Figure 1: Time-lapse microscopy analysis of endothelial to hematopoietic transition in vitro.

Figure 1: Time-lapse microscopy analysis of haemangioblast differentiation. The formation of a blast colony from the haemangioblast can be retrospectively divided in two consecutive phases: a generation of a structure of tightly associated endothelial cells and the production of round non adherent cells expressing the haematopoietic marker CD41.

 

Figure 2: Model of the functional requirements for GFI1/GFI1b and RUNX1 during EHT.

Figure 2: Model of the functional requirements for GFI1/GFI1b and RUNX1 during EHT. RUNX1 is required for both the change in morphology and acquisition of hematopoietic competence (cells turning red). GFI1/GFI1B are essential for the change in morphology and additional unknown transcriptional targets of RUNX1 are required for acquisition of hematopoietic competence.

The Lancrin group studies the hematopoietic system and looks to develop strategies to improve methods for generating blood cells from pluripotent stem cells.

Previous and current research

In adulthood, the continuous generation of blood cells relies on the existence of hematopoietic stem cells (HSC), which have the ability to self-renew and generate all blood cell types. Any pathology affecting these cells could lead to the development of serious diseases such as leukemia and anemia.

HSC are formed during embryonic life from endothelial cells, building blocks of the vascular system, which is responsible for blood circulation in the body. This process is called endothelial to hematopoietic transition (EHT). The EHT is dependent on the activity of the transcription factor RUNX1, a master regulator of blood development.

Using the model of embryonic hematopoiesis based on embryonic stem cells (ESC) differentiation, we could model the EHT (Figure 1) and study the role of RUNX1. We demonstrated that as in the embryo, it could trigger the EHT process but we also discovered that RUNX1 induced the expression of two other transcription factors called GFI1 and GFI1B whose function was to shutdown the expression of endothelial genes and complete the formation of blood cells from the endothelium (Figure 2). Our work revealed the dual function of RUNX1: the shutdown of the endothelial cell fate and the activation of the hematopoietic one.

Future projects and goals

The generation of the ESC-like induced pluripotent stem cells (iPSC) from fully differentiated cell types, such as skin fibroblast, provided a major breakthrough in the field of regenerative medicine. However, important work has to be done to differentiate efficiently iPSC or ESC toward specific cell types including blood cell progenitors such as HSC.

Consequently, the focus of our research is to unravel the mechanisms underlying the formation of HSC from endothelial cells. Combining single cell transcriptomics, computational biology, time-lapse microscopy, and loss and gain of function experiments in vitro and in vivo, we plan to identify signaling pathways and transcriptional regulators involved in the generation of hematopoietic stem and progenitor cells during embryonic life. Our research will help the development of new strategies to improve methods of blood cell generation from ESC or iPSC for regenerative medicine.