Molecular Genetics of Stem Cells

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The daily production of billions of blood cells is essential in maintaining the integrity of the human hematopoietic system. This impressive production originates from a minute proportion of hematopoietic stem cells (HSCs). A disruption of the production mechanism of these cells is responsible for a large variety of human illnesses and clinical problems. For example, uncontrolled growth of bone marrow stem cells causes leukemia; our current inability to stimulate their renewal is a serious impediment to successful human bone marrow transplants.

The origin of adult HSCs can be traced through at least three developmental programs: specification, expansion and maintenance. Whereas stem cell division during expansion is symmetrical, giving rise to two identical daughter cells, a hallmark feature of all HSCs is their regenerative potential through asymmetrical self-renewal divisions, giving rise to one stem cell and one committed progenitor cell. Indeed, maintenance of adult stem cells in the bone marrow is crucial to ensure a steady supply of blood cell precursors for the lifetime of an animal. Moreover, the ability to self-renew is fundamental for the application of HSC-based therapies to a wide range of both malignant and genetic disorders.

Over the last fifteen years, Dr. Sauvageau’s work has led to ground-breaking discoveries in understanding the production of hematopoietic stem cells. With his research team, he identified the potential of the HOXB4 and Bmi1 genes which are instrumental in regulating the self-renewal of these cells. His research unit uses approaches in functional screening to identify genetic networks implicated in this process.

Dr. Sauvageau’s teams has also developed the use of recombinant proteins allowing for the expansion of the hematopoietic stem cells. Clinical phase I of this work will soon begin, with umbilical cord blood as a source of essential stem cells for patients requiring a transplant when there is no compatible donor. These discoveries are a significant advance in the field of blood stem cell transplantation.

Our team’s research focuses on the nature of HSCs and the molecular signals that regulate their proliferation, survival and differentiation. Our experimental approach involves a combination of animal models and tissue culture systems to study the effects of specific molecular determinants of both normal and leukemia stem cells, in vivo and in vitro. We are also interested in the development of tools to achieve a significant expansion of HSC numbers ex vivo to increase the therapeutic potential of these cells.

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