Stem Cell Differentiation & Genomic Processes in Response to Bioactive Nanotopography

干细胞分化

基本信息

批准号：
BB/G006970/1
负责人：
Richard Oreffo
金额：
$ 41.69万
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：
2009
资助国家：
英国
起止时间：
2009 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FG006970%2F1
关键词：
Stem Cell Differentiation Genomic Processes

项目摘要

With an increasing ageing population the clinical requirement to replace degenerated tissues, such as musculoskeletal tissue, is a major socio-economic requirement. A key issue is an understanding of stem cell activity on different materials, specifically a need to understand how stem cells behave on a material surface. We have generated novel data that shows small changes in the shape of a material can relate to large changes in cell behaviour when they are grown on the material surface. These changes in material shape can be at the nanoscale (1 x 10-9 meters); for examples pits, pillars and grooves with widths and heights of under 100 nm can cause cell alignment, increases in adhesion and even cause total non-adhesion (non-contact) through adjustments of spacing and aspect ratio. Other effects nanoscale designs can have on cells are changes in cytoskeleton (proteins involved in cell adhesion, spreading, metabolism and signalling), cell growth and the function of the cell (differentiation). Stem cells are immature cells that have the ability to differentiate into a number of mature cell types. For example, stem cells from bone can differentiate into cells for bone formation and maintenance (osteoblasts and osteocytes) or cells for cartilage formation and maintenance (chondroblasts and chondrocytes), ligament and tendon formation (fibroblasts) and a number of other cell types (fat, endothelial, epithelial). The understanding of the environmental cues allowing cells to chose one type (bone or fat - referred to as lineage) over another would be of great advantage for stem cell biologists and subsequently for materials researchers and tissue engineers could then optimise material design for e.g. hip and knee replacements. In the replacements of load bearing implants for bone (such as the knee and hip), once the material is implanted, bone stem cells in the bone marrow (called mesenchymal or skeletal stem cells) differentiate to become fibroblasts due to lack of appropriate cues from the material. Thus, the material is surrounded by soft tissue rather than hard bone. Over time this causes implant failure leading to older patients undergoing complicated secondary (revision) surgery. Here, we plan to investigate how materials can pass nanoscale mechanical signals to the cell nucleus and how this leads to changes in DNA organisation and subsequent cell differentiation - a process known as direct mechanotransduction. We would view changes in structural proteins of the nucleus (nucleoskeleton) with changes in cell spreading on nanomaterials. These changes could then be related to changes in DNA positioning and gene regulation alongside studies of differentiation. Very little is know about what in their environment triggers stem cell differentiation, we believe that surface shape, also known as topography (like a mountain surface can be flat, rugged, smooth and bumpy), is important. If we can understand these processes we can produce better materials (informed design) that will encourage direct bone bonding (apposition) to an implant, thus removing the need for revision surgery. This would save patient worry, surgical time and the NHS millions of pounds.

随着人群衰老的增加，替代退化组织（例如肌肉骨骼组织）的临床要求是主要的社会经济要求。一个关键问题是了解不同材料的干细胞活性，特别是需要了解干细胞在材料表面上的行为。我们已经生成了新的数据，显示材料形状的小变化可能与细胞表面生长时的细胞行为变化有关。这些物质形状的变化可以在纳米级（1 x 10-9米）处。例如，凹坑，柱子和凹槽的宽度和高度低于100 nm，可能会导致细胞对齐，粘附增加，甚至通过调整间距和纵横比引起总非粘附（非接触）。纳米级设计对细胞的其他影响是细胞骨架的变化（涉及细胞粘附，扩散，代谢和信号传导），细胞生长以及细胞功能（分化）。干细胞是不成熟的细胞，具有分化为多种成熟细胞类型的能力。例如，骨骼中的干细胞可以区分细胞形成骨形成和维持（成骨细胞和骨细胞），或细胞的软骨形成和维持（软骨细胞和软骨细胞），韧带和肌腱形成（成纤维细胞）（成纤维细胞）以及其他细胞类型（脂肪，脂肪，Endothelial，epithelialial，epithelialial）。对环境提示的理解使细胞可以选择一种类型（骨头或脂肪（称为谱系））而不是另一种类型（骨头或脂肪）对干细胞生物学家而言将具有很大的优势，随后，对于材料研究人员和组织工程师而言，可以优化材料设计，例如。臀部和膝盖置换。在骨髓中植入材料后，骨髓中的骨干细胞（称为间充质或骨骼干细胞）的骨骼干细胞替换为骨骼（例如膝盖和髋关节）的载荷植入物（例如膝盖和髋关节），由于缺乏适当的线索，骨髓中的骨干细胞（称为间充质或骨骼干细胞）变成了成纤维细胞。因此，材料被软组织而不是硬骨包围。随着时间的流逝，这会导致植入物失败，导致接受复杂的继发性（修订）手术的老年患者。在这里，我们计划研究材料如何将纳米级的机械信号传递到细胞核，以及这如何导致DNA组织的变化以及随后的细胞分化 - 一种称为直接机械转导的过程。我们将看到核（核骨骼）结构蛋白的变化，并随纳米材料上的细胞扩散而变化。这些变化可能与DNA定位和基因调节的变化以及分化研究有关。我们认为，在其环境中触发干细胞的分化很少，我们认为表面形状，也称为地形（例如山地表面可以是平坦，崎,，光滑和颠簸），这很重要。如果我们能理解这些过程，我们可以生产更好的材料（知情设计），这些材料将鼓励直接骨骼粘合（同名）植入物，从而消除了修订手术的需求。这将节省患者的担忧，手术时间和NHS数百万英镑。

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）

Effects of a surface topography composite with puerariae radix on human STRO-1-positive stem cells.

DOI：
10.1016/j.actbio.2010.02.038
发表时间：
2010-09
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Fahsai Kantawong;Karl E. V. Burgess;Kamburapola Jayawardena;A. Hart;M. Riehle;R. Oreffo;M. Dalby;R. Burchmore
通讯作者：
Fahsai Kantawong;Karl E. V. Burgess;Kamburapola Jayawardena;A. Hart;M. Riehle;R. Oreffo;M. Dalby;R. Burchmore

Embryonic and induced pluripotent stem cells: understanding, creating, and exploiting the nano-niche for regenerative medicine.

DOI：
10.1021/nn3037094
发表时间：
2013-03-26
期刊：
ACS NANO
影响因子：
17.1
作者：
Kingham, Emmajayne;Oreffo, Richard O. C.
通讯作者：
Oreffo, Richard O. C.

Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions.

DOI：
10.1530/rep-09-0300
发表时间：
2010-01
期刊：
Reproduction (Cambridge, England)
影响因子：
0
作者：
Forristal CE;Wright KL;Hanley NA;Oreffo RO;Houghton FD
通讯作者：
Houghton FD

Osteogenic lineage restriction by osteoprogenitors cultured on nanometric grooved surfaces: the role of focal adhesion maturation.

DOI：
10.1016/j.actbio.2013.11.008
发表时间：
2014-02
期刊：
ACTA BIOMATERIALIA
影响因子：
9.7
作者：
Cassidy, John W.;Roberts, Jemma N.;Smith, Carol-Anne;Robertson, Mary;White, Kate;Biggs, Manus J.;Oreffo, Richard O. C.;Dalby, Matthew J.
通讯作者：
Dalby, Matthew J.

Protein Expression of STRO-1 Cells in Response to Different Topographic Features.

STRO-1 细胞响应不同地形特征的蛋白质表达。