Understanding the physical biology of adult blood stem cells

Project Information

PHYSBIOHSC

Grant agreement ID: 715371

DOI

10.3030/715371

Project closed

EC signature date 9 March 2017

Start date 1 May 2017

End date 31 October 2022

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 500 000,00

EU contribution

€ 1 500 000,00

Coordinated by

UNIVERSITY OF YORK
United Kingdom

Periodic Reporting for period 4 - PHYSBIOHSC (Understanding the physical biology of adult blood stem cells)

Reporting period: 2021-03-01 to 2022-10-31

Summary of the context and overall objectives of the project

The PHYSBIOHSC project is focused on understanding blood stem cell biology through a more quantitative lens. The vast majority of efforts have focused on understanding the molecular regulators of blood stem cells in isolation with virtually no consideration for the cell types they interact with or physical/chemical stresses the cells may be under. Evidence from stem cells in other tissues has demonstrated that physical forces alone can influence cellular decision-making and this project aims to ask these types of questions in blood stem cells for the first time. There are already major efforts underway in biological and chemical engineering to produce vast quantities of cells for therapeutic purposes (e.g. bioreactor cultures, etc). However, these efforts are being undertaken with virtually no information about the most fundamental biophysical properties of the stem cell populations that are targeted for expansion. Questions as straightforward as “What happens to a blood stem cell when it is squished through a tiny space?” are fundamental to informing such scale-up efforts, yet there is extremely little research undertaken in the biomechanics of highly purified stem cell populations. Our project explores these questions.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The first research aim was to track the clonal dynamics of different stem cells throughout ageing and this resulted in a research paper published in Nature in 2018 describing a novel method for tracking stem cell clones in people which was followed up by another senior author Nature paper in 2022. This was a collaboration that was initiated after the project had started, but supplanted Aim 1s original methods as a more superior tool to answer the same question. The second and third research aims are focused on developing and using new technologies to explore the physical properties of blood stem cells (e.g. biomechanics) in an effort to better improve our ability to expand blood stem cells outside the body for gene therapy and cell therapy applications in the future. Thus far, we have focused these efforts on technology development and have seen good progress with two new microfluidic devices which allow us to better explore the mechanical properties of blood stem cells. One of these has now been taken forward for commercialisation development.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Overall, the project has proceeded well with the first major publication out in 2018 and a large number of technological advancements that position us well for future publications and potential commercial application. We have a fully functioning microfluidics fabrication setup and have both experts and non-experts using this equipment (i.e. biologists have been trained to undertake some of the fabrication steps). In September 2019, our lab relocated from the University of Cambridge to the University of York and all things considered, this has been a relatively smooth transition which has not resulted in lost time or lost personnel. Some activity remained at the university of Cambridge (including Ms Belmonte’s research assistant post) under a third party agreement. We have extended Dr Rubio-Lara’s position as the work in 3D matrices is showing great promise for culturing and manipulating blood stem cells outside the body. Dr. Rezk has driven the microfluidics portion of the project and is now attempting to spin out a company based on its design.

New method of clonal tracking of blood stem cells (Nature 2018)