Abstract

Modelling Human Gastrulation: A Platform for Directing Pluripotent Stem Cell Differentiation to Clinically Relevant Cells

Roger Pedersen, Professor, University of Cambridge

Human pluripotent stem cells (hPSCs) offer exciting possibilities for treatments of currently intractable diseases and provide models for human development and drug discovery. Achieving the promise of hPSCs requires robust approaches for generating differentiated cell types that are equivalent to in vivo generated cells. Recent work from our laboratory demonstrates that lineage decisions, made by hPSCs as they are induced to exit pluripotency, establish their developmental trajectory, thereby modeling human gastrulation and defining their potential for differentiation into cell types useful in drug discovery (Mendjan et al., Cell Stem Cell 15: 310-25, 2014). In an alternative approach, we demonstrated that hPSCs can be reprogrammed to the megakaryocyte (MK) lineage using transcription factor-based forward programming (FoP) (Moreau et al., Nat. Commun. 7: 11208, 2016). The functional similarity of platelets generated from FoP-MKs to blood-derived platelets affirms their utility for research and therapeutic applications. Finally, it is important for both basic research and translational goals to assess the functional capacity of hPSCs for normal organized tissue development in an embryonic context. We achieved this objective by establishing an interspecies post-implantation chimera assay in which stage-matching of hPSCs by transplant to gastrulating mouse embryos enabled efficient interspecies chimera formation, with widespread cell dispersal and region-specific differentiation (Mascetti and Pedersen, Cell Stem Cell 18: 67-72, 2016; Mascetti and Pedersen, Cell Stem Cell 19: 163-175, 2016). This work provides in vivo functional validation for pluripotency of hPSCs and endorses their utility as a bona fide resource for regenerative medicine.