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.
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.
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 research.
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.
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 research.
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
Oosthuyzen W
(2016)
Vasopressin Regulates Extracellular Vesicle Uptake by Kidney Collecting Duct Cells.
in Journal of the American Society of Nephrology : JASN
Batsivari A
(2017)
Understanding Hematopoietic Stem Cell Development through Functional Correlation of Their Proliferative Status with the Intra-aortic Cluster Architecture.
in Stem cell reports
Campana L
(2018)
The STAT3-IL-10-IL-6 Pathway Is a Novel Regulator of Macrophage Efferocytosis and Phenotypic Conversion in Sterile Liver Injury.
in Journal of immunology (Baltimore, Md. : 1950)
Hindle P
(2017)
The Infrapatellar Fat Pad as a Source of Perivascular Stem Cells with Increased Chondrogenic Potential for Regenerative Medicine.
in Stem cells translational medicine
Reid James
(2023)
The effects of morphology and composition in electrospun scaffold for vascular tissue engineering applications
in TISSUE ENGINEERING PART A
Burton TP
(2017)
The effect of electrospun polycaprolactone scaffold morphology on human kidney epithelial cells.
in Biomedical materials (Bristol, England)
Bird TG
(2018)
TGFß inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.
in Science translational medicine
Gogolok S
(2016)
STAR: a simple TAL effector assembly reaction using isothermal assembly.
in Scientific reports
Axton RA
(2017)
SplitAx: A novel method to assess the function of engineered nucleases.
in PloS one
Barreiro-Iglesias A
(2015)
Serotonin Promotes Development and Regeneration of Spinal Motor Neurons in Zebrafish.
in Cell reports
Bate TSR
(2021)
Response differences of HepG2 and Primary Mouse Hepatocytes to morphological changes in electrospun PCL scaffolds.
in Scientific reports
Chantzoura E
(2015)
Reprogramming Roadblocks Are System Dependent.
in Stem cell reports
Bredenkamp N
(2014)
Regeneration of the aged thymus by a single transcription factor.
in Development (Cambridge, England)
Ember KJI
(2017)
Raman spectroscopy and regenerative medicine: a review.
in NPJ Regenerative medicine
Duffin R
(2016)
Prostaglandin E 2 constrains systemic inflammation through an innate lymphoid cell-IL-22 axis
in Science
Meseguer-Ripolles J
(2017)
Pluripotent Stem Cell-Derived Human Tissue: Platforms to Evaluate Drug Metabolism and Safety.
in The AAPS journal
Ehrlich K
(2017)
pH sensing through a single optical fibre using SERS and CMOS SPAD line arrays.
in Optics express
Hindle P
(2016)
Perivascular Mesenchymal Stem Cells in Sheep: Characterization and Autologous Transplantation in a Model of Articular Cartilage Repair.
in Stem cells and development
Ferreira-Gonzalez S
(2018)
Paracrine cellular senescence exacerbates biliary injury and impairs regeneration.
in Nature communications
Lucendo-Villarin B
(2017)
Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells.
in Archives of toxicology
Barrett NA
(2016)
Mll-AF4 Confers Enhanced Self-Renewal and Lymphoid Potential during a Restricted Window in Development.
in Cell reports
Dunphy S
(2018)
Mechanical characterisation of directionally frozen polycaprolactone scaffolds using 1,4-dioxane and glacial acetic acid for articular cartilage tissue engineering
in Biomedical Physics & Engineering Express
Greenhalgh SN
(2019)
Loss of Integrin avß8 in Murine Hepatocytes Accelerates Liver Regeneration.
in The American journal of pathology
Péault B
(2016)
Isolation of Perivascular Multipotent Precursor Cell Populations from Human Cardiac Tissue
in Journal of Visualized Experiments
Economou C
(2015)
Intrinsic factors and the embryonic environment influence the formation of extragonadal teratomas during gestation.
in BMC developmental biology
Haideri SS
(2017)
Injection of embryonic stem cell derived macrophages ameliorates fibrosis in a murine model of liver injury.
in NPJ Regenerative medicine
Gao Y
(2021)
Influence of surface topography on PCL electrospun scaffolds for liver tissue engineering.
in Journal of materials chemistry. B
Souilhol C
(2016)
Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells.
in Nature communications
Ulyanchenko S
(2016)
Identification of a Bipotent Epithelial Progenitor Population in the Adult Thymus.
in Cell reports
Reid JA
(2020)
Hybrid cardiovascular sourced extracellular matrix scaffolds as possible platforms for vascular tissue engineering.
in Journal of biomedical materials research. Part B, Applied biomaterials
Vukovic M
(2015)
Hif-1a and Hif-2a synergize to suppress AML development but are dispensable for disease maintenance.
in The Journal of experimental medicine
Lu WY
(2015)
Hepatic progenitor cells of biliary origin with liver repopulation capacity.
in Nature cell biology
Guitart AV
(2017)
Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.
in The Journal of experimental medicine
Grant R
(2018)
From scaffold to structure: the synthetic production of cell derived extracellular matrix for liver tissue engineering
in Biomedical Physics & Engineering Express
O'Neill KE
(2016)
Foxn1 Is Dynamically Regulated in Thymic Epithelial Cells during Embryogenesis and at the Onset of Thymic Involution.
in PloS one
Alwahsh SM
(2021)
Fibroblast growth factor 7 releasing particles enhance islet engraftment and improve metabolic control following islet transplantation in mice with diabetes.
in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Lucendo-Villarin B
(2017)
Erratum to: Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells.
in Archives of toxicology
Jackson M
(2016)
Enforced Expression of HOXB4 in Human Embryonic Stem Cells Enhances the Production of Hematopoietic Progenitors but Has No Effect on the Maturation of Red Blood Cells.
in Stem cells translational medicine
Choudhury D
(2017)
Endoscopic sensing of alveolar pH.
in Biomedical optics express
Baskapan B
(2022)
Electrospinning Fabrication Methods to Incorporate Laminin in Polycaprolactone for Kidney Tissue Engineering.
in Tissue engineering and regenerative medicine
Bressan RB
(2017)
Efficient CRISPR/Cas9-assisted gene targeting enables rapid and precise genetic manipulation of mammalian neural stem cells.
in Development (Cambridge, England)
Handley EL
(2023)
Effects of electrospun fibers containing ascorbic acid on oxidative stress reduction for cardiac tissue engineering.
in Journal of applied polymer science
Drissen R
(2016)
Distinct myeloid progenitor-differentiation pathways identified through single-cell RNA sequencing.
in Nature immunology
Wang Y
(2017)
Defined and Scalable Generation of Hepatocyte-like Cells from Human Pluripotent Stem Cells.
in Journal of visualized experiments : JoVE
Bate TSR
(2020)
Controlling Electrospun Polymer Morphology for Tissue Engineering Demonstrated Using hepG2 Cell Line.
in Journal of visualized experiments : JoVE
Ruetz T
(2017)
Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming.
in Cell stem cell
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 |
Description | Cytochroma develops drug discovery technology. |
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 | https://cytochroma.org/ |
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 |