Molecular mechanisms of lineage commitment in the hematopoietic system

Tissue-specific stem cells are responsible for the formation and regeneration of human organs such as the blood, intestine and skin. Stem cells are characterized by a broad developmental potential, as they give rise to all specialized cell types that are essential for an organ to function correctly. In particular, the hematopoietic stem cell is known to generate all mature blood cell types throughout adult life. This stem cell initially differentiates to a progenitor cell, which then has to make a choice between several different pathways and subsequently develops into mature cells of the selected lineage. Until recently, little was known about how these lineage decisions are reached by the stem cell. The long-standing research efforts of Meinrad Busslinger and his team at the IMP (Research Institute of Molecular Pathology, Vienna) have now provided insight into how this decision-making process takes place in the blood stem cell. The B-cells of the blood take care of immune protection by producing antibodies that eliminate foreign antigens. The generation of B-cells from blood stem cells requires the expression of specific genes from the genome. Transcription factors are known to govern the process by which the information of genes is made available within a cell. A transcription factor by the name of Pax5 proved to be responsible for the development of B-cells from the blood stem cell. Meinrad Busslinger and his team first identified Pax5 as a B-cell-specific transcription factor, then isolated its gene and studied its function by selectively eliminating the Pax5 gene from the mouse genome. Hematopoietic stem cells lacking this transcription factor were still able to give rise to all blood cell types with the notable exception of B-cells. More surprisingly, reintroduction of a functional Pax5 gene deprived these progenitor cells of their different developmental options, as they were now only able to differentiate along the B-cell pathway. These experiments unequivocally identified Pax5 as the decisive factor that determines commitment to the B-cell lineage. Pax5 thereby restricts the stem cell to the B-cell pathway by activating B-cell-specific genes and by simultaneously repressing those genes, which are normally expressed in other blood cell types. These discoveries have provided novel insight into the fundamental mechanism of lineage commitment and are thus likely to have broad medical implications. Busslinger`s team is currently investigating whether this new concept is generally applicable to the development of other organs such as the midbrain and kidney.

Tissue-specific stem cells are responsible for the formation and regeneration of human organs such as the blood, intestine and skin. Stem cells are characterized by a broad developmental potential, as they give rise to all specialized cell types that are essential for an organ to function correctly. In particular, the hematopoietic stem cell is known to generate all mature blood cell types throughout adult life. This stem cell initially differentiates to a progenitor cell, which then has to make a choice between several different pathways and subsequently develops into mature cells of the selected lineage. Until recently, little was known about how these lineage decisions are reached by the stem cell. The long-standing research efforts of Meinrad Busslinger and his team at the IMP (Research Institute of Molecular Pathology, Vienna) have now provided insight into how this decision-making process takes place in the blood stem cell. The B-cells of the blood take care of immune protection by producing antibodies that eliminate foreign antigens. The generation of B-cells from blood stem cells requires the expression of specific genes from the genome. Transcription factors are known to govern the process by which the information of genes is made available within a cell. A transcription factor by the name of Pax5 proved to be responsible for the development of B-cells from the blood stem cell. Meinrad Busslinger and his team first identified Pax5 as a B-cell-specific transcription factor, then isolated its gene and studied its function by selectively eliminating the Pax5 gene from the mouse genome. Hematopoietic stem cells lacking this transcription factor were still able to give rise to all blood cell types with the notable exception of B-cells. More surprisingly, reintroduction of a functional Pax5 gene deprived these progenitor cells of their different developmental options, as they were now only able to differentiate along the B-cell pathway. These experiments unequivocally identified Pax5 as the decisive factor that determines commitment to the B-cell lineage. Pax5 thereby restricts the stem cell to the B-cell pathway by activating B-cell-specific genes and by simultaneously repressing those genes, which are normally expressed in other blood cell types. These discoveries have provided novel insight into the fundamental mechanism of lineage commitment and are thus likely to have broad medical implications. Busslinger`s team is currently investigating whether this new concept is generally applicable to the development of other organs such as the midbrain and kidney.