When an animal is exposed to a large dose of x-rays, most of the hematopoietic cells are destroyed and the animal dies within a few days as a result of its inability to manufacture new blood cells. The animal can be saved, however, by a transfusion of cells taken from the bone marrow of a healthy, immunologically compatible donor. Among these cells there are some that can colonize the irradiated host and permanently reequip it with hematopoietic tissue (Figure 22–30). Such experiments prove that the marrow contains hematopoietic stem cells. They also show how we can assay for the presence of hematopoietic stem cells and hence discover the molecular features that distinguish them from other cells.
For this purpose, cells taken from bone marrow are sorted (using a fluorescence-activated cell sorter) according to the surface antigens that they display, and the different fractions are transfused back into irradiated mice. If a fraction rescues an irradiated host mouse, it must contain hematopoietic stem cells. In this way, it has been possible to show that the hematopoietic stem cells are characterized by a specific combination of cell-surface proteins, and by appropriate sorting we can obtain virtually pure stem-cell preparations. The stem cells turn out to be a tiny fraction of the bone marrow population—about 1 cell in 50,000–100,000; but this is enough. A single such cell injected into a host mouse with defective hematopoiesis is sufficient to reconstitute its entire hematopoietic system, generating a complete set of blood cell types, as well as fresh stem cells. This and other experiments (using artificial lineage markers) show that the individual hematopoietic stem cell is multipotent and can give rise to the complete range of blood cell types, both myeloid and lymphoid, as well as to new stem cells like itself (Figure 22–31).
Figure 22–29 A megakaryocyte among other developing blood cells in the bone marrow. the megakaryocyte’s enormous size results from its having a highly polyploid nucleus. one megakaryocyte produces about 10,000 platelets, which split off from long processes that extend through holes in the walls of an adjacent blood sinus.
mouse survives; the injected stem cells colonize its hematopoietic tissues and generate a steady supply of new blood cells
Figure 22–30 Rescue of an irradiated mouse by a transfusion of bone marrow cells. an essentially similar procedure is used in the treatment of leukemia in human patients by bone marrow transplantation.
Commitment is a Stepwise process
Hematopoietic stem cells do not jump directly from a multipotent state into a commitment to just one pathway of differentiation; instead, they go through a series of progressive restrictions. The first step, usually, is commitment to either a myeloid or a lymphoid fate. This is thought to give rise to two kinds of progenitor cells, one capable of generating large numbers of all the different types of myeloid cells, and the other giving rise to large numbers of all the different types of lymphoid cells. Further steps give rise to progenitors committed to the production of just one cell type. The steps of commitment correlate with changes in the expression of specific transcription regulators, needed for the production of different subsets of blood cells.
divisions of Committed progenitor Cells amplify the number of Specialized blood Cells