The Computational and Chemical Biology of the Stem Cell Niche

Lead Research Organisation: University of Edinburgh
Department Name: MRC Centre for Regenerative Medicine

Abstract

Stem cells in tissue exist within a specialist environment termed the "niche".
The niche ("the soil") that surrounds stem/progenitor cells ("the seed") in developing or damaged organs has a profound effect upon the behavior of the stem cells.
The focus of this application is to bring together stem cell researchers together with chemists to synthesize artificial niches that will enable stem cell to: (1) grow in a more efficient and controlled manner (2) be differentiated into functioning cells that could be used to repair damaged tissue. This project will produce large amounts of data and so to efficiently capture and analyse all this data we will collaborate actively with experts in the handling and analysis of such large amounts of data - bioinformaticians.
This facility will be available to all stem cell and regenerative medicine researchers throughout the UK at minimal cost to help the UK regenerative medicine community as a whole to rapidly develop new stem cell based and regenerative therapies for patients. We envisage the creation of implantable artificial niches that will control and guide the development of replacement issues from stem cells.

Technical Summary

UKRMP Centre for The Computational and Chemical Biology of the Niche (CCBN)
The resource requested is the use of MRC funds to i) immediately fit out of existing "shelled" space to create a dry-lab Computational and Chemical Biology Centre for stem cell niche analysis within the Systems Medicine building at the Institute of Genetics and Molecular Medicine (IGMM) and ii) purchase the equipment required to upgrade our existing facilities for next-generation Chemistry, together with the construction using matched University funds of iii) a dedicated wet-lab facility for niche Chemistry as an extension of the SCRM building that houses the MRC-CRM and the newly created UKRMP Hub for engineering and exploiting the stem cell niche.
These facilities will function as a "research hotel" for the UK stem cell and regenerative medicine community. Visiting researchers will occupy dry-computational and/or wet lab space for a period of time, with minimal barriers, to develop their particular cell/niche activity, thereby maximising the national strategic value of the investment and accelerating the translation of regenerative medicines.

Planned Impact

Regenerating damaged tissues and restoring their function is one of the major goals of biomedicine. Diseases that cause tissue degeneration and injury present a huge and ever-increasing clinical burden, in the UK costing the NHS well over £1 bn/year, with musculoskeletal disease alone accounting for 8.8 million UK working days lost/annum.

The Centre for Computational and Chemical Biology of the Niche will bring together experts I stem cell biology/regenerative medicine with chemists and bioinformaticians and thereby expedite stem/progenitor cell discoveries and translate these finding to the clinic. We will achieve this by determining how local tissue niche composition directs stem cell phenotype, growth and differentiation. By creating niche-based biomaterial platforms for tissue-specific engraftment and regulation of cell phenotype we will be able to develop regenerative artificial niches for patients with hitherto untreatable diseases.

We will utilise high throughput, high content and phenotype screens to fast track achievement of these key goals. The bringing together of these 3 separate disciplines has the potential to boost regenerative medicine research worldwide. By promoting this facility as a "research hotel" for the UK wide stem cell and regenerative medicine community we will maximise the impact of this capital investment. By drawing upon internationally recognised strengths in extracellular signals in the niche direct cell behavior and phenotype and their ability to repair tissues, allowing us to address directly the well-recognised need to understand and exploit the cellular microenvironment to drive effective tissue regeneration.
To engage with UK and international bio-medical communities, we will use the data sharing, networking and, teleconferences and workshops of the existing UKRMP hubs. By having meetings open to hub members, national (UKRMP hub) and international colleagues, this will strengthen the UK standing in international stem cell rsearch.

We will participate at a high level in major national and international conferences where we will report our scientific discoveries and translational advances; disseminate our data in high-impact scientific journals, thus contributing prominently to the development of a world-leading UK 'brand' in tissue regeneration and repair.

The Centre for Computational and Chemical Biology of the Niche will be of interest to industry, e.g. in the development of niche-based products and tools such as stem cell selection systems, marker arrays, lineage pathway inducers, natural epitope-derived bio-materials and extra-cellular matrix products. Our University has a strong records of exploiting innovative research findings through commercialisation of intellectual property (now through Edinburgh BioQuarter). Outputs for exploitation may include licensing of cellular and extra-cellular matrix reagents/biologics and protocols, in-house assays/technologies, co-development of technologies licensing of IP, consultancies.

