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The stem cell concept revisited: self-renewal capacity is a dynamic property of hemopoietic cells
A rigid developmental program of stem cell division and progressive maturation into blood cells is challenged. It is proposed that the capacity for self-renewal is not limited to pluripotent stem cells but is shared by committed progenitors and even cells of later compartments. The relative probability of self-replication vs maturation in mitotic cells is controlled by extracellular influences. At the cell population level, the balance between proliferation and maturation and between compartments is regulated by feedback interactions. Inducibility of maturation in response to regulatory signals is smaller at earlier stages; consequently, at steady state primitive cells self-renew while their more differentiated progeny are forced to be transitory. The proposed dynamic linkage between compartments can be destabilized in a number of ways, resulting in defective hemopoiesis or leukemia. At all stages hemopoietic cells are able to change their patterns of gene expression, in an inheritable manner, in response to changes in their microenvironment. In particular, the capacity for self-renewal itself can vary even within a conventionally-defined compartment. On this basis of adaptive differentiation and self-renewal it is possible to account for the progression of chronic myelocytic leukemia and its "blastic conversion"; to analyse the hemopoietic system's response to various physiological and experimental perturbations; and to re-interpret the excessive phenotypic plasticity and apparent "lineage infidelity" manifested by leukemic cells and cell lines.
A rigid developmental program of stem cell division and progressive maturation into blood cells is challenged. It is proposed that the capacity for self-renewal is not limited to pluripotent stem cells but is shared by committed progenitors and even cells of later compartments. The relative probability of self-replication vs maturation in mitotic cells is controlled by extracellular influences. At the cell population level, the balance between proliferation and maturation and between compartments is regulated by feedback interactions. Inducibility of maturation in response to regulatory signals is smaller at earlier stages; consequently, at steady state primitive cells self-renew while their more differentiated progeny are forced to be transitory. The proposed dynamic linkage between compartments can be destabilized in a number of ways, resulting in defective hemopoiesis or leukemia. At all stages hemopoietic cells are able to change their patterns of gene expression, in an inheritable manner, in response to changes in their microenvironment. In particular, the capacity for self-renewal itself can vary even within a conventionally-defined compartment. On this basis of adaptive differentiation and self-renewal it is possible to account for the progression of chronic myelocytic leukemia and its "blastic conversion"; to analyse the hemopoietic system's response to various physiological and experimental perturbations; and to re-interpret the excessive phenotypic plasticity and apparent "lineage infidelity" manifested by leukemic cells and cell lines.