Stem Cell Differentiation & Genomic Processes in Response to Bioactive Nanotopography
Lead Research Organisation:
University of Glasgow
Department Name: Institute of Biomedical & Life Sciences
Abstract
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.
Technical Summary
Topographical changes as small as 20 nm can be the difference between bone formation or lack of differentiation in stem cells. We intend to exploit this exquisite control to study the skeletal stem cell / material interface. It has been shown that the interphase nucleus has relative organisation, with chromosomes being arranged into discrete territories. Whereupon, it has then been speculated that by changing interphase chromosome positioning, the probability of transcription is altered. While research in this area is in its infancy, we have spent the last five years collecting data towards a grant application and have a unique system with which to study this without the use of invasive methodology. It is known that the cytoskeleton is central to mechanotransduction, both indirect (signalling cascades) and direct (force transduction). Our previous studies with skeletal stem cells and nanotopography have shown that topography confers changes in cell spreading and cytoskeletal organisation upon the cells. Furthermore, our previous studies with fibroblasts have shown changes in nuclear organisation and gene regulation with changes in cytoskeletal organisation. Here, it is intended than nanotopography will be used to cause changes in nuclear organisation (lamin nucleoskeleton, chromosome territories and methylation patterns) and differentiation will be monitored. Thus, the topography would be used to induce mechanotransductive effects in mesenchymal stem cells. Liking these results to microarray data and using resources such as the Stanford Source, we can plot where in the genome changes due to direct mechanotransduction are occurring. This will allow us to observe if large changes in interphase chromosome positioning due to direct mechanotransduction lead to large changes in gene regulation. Potentially, this could be a major route of cell differentiation and help us to develop materials, through rational design, to elicit directed differentiation.
Organisations
- University of Glasgow (Lead Research Organisation)
- Engineering and Physical Sciences Research Council (Co-funder)
- Max Planck Society (Collaboration)
- Bone Cancer Research Trust (Collaboration)
- Biogelx (Collaboration)
- University of Navarra (Collaboration)
- Atelerix (Collaboration)
- UNIVERSITY OF SOUTHAMPTON (Collaboration)
Publications
Aguayo S
(2016)
Influence of biomaterial nanotopography on the adhesive and elastic properties of Staphylococcus aureus cells
in RSC Advances
Al-Fotawei R
(2014)
Radiological assessment of bioengineered bone in a muscle flap for the reconstruction of critical-size mandibular defect.
in PloS one
Al-Jarsha M
(2018)
Engineered Coatings for Titanium Implants To Present Ultralow Doses of BMP-7.
in ACS biomaterials science & engineering
Alakpa EV
(2017)
Nacre Topography Produces Higher Crystallinity in Bone than Chemically Induced Osteogenesis.
in ACS nano
Alfotawi R
(2013)
Assessment of cellular viability on calcium sulphate/hydroxyapatite injectable scaffolds.
in Journal of tissue engineering
Allan C
(2018)
Osteoblast response to disordered nanotopography.
in Journal of tissue engineering
Ballester-Beltrán J
(2017)
Confined Sandwichlike Microenvironments Tune Myogenic Differentiation.
in ACS biomaterials science & engineering
Bathawab F
(2016)
Lateral Chain Length in Polyalkyl Acrylates Determines the Mobility of Fibronectin at the Cell/Material Interface.
in Langmuir : the ACS journal of surfaces and colloids
Cassidy JW
(2014)
Osteogenic lineage restriction by osteoprogenitors cultured on nanometric grooved surfaces: the role of focal adhesion maturation.
