Understanding the Maintenance and Heritability of Hematopoietic Stem Cell Memories: High-Throughput Drug Screening Meets Single-Cell Barcoding

Project Information

EpiHTStem

Grant agreement ID: 101109276

DOI

10.3030/101109276

Project closed

EC signature date 13 March 2023

Start date 1 April 2023

End date 31 March 2025

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 165 312,96

Coordinated by

FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Spain

Periodic Reporting for period 1 - EpiHTStem (Understanding the Maintenance and Heritability of Hematopoietic Stem Cell Memories: High-Throughput Drug Screening Meets Single-Cell Barcoding)

Reporting period: 2023-04-01 to 2025-03-31

Summary of the context and overall objectives of the project

Hematopoietic stem cells (HSCs), are a group of cells living in the bone marrow that have the capacity to generate all of the immune cells present in our blood. As we age, HSCs are exposed to different changes in their environment (like infections) that have the capacity to alter their function. Particularly, as we age, HSCs start to lose the capacity to generate blood. These alterations in the capacity to generate blood of HSCs have been associated with increased chances of developing leukemias and to cardiovascular diseases and, until now, there are not treatments to improve and rejuvenate the activity of HSCs. Our objective with this project is to create a novel scientific platform that could allow us to screen for compounds (hundreds of them at the same time) that could "heal" this HSCs and give them again the capacity to produce blood, in the same way that they could do when they were younger, for example.

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

In this project, we have been able to generate a novel platform to screen for compounds that, upon an acute exposure, can alter (in the long term) the capacity of cells to respond to specific stimuli. For example, in the case of Hematopoietic Stem Cells, their capacity to generate blood upon an infection. We have named this new tool RABseq (Random Arrayed Barcoding Sequencing). Using RABseq, we have found 6 novel compounds with the capacity to rejuvenate HSCs. Specifically, these compounds seem to boost the potential to generate blood of aged HSCs, making them more similar to young HSCs.

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)

After successfully applying RABseq and finding novel compounds to improve the function of HSCs, our next steps will be focused in trying to validate the hits from our screening and to assess their viability to be used as therapy to rejuvenate HSCs. In order to ensure further uptake of this method, new research with the aim to improve its throughput (to increase the number of compounds that we can analyze per experiment) as well its cost (right now these are very expensive experiments to run for thousands of compounds) will be key. We believe that a low-cost and very high-throughput RABseq could be very relevant in order to find compounds with a very wide variety of applications (improvement of chemotherapy treatments, reduced rejection upon transplants, better engraftment of bone marrow transplants, etc).