Publications

10 25 50

 
Title Drug toxicity screening assay 
Description Tools for drug toxicity screening based on stem cell derived hepatocytes 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Industrial collaboration with Astra Zeneca 
 
Title High throughput semi-automated stem cell derived hepatocyte differentiation protocol 
Description High throughput semi-automated stem cell derived hepatocyte differentiation protocol 
Type Of Material Improvements to research infrastructure 
Year Produced 2017 
Provided To Others? No  
Impact High throughput semi-automated stem cell derived hepatocyte differentiation protocol 
 
Title High throughput, high content imaging platform to evaluate "hepatocyteness" of cells 
Description High throughput, high content imaging platform to evaluate "hepatocyteness" of cells 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? Yes  
Impact High throughput, high content imaging platform to evaluate "hepatocyteness" of cells 
 
Title Screening strategies for endogenous liver regeneration 
Description Screening strategies for endogenous liver regeneration 
Type Of Material Technology assay or reagent 
Year Produced 2016 
Provided To Others? No  
Impact Screening strategies for endogenous liver regeneration 
 
Description AstraZeneca and Dave Hay Collaboration: Toxicity Testing 
Organisation AstraZeneca
Department Toxicology Sciences
Country United Kingdom 
Sector Private 
PI Contribution Provided screening platform/technology that had been developed during UKRMP funded research.
Collaborator Contribution AZ provided a library of compounds for testing as well as AZ generated data for comparative purposes
Impact Plans for joint publication of results. Screening platform currently being investigated a spin out opportunity. PDRA has been awarded an RSE Fellowship to pursue this opportunity.
Start Year 2016
 
Description Collaboration between UoE and NPSC 
Organisation National Phenotypic Screening Centre
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Use of Operetta to develop assay to be translated into NPSC. UoE academic Dr Steve Pollard.
Collaborator Contribution Use of Operetta to develop assay to be translated into NPSC. UoE academic Dr Steve Pollard.
Impact Translation of assay into HTS. Translational outcomes e.g. drug screening.
Start Year 2016
 
Company Name CYTOCHROMA LIMITED 
Description Cytochroma's high throughput, automated screening platform delivers accurate toxicity information. From cell culture, to compound addition, all the way to data analysis and delivery. The Cytochroma assay is more sensitive than current cell health based assays and delivers significantly more information. It is fully customisable, at each step delivering all the data needed. 
Year Established 2017 
Impact Dr Kate Cameron is fully funded by the BBSRC (Biotechnology and Biological Sciences Research Council) as one of the high prestigious Royal Society of Edinburgh Enterprise Fellowships. In the past few months she was awarded the highest amount possible, and special Higgs prize by Scottish EDGE in June. She came second in UoE annual competition Inspire Launch Grow awards and more recently, in September she placed in the top 2.5% of entrants, in the Converge Challenge. Funding and support from UoE, RSE + BBSRC has supported the lease of laboratory and office facilities at Roslin Innovation Centre, where she is currently based.
Website http://www.cytochroma.uk/
 
Description CCBN Promotional Symposium 
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 Half day workshop/symposium held at UKRMP Niche Hub F2F meeting but opened up to external participants. Talks from academics using CCBN instrumentation.
Year(s) Of Engagement Activity 2015
 
Description Industry Engagement Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact A half day workshop highlighting engagement opportunities with UKRMP and MRC CRM researchers.
Year(s) Of Engagement Activity 2017
 
Description New Collaboration to Accelerate Drug Discovery Using Stem Cell Technology 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact A press release with the University of Dundee National Phenotypic Screening Centre (NPSC)
marking the signing of a Memorandum of Understanding with the Centre "that commits them to work more closely together as they strive to translate novel biological discoveries into new stem cell therapies".
Year(s) Of Engagement Activity 2017
URL http://www.drugdiscoverytoday.com/view/45514/scottish-universities-collaborate-to-accelerate-drug-di...
 
Description Operetta Image and Data Analysis Training 
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 Operetta Image and Data Analysis Training
Year(s) Of Engagement Activity 2016
 
Description Operetta Training 
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 Training session on Operetta
Year(s) Of Engagement Activity 2016
 
Description Press release: Stem cell liver implants show promise 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Press release from CRM resulting in media coverage on websites and in newspapers.
Scottish Daily Mail
https://www.pressreader.com/uk/scottish-daily-mail/20180828/281977493484972
Online
https://www.fiercebiotech.com/research/growing-human-stem-cells-into-functional-3d-liver-tissue
https://www.rdmag.com/article/2018/08/new-liver-tissue-implants-showing-promise
MRC website
https://mrc.ukri.org/news/browse/liver-tissue-implants-show-promising-support-of-liver-function/
Year(s) Of Engagement Activity 2018
URL http://www.crm.ed.ac.uk/news/stem-cell-liver-implants-show-promise
 
Description Raman Spectroscopy Workshop 
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 To explore using Raman Spectroscopy in Regenerative Medicine, the Niche Hub, together with OPTIMA-CDT and the Chemistry and Computational Biology of the Niche research facility (CCBN) held a one day workshop (Edinburgh, 23/02/2016). The day ended with a round table discussion on how to further the translation of Raman into regenerative medicine, which has resulted in an MRC Confidence in Concept award and a discussion paper which will appear in print later this year (npj Regenerative Medicine).
Year(s) Of Engagement Activity 2016
 
Description Regeneration Innovation 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Workshop to encourage and stimulate translation and commercialisation of research from the CRM. Speed networking and an innovation competition were included as acitvities as well as presentations from existing industry collaborations.
Year(s) Of Engagement Activity 2018
 
Description Tour of Facility 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Tour of facility by Head of New Technology from Sanofi-Genzyme
Year(s) Of Engagement Activity 2017