in Acta biomaterialia
Description | We investigated how surfaces can be used to better grow stem cells. Stem cells in the body live in specialised niches that are very different to cell culture plastic. We showed that topography could be used to recreate effects of the niche on mesenchymal stem cell growth. We also investigated the role of mechanotransduction in this process. |
Exploitation Route | Design of new implants. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | We have patented our findings on nanotopographies for prolonged stem cell growth and have now distributed the surfaces to a number of UK and international research groups for further testing. We have also developed our topographies into array format to aid research through high-throughput screening. We have also developed a novel metabolomics / topography approach to investigate identification of bioactive metabolites. |
First Year Of Impact | 2012 |
Sector | Healthcare,Manufacturing, including Industrial Biotechology |
Description | Glasgow Orthopaedic Research Initiative |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | Healickick (EU grant) translational day |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Preparing surgeons for the technologies and getting advice how to best present the technologies in product form |
Description | 'EPSRC and SFI Centre for Doctoral Training in Engineered Tissues for Discovery, Industry and Medicine |
Amount | £7,013,578 (GBP) |
Funding ID | EP/S02347X/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2019 |
End | 12/2027 |
Description | EcMagine': Extracellular Matrix ageing across the life course interdisciplinary research network |
Amount | £176,275 (GBP) |
Funding ID | BB/W018314/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2022 |
End | 02/2024 |
Description | Engineering growth factor microenvironments - a new therapeutic paradigm for regenerative medicine |
Amount | £3,661,144 (GBP) |
Funding ID | EP/P001114/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2016 |
End | 09/2021 |
Title | Temporal transcriptional pattern in human bone merrow derived mesenchymal stem cell differentiation |
Description | Identification of transcription factors and bone marker genes expression pattern through MSCs osteogenic differentiation. |
Type Of Material | Model of mechanisms or symptoms - in vitro |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | This transcriptional pattern has been adopted by other research projects on which MSCs osteogenic differentiation is stimulated by physical cues. |
Description | COllaboration with Atelerix |
Organisation | Atelerix |
Country | United Kingdom |
Sector | Private |
PI Contribution | Thi sis a joint PhD project in which we are designing in vitro stem cell niches |
Collaborator Contribution | Provision and tailoring of hydrogel materials |
Impact | Early collaboration |
Start Year | 2021 |
Description | Collaboration with BiogelX |
Organisation | Biogelx |
Country | United Kingdom |
Sector | Private |
PI Contribution | We bring cell culture expertise |
Collaborator Contribution | They bring materials expertise |
Impact | We are working on enhancing their hydrogels |
Start Year | 2018 |
Description | Collaboration with Bone Cancer Research Trust |
Organisation | Bone Cancer Research Trust |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | We are developing models of sarcoma that are useful for bone cancer research |
Collaborator Contribution | They are supporting us with training placements, access to patients and advice. |
Impact | Development of better tissue models and enhanced training. |
Start Year | 2020 |
Description | Collaboration with Max Planck Institute of Colloids and Interfaces |
Organisation | Max Planck Society |
Department | Max Planck Institute of Colloids and Interfaces |
Country | Germany |
Sector | Charity/Non Profit |
PI Contribution | We are providing cells and materials |
Collaborator Contribution | They are testing our cells and materials |
Impact | Development of novel cell therapies and biomaterials for bone regeneration |
Start Year | 2020 |
Description | Collaboration with University of Navarra |
Organisation | University of Navarra |
Country | Spain |
Sector | Academic/University |
PI Contribution | Provision of cells and materials |
Collaborator Contribution | testing of cells and materials |
Impact | Developing bone technologies together |
Start Year | 2020 |
Description | Souhtampton Collaboration |
Organisation | University of Southampton |
Department | Bone and Joint Research Group |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is a long term collaboration where cells, materials and expertise are shared to drive research |
Collaborator Contribution | This is a long term collaboration where cells, materials and expertise are shared to drive research |
Impact | A large number of papers, grants and IP. |
Title | RETENTION OF A STEM CELL PHENOTYPE |
Description | We discovered a nanotopography that allows prolonged stem cell growth |
IP Reference | US20110306134 |
Protection | Patent granted |
Year Protection Granted | 2010 |
Licensed | No |
Impact | We have a recent option in place with Porvair Scientific that we hope will lead to full license. |
Description | BORS |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | We organised the British Orthopedic Society annual conference in Glasgow. The conference sparked discussion after every talk and new collaborations were initiated between research and clinical groups. |
Year(s) Of Engagement Activity | 2016 |
Description | BRIC Conference (Sheffield, Hexham, Cardiff, Glasgow, Manchester) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Bi-annual conferences with funders (BRIC)/industry members and academics to update on research activities. |
Year(s) Of Engagement Activity | 2014,2015,2016 |
Description | Cell block science |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | Presented at prisoner outreach day at HMP Shotts |
Year(s) Of Engagement Activity | 2019 |
Description | Centre for Doctoral Training Retreat |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Retreat to The Burn for formal PGR student training in entrepreneurship |
Year(s) Of Engagement Activity | 2021 |
Description | Conference organisation CCE-GLORI 2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | The local CCE-GLORI workshop is organised by Dr Monica P. Tsimbouri every year. It is a workshop where postgraduate students present their work to their peers and supervisors and discussion then follows the talks. This is highly beneficial to students and promotes collaboration. |
