Developing biomimetic matrices for enhanced cellular reprogramming

开发仿生基质以增强细胞重编程

• 批准号: MR/M011089/1
• 负责人: Kevin Chalut
• 金额: $ 39.4万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM011089%2F1
• 关键词: Developing; biomimetic; matrices; enhanced; cellular

The Nobel Prize winning discovery of induced pluripotent stem (iPS) cells by Takashi and Yamanaka in 2006 represented a groundbreaking advance in stem cells and regenerative medicine. Pluripotency is a functional state that implies the ability to form all tissues in the organism; it simulates the very beginnings of the founder tissue of a foetus. The ability to create this pluripotent state from adult cells in a laboratory liberated researchers from having to rely on embryos to produce these cells, and furthermore allowed them to have cells that were potentially competent to produce any type of cell for tissue regeneration. Given that iPS cells come from adult cells from a prospective patient, the likelihood of rejection from tissues is also significantly reduced. iPS cells therefore represent an attractive source of patient-specific cells for drug discovery, as well as more directly for genetic correction and treatment of numerous human diseases. However, current reprogramming strategies typically take weeks and the efficiency of this process is extremely low. Furthermore, there is much work to be done to optimize the induction of pluripotency in human cells. Therefore, there is significant scope for advancing the process by which pluripotency is induced. In particular, almost nothing is known about how physical cues such as shape, topography and stiffness might regulate the establishment of pluripotency. The lack of insight into how physical cues drive pluripotent reprogramming is particularly interesting considering that pluripotency is originally established in a highly physical environment - the developing embryo. The inspiration for the proposed research is to take what we know about the developing embryo - its spherical shape, its softness, the chemical contacts of pluripotent cells in the embryo - and attempt to create it in laboratory conditions. This is in contrast to the way most iPS research is done, in which the cells are plated on a flat, hard dish made from plastic. We are synthesizing biomimetics - meaning materials that mimic biomaterials - to simulate the embryonic environment as closely as possible to optimise the induction of pluripotency in cells. We propose that this will make the process of reprogramming more efficient, and also that these cells will be highly amenable to being guided into specific tissue cells. We can use the same biomimetic ideas to guide the cells into specific lineages. The ultimate goal of this type of research is to receive cells from a patient and create - using biomimetics - tissue competent cells for regenerating organs. This is a highly cross-disciplinary proposal that will also lend greater insight into pluripotent cell function, and how these cells interact with their environment. The research will impact biotechnology, regenerative medicine and stem cell biology. It will bring to bear new insight into how stem cells work, and how we can investigate them. Using our connections in stem cells, biophysics, and biotechnology, we will widely circulate our results, generating impact in several academic disciplines. Given its high potential for impact in regenerative medicine and its highly cross-disciplinary nature, the proposed research is highly suited for the portfolio of the MRC.

2006年，Takashi和Yamanaka获得诺贝尔奖的诱导多能干细胞（iPS）的发现代表了干细胞和再生医学的突破性进展。多能性是一种功能状态，意味着能够在生物体中形成所有组织；它模拟了胎儿初始组织的初始阶段。在实验室中从成年细胞中创造出这种多能状态的能力使研究人员从依赖胚胎来产生这些细胞中解放出来，并且进一步允许他们拥有能够产生任何类型细胞用于组织再生的细胞。鉴于iPS细胞来自潜在患者的成人细胞，组织排斥的可能性也大大降低。因此，诱导多能干细胞是一种有吸引力的患者特异性细胞来源，可用于药物发现，也可更直接地用于基因校正和治疗许多人类疾病。然而，目前的重编程策略通常需要数周时间，而且这个过程的效率极低。此外，在优化人类细胞多能性诱导方面还有很多工作要做。因此，推进多能性诱导的过程有很大的空间。特别是，关于形状、地形和刚度等物理线索如何调节多能性的建立，我们几乎一无所知。考虑到多能性最初是在高度物理环境中建立的，即发育中的胚胎中，缺乏对物理线索如何驱动多能性重编程的深入了解尤其有趣。这项拟议研究的灵感是利用我们对发育中的胚胎的了解——它的球形、柔软度、胚胎中多能细胞的化学接触——并试图在实验室条件下创造出胚胎。这与大多数iPS研究的方法不同，在大多数iPS研究中，细胞被镀在由塑料制成的扁平硬盘上。我们正在合成仿生学，即模仿生物材料的材料，尽可能地模拟胚胎环境，以优化细胞多能性的诱导。我们认为，这将使重编程过程更有效，而且这些细胞将非常容易被引导到特定的组织细胞中。我们可以用同样的仿生思想来引导细胞进入特定的谱系。这类研究的最终目标是从病人身上获得细胞，并利用仿生学创造出用于再生器官的组织能力细胞。这是一个高度跨学科的建议，也将有助于更深入地了解多能细胞的功能，以及这些细胞如何与环境相互作用。这项研究将影响生物技术、再生医学和干细胞生物学。这将使我们对干细胞如何工作以及我们如何研究它们有了新的认识。利用我们在干细胞、生物物理学和生物技术方面的联系，我们将广泛传播我们的成果，在几个学科中产生影响。鉴于其在再生医学方面的巨大潜力及其高度跨学科的性质，拟议的研究非常适合MRC的投资组合。

项目成果

StemBond hydrogels optimise the mechanical microenvironment for embryonic stem cells

StemBond 水凝胶优化胚胎干细胞的机械微环境

• DOI: 10.1101/768762
• 发表时间: 2019
• 作者: Labouesse C

Microfluidic platform for live cell imaging of 3D cultures with clone retrieval

用于 3D 培养物活细胞成像和克隆检索的微流体平台

• DOI: 10.1101/2020.02.17.952689
• 发表时间: 2020
• 作者: Mulas C

StemBond hydrogels control the mechanical microenvironment for pluripotent stem cells.

• DOI: 10.1038/s41467-021-26236-5
• 发表时间: 2021-10-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Labouesse C;Tan BX;Agley CC;Hofer M;Winkel AK;Stirparo GG;Stuart HT;Verstreken CM;Mulas C;Mansfield W;Bertone P;Franze K;Silva JCR;Chalut KJ
• 通讯作者: Chalut KJ