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: New model of blood cell origin: The haemangioblast and the haemogenic endothelium are part of the same developmental pathway to generate blood cell progenitors during embryonic life.
The Lancrin group studies the haematopoietic system and looks to develop strategies to improve methods for generating blood cells from stem cells.
Previous and current research
The continuous generation of blood cells throughout life relies on the existence of haematopoietic stem cells (HSC) generated during embryogenesis. They have the ability to self-renew and to generate all types of blood cells. Any pathology affecting these cells could lead to the development of serious diseases such as leukaemia and anaemia. That is why understanding how HSC and haematopoietic progenitors are produced during embryonic life is so important.
The origin of blood cells has been the subject of an intense scientific debate during the last decade. It has been proposed that during embryonic development, haematopoietic cells arise from a mesodermal progenitor with smooth muscle, endothelial, and haematopoietic potential called the haemangioblast. However, a conflicting theory instead associates the first haematopoietic cells with a phenotypically differentiated endothelial cell with haematopoietic potential (i.e. a haemogenic endothelium).
To investigate the cellular origin of blood cells, we used a model of early haematopoiesis based on the differentiation potential of the mouse embryonic stem cells (ESC) in vitro. These cells are derived from the inner cell mass of the blastocyst – an early-stage mouse embryo – and have the capacity to generate any cell types. Using this system coupled with time-lapse microscopy, clonogenic assays and flow cytometry analysis, we have demonstrated that the haemangioblast generates haematopoietic progenitors through the formation of a haemogenic endothelium stage, providing the first direct link between these two precursor populations. Together our results merge the two a priori conflicting theories on the origin of haematopoietic development into a single linear developmental process. This finding allowed us to identify the haemogenic endothelium as the immediate precursor of blood cells (figures 1 and 2).
Future projects and goals
Recently, 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. Indeed iPSC offer a great opportunity to implement replacement therapy by bypassing the use of human embryos to generate ESC, therefore decreasing ethical concerns. 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, in order to better understand the development of the haematopoietic system, the focus of our research is to unravel the mechanisms underlying the generation of haemogenic endothelium from its precursor, the haemangioblast, and its subsequent commitment to haematopoiesis. Combining genomics, time-lapse microscopy, and loss and gain of function experiments in vitro and in vivo, we plan to identify and study the genes responsible for the generation of the first blood progenitors during embryonic life. Our research will bring a further understanding of the mechanisms of cell fate decisions leading to the production of the first haematopoietic cells and enable the development of new strategies to improve methods of blood cell generation from ESC or iPSC for regenerative medicine.