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AUTOMATIC CELL FATE ENGINEERING USING MICROFLUIDICS DEVICES

使用微流控设备进行自动细胞命运工程

基本信息

批准号：
EP/R041695/1
负责人：
Lucia Marucci
金额：
$ 31.94万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FR041695%2F1
关键词：
AUTOMATIC CELL FATE ENGINEERING USING

项目摘要

Stem cells are pluripotent cells that can both proliferate indefinitely producing cells identical to them, and specialise into more mature cells types. In adults, stem cells have a repair function in case of damage; adult stem cells are currently used in medical therapy. The major limitation of adult stem cells' medical applications is their low availability, and the difficulty to expand them in culture.Such issues were thought to be overcome thanks to the astonishing discovery of reprogramming by the Nobel Prize-winning Shinya Yamanaka: differentiated (i.e. somatic) cells can be programmed back to a stem-like state, obtaining the so-called induced Pluripotent Stem Cells (iPSCs). iPSCs can be subsequently converted into any cell type, to be used for regenerative and personalised medicine purposes. In Japan, the first clinical trial using iPSC-derived cells in humans is on going to cure age-related macular degeneration.iPSC therapy still faces, however, major challenges: it is difficult to reprogram somatic cells and maintain iPSCs in the pluripotent state; also, iPSC differentiation is often inefficient.In this research, we aim at applying state-of-the-art Synthetic Biology and Control Engineering tools to automatize and optimise the manufacturing of iPSC-derived cells. We will prove, using mouse cell lines, that each of the 3 mentioned challenges can be addressed if, while providing inputs that trigger pluripotency or differentiation, cells are continuously observed and inputs are consequently "adjusted" to obtain the target phenotype. This closed-loop strategy will be implemented by means of microfluidics and microscopy, that allow monitoring in real-time living cells, comparing relevant cellular outputs to the target one and applying control algorithms that allow acting on the cells to minimise the error. While proving that, by "closing the loop", it is possible to automatically control stem cell fate, we will provide a platform that allows, at the end of the experiment, to retrieve from the microfluidics device the desired cell type with high efficiency and reproducibility.

干细胞是多能细胞，既可以无限增殖，产生与它们相同的细胞，又可以分化成更成熟的细胞类型。在成人中，干细胞在损伤的情况下具有修复功能;成人干细胞目前用于医学治疗。成体干细胞在医学上的应用主要局限于其低可用性和难以在培养中扩增。诺贝尔奖获得者山中伸弥（Shinya Yamanaka）的惊人发现“重编程”（reprogramming）解决了这一问题：分化的（即体细胞）细胞可以被编程回干细胞样状态，获得所谓的诱导多能干细胞（iPSCs）。iPSC随后可以转化为任何细胞类型，用于再生和个性化医疗目的。在日本，第一个使用iPSC衍生细胞治疗老年性黄斑变性的临床试验正在进行中。然而，iPSC治疗仍然面临着重大挑战：难以重新编程体细胞并保持iPSC处于多能状态;而且，iPSC分化通常是低效的。在这项研究中，我们的目标是应用最先进的合成生物学和控制工程工具来自动化和优化iPSC衍生细胞的制造。我们将使用小鼠细胞系证明，如果在提供触发多能性或分化的输入的同时连续观察细胞并因此“调整”输入以获得目标表型，则可以解决上述3个挑战中的每一个。这种闭环策略将通过微流体和显微镜来实现，允许实时监测活细胞，将相关细胞输出与目标细胞输出进行比较，并应用控制算法，允许作用于细胞以最小化误差。在证明通过“闭环”可以自动控制干细胞命运的同时，我们将提供一个平台，该平台允许在实验结束时以高效率和再现性从微流体装置中检索所需的细胞类型。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Towards Engineering Biosystems with Emergent Collective Functions

迈向具有新兴集体功能的工程生物系统

DOI：
10.20944/preprints202005.0058.v1
发表时间：
2020
期刊：
影响因子：
0
作者：
Gorochowski T
通讯作者：
Gorochowski T

A low cost, open source Turbidostat design for in-vivo control experiments in Synthetic Biology

用于合成生物学体内控制实验的低成本开源恒浊器设计

DOI：
10.1101/617423
发表时间：
2019
期刊：
影响因子：
0
作者：
Guarino A
通讯作者：
Guarino A

Control-Based Continuation: A New Approach to Prototype Synthetic Gene Networks.

DOI：
10.1021/acssynbio.1c00632
发表时间：
2022-07-15
期刊：
ACS SYNTHETIC BIOLOGY
影响因子：
4.7
作者：
de Cesare, Irene;Salzano, Davide;di Bernardo, Mario;Renson, Ludovic;Marucci, Lucia
通讯作者：
Marucci, Lucia

Numerical methods for control-based continuation of relaxation oscillations