Year(s) Of Engagement Activity | 2019 |
Description | Conference organisation-GLORI2020 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Dr Monica P. Tsimbouri organises GLORI bi-annually. This conference encourages collaboration between the basic sciences, applied sciences, engineering and clinic. This has the aim of bringing the latest ideas in basic materials research into use to deliver the next-generation of orthopaedic care. It combines expertise from orthopaedic surgeons, plastic surgeons, biologists, engineers and chemists. The conference is free for attendance and involves oral and poster presentations from professionals, scientists, clinicians and postgraduate students. It is always well attended. It is sponsored by industry who are also involved in the conference. |
Year(s) Of Engagement Activity | 2020 |
Description | DTC |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Dr MP Tsimbouri. Talk sparked questions and discussion The DTC students were interested in doing a project on the subject covered |
Year(s) Of Engagement Activity | 2010,2011,2012,2013 |
Description | European Society for Biomaterials Keynote (Dalby) Talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Keynote conference talk |
Year(s) Of Engagement Activity | 2021 |
Description | GLORI conference organisation |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Planning and Organisation of Dr Monica P Tsimbouri the scientific mentor of the Glasgow Orthopaedic Research Initiative (GLORI). GLORI has been established to encourage collaboration between the basic sciences, applied sciences, engineering and clinic. This has the aim of bringing the latest ideas in basic materials research into use to deliver the next-generation of orthopaedic care. It combines expertise from orthopaedic surgeons, biologists, engineers and chemists not only from Glasgow and Strathclyde Universities but the rest of Scotland too and also with the view to expand to the rest of the UK. |
Year(s) Of Engagement Activity | 2018 |
Description | Healickick (EU grant) translation day |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Discussion between academics and surgeons around technologies we have developed. |
Year(s) Of Engagement Activity | 2021 |
Description | Invited talk at British Orthopaedic Research Society |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Discussed research training of junior surgeons |
Year(s) Of Engagement Activity | 2021 |
Description | Keynote talk (Dalby) at Tissue Engineerign and Regenerative medicien International Society |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Keynote talk at a major conference |
Year(s) Of Engagement Activity | 2021 |
Description | Media interest BBC (nanokicking) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Talk sparked public interest Many interested enquirers. |
Year(s) Of Engagement Activity | 2012 |
Description | Media interest BBC (orthopaedic materials) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Sparked public interest Enquieries from the public |
Year(s) Of Engagement Activity | 2013 |
Description | Media interest BBC (stem cell growth) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Talk sparked public interest Enquieries from the public |
Year(s) Of Engagement Activity | 2011 |
Description | Nanotoxicology Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk for the Naotoxicology Society |
Year(s) Of Engagement Activity | 2016 |
Description | Oral presentation-GLORI2020 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Ms Laila Damiati delivered an oral presentation with the title: "Biofunctional and Antibacterial Titanium Nanotopography for Orthopaedic Implants". |
Year(s) Of Engagement Activity | 2020 |
URL | https://glasgow.thecemi.org/2020/03/13/glori-2020-symposium/ |
Description | Royal Society of Chemistry Biomaterials Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Conference presentation |
Year(s) Of Engagement Activity | 2017 |
Description | Scottish Metabolomics Network |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | Invited talk |
Year(s) Of Engagement Activity | 2016 |
Description | TCES 2010 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | paper presentation |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Dr Monica P Tsimbouri. exiting discussion after talk Interested parties continued discussion |
Year(s) Of Engagement Activity | 2010 |
Description | TCES 2012 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | paper presentation |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Dr P Tsimbouri. talk sparked questions and discussion afterwards Engagement with company Reps and received very good discount on equipment. |
Year(s) Of Engagement Activity | 2012 |
Description | TCES 2014 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Scientific report |
Year(s) Of Engagement Activity | 2014 |
Description | TERMIS EU 2011 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | paper presentation |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Dr Monica P Tsimbouri. Talk sparked questions and discussion afterwards There was further discussion during a later session about my talk |
Year(s) Of Engagement Activity | 2011 |
Description | Talk in Portugal |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited talk for Dalby at University of Aviero |
Year(s) Of Engagement Activity | 2022 |
Description | UKSB |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Type Of Presentation | paper presentation |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Dr M. P. Tsimbouri. Interesting discussion following presentation Discussion lead to problem solving for a fellow scientist |
Year(s) Of Engagement Activity | 2010 |
Description | Yorkhill Research Day 2014 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Questions and discussion followed presentation. Poster award obtained. |
Year(s) Of Engagement Activity | 2014 |
Description | school workshop: Bones and bone cells, 2017 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Dr P.M. Tsimbouri has organised a full day workshop for P5,P6 and P7 school pupils at the Milngavie primary school. The workshop involves presentation slides and Q/A session with the children about the skeleton, bones and bone cells. This followed by hands on experience looking at fixed cells using bright field microscopes. The children were given colour-in pages and also word searches to take home. |
Year(s) Of Engagement Activity | 2015,2017 |