Single-cell OMICS-informed in vitro models of human development
| Title | Single-cell OMICS-informed in vitro models of human development |
|---|---|
| Acronym | CatchTheWave |
| Start date | 2026-06-01 |
| End date | 2031-05-31 |
| Sponsor | European Research Council - Starting Grant (ERC-StG) |
| Institution | The Sahlgrenska Academy at University of Gothenburg |
Associated cell lines
Project Description
From immunotherapy to restoring neural function in Parkinson’s disease, cell-based therapies are shaping medicine. Human pluripotent stem cells (hPSCs) could be an invaluable resource, given their unlimited in vitro self-renewal and ability to differentiate into any cell-type. However, in vitro hPSC-derived cells show defective performance in transplantation assays. Using the long-sought in vitro production of hematopoietic stem cells (HSCs) as a model, I propose a strategy to assess and rectify the accuracy of hPSC differentiation protocols in recapitulating embryonic cell fate decision processes: AIM1 Establish an analysis workflow to systematically compare hPSC-derived developmental trajectories with in vivo mammalian embryonic development, using time-resolved single-cell RNA sequencing (scRNAseq) data. I will benchmark an hPSC differentiation dataset featuring emergence of an HSC signature against a range of published developmental datasets, including both human fetal samples and animal models. AIM2 Probe intrinsic variability of embryoid body (EB)-based hPSC differentiation by integrating cell-type composition (by scRNAseq), time-lapse secretome and morphology of 24 individual EBs. I will thus identify cell-types and secreted factors enriched in the rare EBs comprising an HSC signature. AIM3 Determine the functional relevance of genes identified as in vitro de-regulated (Aim 1) and/or associated with HSC signature emergence in vitro (Aim 2) using a targeted genetic screen in hPSC differentiation followed by robust transplantation in immunodeficient mice. AIM4 Define the cell autonomous role of genes with confirmed functional relevance for production of HSCs from hPSC (Aim 3) by multiomic profiling of mosaic EBs. By leveraging the rise in single-cell developmental Atlases, I will obtain robust generation of hPSC-derived HSCs through innovative declinations of EB-based hPSC differentiation, establishing a new paradigm towards clinical translation of hPSCs.