Developing biomimetic matrices for enhanced cellular reprogramming

2006年，Takashi和Yamanaka获得了诺贝尔奖，他们发现了诱导多能干细胞（iPS），这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，意味着有能力形成有机体中的所有组织;它模拟了胎儿创始组织的开始。在实验室中从成体细胞中创造这种多能状态的能力使研究人员不必依赖胚胎来产生这些细胞，而且还使他们能够拥有潜在的细胞，可以产生任何类型的细胞用于组织再生。鉴于iPS细胞来自预期患者的成体细胞，组织排斥的可能性也显著降低。因此，iPS细胞代表了用于药物发现的患者特异性细胞的有吸引力的来源，以及更直接地用于许多人类疾病的遗传校正和治疗。然而，目前的重编程策略通常需要数周时间，并且该过程的效率极低。此外，还有许多工作要做，以优化人类细胞中多能性的诱导。因此，存在推进诱导多能性的过程的显著空间。特别是，几乎没有什么是已知的物理线索，如形状，地形和刚度可能会调节多能性的建立。考虑到多能性最初是在一个高度物理的环境--发育中的胚胎--中建立的，对物理线索如何驱动多能性重编程缺乏深入了解是特别有趣的。这项研究的灵感来自于我们对发育中的胚胎的了解--它的球形、柔软性、胚胎中多能细胞的化学接触--并试图在实验室条件下创造它。这与大多数iPS研究的方式相反，在大多数iPS研究中，细胞被接种在由塑料制成的平坦坚硬的盘子上。我们正在合成仿生学--即模仿生物材料的材料--以尽可能接近地模拟胚胎环境，从而优化细胞中多能性的诱导。我们认为，这将使重编程的过程更有效，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患者身上获得细胞，并使用仿生学创造出用于再生器官的组织感受态细胞。这是一个高度跨学科的提议，也将使人们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。它将为干细胞如何工作以及我们如何研究它们带来新的见解。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，在多个学科产生影响。鉴于其在再生医学中的高潜力影响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。

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.