损肌肉中更好的血液流动。这种表型的诱导表明，这些细胞和这种分化系统可能在临床上用于治疗心血管疾病患者的缺血性疾病。在最近结束的之前的资助中，我们能够从临床级别的HES细胞中培养出内皮细胞，从而证明了这些细胞可以在质量和数量上达到潜在临床使用的要求。这是一种强大的方法，还没有在人类身上进行过测试。这就是我们目前拨款申请的目的。在这项提案中，我们将解决一个非常重要的问题，这个问题现在是进一步开发该产品以实现城域网首次应用所必需的。我们需要这笔赠款资金，以完成细胞在临床上可接受的级别的开发。我们将进一步完善生产方案，对细胞培养产生的细胞进行全面测试，并进行详细的分析。然后，我们将在两个重要的动物模型--小鼠和兔身上测试这些细胞的安全性以及它们在诱导血管生长方面的能力。最后，我们将评估注射后细胞的去向，看看细胞在组织中的滞留情况，扩散到其他组织和器官的情况，以及它们在那里停留的时间。这些都是重要的问题，如果拨款成功，我们将获得监管部门的批准。

项目成果

Colon cancer-derived myofibroblasts increase endothelial cell migration by glucocorticoid-sensitive secretion of a pro-migratory factor.

• DOI: 10.1016/j.vph.2016.10.004
• 发表时间: 2017-02
• 期刊: Vascular pharmacology
• 影响因子: 4
• 作者: Drebert Z;MacAskill M;Doughty-Shenton D;De Bosscher K;Bracke M;Hadoke PWF;Beck IM
• 通讯作者: Beck IM

Transcriptional dynamics of pluripotent stem cell-derived endothelial cell differentiation revealed by single-cell RNA sequencing.

• DOI: 10.1093/eurheartj/ehz351
• 发表时间: 2020-03-01
• 期刊: EUROPEAN HEART JOURNAL
• 影响因子: 39.3
• 作者: McCracken, Ian R.;Taylor, Richard S.;Kok, Fatma O.;de la Cuesta, Fernando;Dobie, Ross;Henderson, Beth E. P.;Mountford, Joanne C.;Caudrillier, Axelle;Henderson, Neil C.;Ponting, Chris P.;Baker, Andrew H.
• 通讯作者: Baker, Andrew H.