The defining property of stem cells is their ability to generate progeny (offspring) with different cell fates: daughter stem cells (to maintain stem cell number) and daughter pro genitor cells committed to differentiation. And there needs to be a balance between stem cell proliferation and the generation of differentiated progeny.
In the classical stem cell view, individual stem cells divide to give the different daughter cells as a result of intrinsic or extrinsic asymmetry. In the former case, the daughter cells acquire different cell fates as a result of asymmetric division of the parent stem cell causing unequal distribution in the daughter cells of a protein that regulates cell fate (Figure 1A). The alternative is extrinsic asymmetry: here stem cell division is symmetrical, but asymmetry arises when the daughter cells are placed in different microenvironments where they receive different external chemical signals, causing one of them to remain a stem cell and the other to become a progenitor cell committred to differentiation (Figure 1B).
Fig1. Asymmetry arising at or from cell division can explain how stem cells generate both new stem cells and differentiated cell progeny. (A) Intrinsic (autonomous) asymmetry can arise as a result of asymmetric division of a stem cell, S, to give a daughter stem cell and a daughter progenitor cell, P, committed to differentiation. Before cell division a cell fate regulator, such as a polarity protein, accumulates at one pole of the cell and the plane of division is adjusted by re-orienting the mitotic spindle so that one daughter cell receives the great majority of the cell fate regulator. (B) Alternatively, extrinsic asymmetry can be involved: cell division is symmetrical but the two daughter cells receive different external signals from their microenvironments. Tissue-specific stem cells occur in specialized microenvironments (stem cell niches) where stem cell differentiation is suppressed by signals (red curly arrows) received from immediately neighboring cells (not shown) within the niche. When the physical site occupied by a stem cell in its niche is extremely limited and confined to the niche boundary, just one daughter cell can remain at the original stem cell location (and becomes a stem cell); the other daughter cell exits from the niche, escapes the differentiation-suppressing signal, and becomes a progenitor cell, P, that gives rise to differentiated cells. (C) Population-based origin of asymmetry. Asymmetry can also arise at the population level: some stem cells produce identical daughter stem cells, while others divide to produce daughter progenitor cells committed to differentiation. (D) Downstream asymmetry. When a tissue specific stem cell gives rise to progenitors committed to a differentiation pathway, it first produces transit amplifying cells, TA, that divide quickly by symmetrical divisions to rapidly expand the population of cells committed to differentiate (with multiple TA generations rather than the two generations shown here for simplicity). Asymmetry at subsequent cell divisions can produce different types of differentiated cells.
Symmetrical stem cell divisions are now believed to be very common and recent evidence suggests that the balance between stem cell renewal and differentiation can also be obtained at a population level. That is, some stem cells may divide to give identical daughter stem cells, while other stem cells divide to generate two progenitor cells com mitted to differentiation (Figure 1C).
Whichever way the stem cell generates a progenitor cell committed to differentiation, asymmetry is required to create downstream differentiated cells. The progenitor cell first produces transit amplifying cells that go through a finite number of symmetrical cell divisions to rapidly expand their numbers before generating the different types of differentiated cells found in the tissue (Figure 1D). Transit amplifying cells normally account for the majority of dividing cells in an adult tissue. They can be multipotent, but they are not stem cells: they are very short-lived, and more dispensable, than adult stem cells (which can continue to divide over very long periods, up to a whole lifetime).
