The use of microRNAs and nanotopography to modulate skeletal stem cell fate and function

使用 microRNA 和纳米形貌来调节骨骼干细胞的命运和功能

• 批准号: BB/L021072/1
• 负责人: Richard Oreffo
• 金额: $ 49.56万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL021072%2F1
• 关键词: use; microRNAs; nanotopography; modulate; skeletal

Medical advances have led to a welcome increase in life expectancy. However, increased aging populations pose new challenges and emphasize the need for novel approaches to aid and repair tissue lost through damage or disease. By 2020 approximately 20% of the UK population will be over 65 and the numbers of hip fractures worldwide will increase from 1.7 million in 1990 to 6.3 million in 2050. Thus, there is now an urgent need to understand how to maintain stem cells and then how to direct them into cell types we want such as bone and cartilage to enhance bone repair and improve quality of life for the patient. However, despite intensive research interest there is limited information on how to reproducibly maintain the bone stem cells (known as skeletal or mesenchymal stem cells); or indeed how to tell a bone stem cell to make bone or cartilage. Fortunately, human bone marrow contains these special skeletal stem cells. These stem cells can easily be obtained from these tissues and have the potential to form a variety of tissue types such as cartilage, bone, muscle, tendon, ligament and fat (for this reason, skeletal stem cells are currently one of the most exciting and promising areas for tissue engineering and reparative medicine and in the future this will allow stem cell-based therapies to be developed to treat or cure diseases).We are particularly interested in understanding how to maintain stem cells and to switch (differentiate) these bone stem cells to new bone and cartilage fat for regenerative medicine. For this approach to be successful, it is crucial to understand the way in which these skeletal stem cells change to become mature bone or retain their stem characteristics. Unlocking the molecular signals is the key to developing understanding and being able to undertake these studies in the absence of chemical cues is critical (to avoid confusing signals due to the chemicals used); we have powerful early data showing small nucleotides called microRNAs are key.MicroRNAs (miRNAs), are very small (only 18-25 nucleotides) non-protein-coding single-stranded RNAs that have the ability to regulate gene transcription. They have important and varied roles in many biological and disease related processes. There is new and exciting data to suggest i) a number of miRNAs are specifically expressed in stem cells, ii) they can control stem cell self-renewal, and, iii) they can control the ability of stem cells to form different tissue types. In addition we have data on nanotopographical surfaces (surfaces that can change or maintain our stem cells without any chemical cues) indicating the key role of microRNAs in keeping or changing bone stem cells. We will look at how these microRNAs affect cell behaviour and cytoskeleton (proteins involved in cell adhesion, spreading, metabolism and signalling), cell growth and differentiation.The results of this proposed project will open the way to modulate bone stem cells and thus drive the stems cells towards the desired cell type and provides exciting healthcare opportunities that will benefit many.

医疗进步导致了预期寿命的可喜增加。但是，增加的人口构成了新的挑战，并强调需要通过损害或疾病损失的新方法来帮助和修复组织。到2020年，英国人口的大约20％将超过65％，全球髋部骨折的数量将从1990年的170万增加到2050年的630万。因此，现在迫切需要了解如何维持干细胞，然后如何将其引导到我们想要的细胞类型中，例如我们想要的骨骼和软骨，以增强骨骼修复和改善患者的生活质量。然而，尽管有密集的研究感兴趣，但关于如何可重复维持骨干细胞（称为骨骼或间充质干细胞）的信息有限。或实际上如何告诉骨干细胞制造骨骼或软骨。幸运的是，人骨髓包含这些特殊的骨骼干细胞。这些干细胞可以很容易地从这些组织中获得，并有可能形成多种组织类型，例如软骨，骨骼，肌肉，肌腱，韧带和脂肪（因此，骨骼干细胞目前是组织工程和最有希望的区域之一，用于组织工程和恢复性药物，并且在将来可以使干细胞的疗法及其造成的细胞尤其不感兴趣，从而尤其要开发出来的植物和细胞）。这些骨干细胞可用于新骨和软骨脂肪，用于再生医学。为了使这种方法成功，了解这些骨骼干细胞变化以变成成熟骨头或保留其茎特征的方式至关重要。解锁分子信号是发展理解和能够在没有化学提示的情况下进行这些研究的关键（以避免由于所使用的化学物质而引起的信号）；我们有强大的早期数据，显示称为microRNA的小核苷酸是关键。Micrornas（miRNA）非常小（只有18-25个核苷酸）非蛋白质编码的单链RNA，具有调节基因转录的能力。它们在许多与生物学和疾病相关的过程中具有重要的作用。有新的和令人兴奋的数据可以建议i）许多miRNA在干细胞中特异性表达，ii）它们可以控制干细胞的自我更新，iii）他们可以控制干细胞形成不同组织类型的能力。此外，我们还拥有有关纳米形态表面的数据（可以改变或维护干细胞而无需任何化学提示的表面），表明microRNA在保持或改变骨干细胞中的关键作用。我们将研究这些microRNA如何影响细胞行为和细胞骨架（与细胞粘附，扩散，代谢和信号传导有关的蛋白质），细胞生长和分化。该提出的项目的结果将为调节骨干细胞的方式开辟道路，从而为所需的细胞类型驱动干细胞，并提供令人兴奋的医疗机会，从而使许多人受益。

项目成果

Bone Tissue Engineering.

• DOI: 10.1007/s40610-015-0022-2
• 发表时间: 2015
• 期刊: Current molecular biology reports
• 作者: Black CR;Goriainov V;Gibbs D;Kanczler J;Tare RS;Oreffo RO
• 通讯作者: Oreffo RO

Harnessing Nanotopography to Enhance Osseointegration of Clinical Orthopedic Titanium Implants-An in Vitro and in Vivo Analysis.

• DOI: 10.3389/fbioe.2018.00044
• 发表时间: 2018
• 期刊: Frontiers in bioengineering and biotechnology
• 影响因子: 5.7
• 作者: Goriainov V;Hulsart-Billstrom G;Sjostrom T;Dunlop DG;Su B;Oreffo ROC
• 通讯作者: Oreffo ROC

Osteoarthritis treatment with a novel nutraceutical acetylated ligstroside aglycone, a chemically modified extra-virgin olive oil polyphenol.

使用新型营养保健品乙酰化藁苷苷元（一种化学改性的特级初榨橄榄油多酚）治疗骨关节炎。

• DOI: 10.1177/2041731420922701
• 发表时间: 2020
• 期刊: Journal of tissue engineering
• 影响因子: 8.2
• 作者: De Andrés MC

The Potential of microRNAs for Stem Cell-based Therapy for Degenerative Skeletal Diseases.

• DOI: 10.1007/s40610-017-0076-4
• 发表时间: 2017
• 期刊: Current molecular biology reports
• 作者: Budd E;Waddell S;de Andrés MC;Oreffo ROC
• 通讯作者: Oreffo ROC

Quantitative temporal interrogation in 3D of bioengineered human cartilage using multimodal label-free imaging.

• DOI: 10.1039/c8ib00050f
• 发表时间: 2018-10
• 期刊: Integrative biology : quantitative biosciences from nano to macro
• 作者: Catarina Costa Moura;S. Lanham;Tual Monfort;K. Bourdakos;Rahul S. Tare;R. Oreffo;S. Mahajan