In search of "stemness"

Abstract

Stem cells have been identified and characterized in a variety of tissues. In this review we examine possible shared properties of stem cells. We suggest that irrespective of their lineal origin, stem cells have to respond in similar ways to regulate self-renewal and differentiation and it is likely that cell-cycle control, asymmetry/differentiation controls, cellular protective and DNA repair mechanisms, and associated apoptosis/senescence signaling pathways all might be expected to be more highly regulated in stem cells, likely by similar mechanisms. We review the literature to suggest a set of candidate stemness genes that may serve as universal stem cell markers. While we predict many similarities, we also predict that differences will exist between stem cell populations and that when transdifferentiation is considered genes expected to be both similar and different need to be examined.

Figure 1

Comparing stem cell common genes with microarray analysis by different groups. Three independent studies revealed only one gene is common among three stem cell populations: ESC, NSC, and HSC.

Figure 2

Possible stem cell division pathways. Stem cells can remain quiescent or enter cell cycling in three ways: asymmetric division gives rise to a stem cell daughter and a precursor daughter; two kinds of symmetric division will generate twin daughter cells of either stem cell or progenitor properties.

Figure 3

Isolating neural stem cells from negative selection of lineage markers. (A,B): Rat E14.5 spinal cord neural cells were stained with anti-NCAM and A2B5 and sorted on a fluorescence-activated cell sorting machine. A2B5⁻/NCAM⁻ (Lin⁻) cells were collected from M1 gate and applied for clonal analysis. (C): A sample of Lin⁻ clones was induced to differentiate and triple-labeled with three lineage markers: GalC (green), βIII tubulin (red), and GFAP (blue) after culture of 24 days.

Figure 4

One sample of human mobilized peripheral blood stem/progenitor cells positive for the green ALDH reaction product and Hoechst 33342 nuclear stain (63×). Human mobilized peripheral blood cells were stained with Aldefluor, a fluorescent substrate of ALDH. ALDH⁺ cells were sorted and comprised 0.5% of the live cells as gated by FSC and SSC. The confocal microscopy was done by Dr. Sandra Foster of StemCo Biomedical and Dr. Robert Zucker of the US Environmental Protection Agency. (Photo courtesy StemCo Biomedical Inc.)

Figure 5

Cell cycle regulation of stem cells. The cell cycle in somatic cells is controlled by the G1/S checkpoint. In contrast, ES cells move rapidly through the cell cycle and are regulated at the S/G2 checkpoint. Once ES cells differentiate, the cell cycle rate slows and is regulated like that of somatic cells. One notable exception is that most somatic cells delay at the G1/S checkpoint in response to DNA damage to effect repair. In contrast, stem cell populations are very sensitive to UV damage and enter apoptosis. Signals that trigger self-renewal divisions vs asymmetric divisions also affect cell-cycle regulation. Some of these differentiation signals are intrinsic via polar segregation of genes during mitosis or via expression of asymmetry genes. The linkage between cell-cycle control and self-renewal/differentiation is not well understood. In stem cells, the cell-cycle controls that delay progression of cycle vs enter apoptosis are weighted towards apoptosis. As stem cells differentiate to more specialized cells, the weighting shifts toward cell-cycle delay/DNA repair. Depending upon the tissue, stem cells can remain quiescent in G1- or G0-like state for long periods and then may be reactivated. Growth factors/mitogens affect stem cells in vitro and may play a role in reactivation in vivo. In other tissues, stem cells are continuously active (testes, hematopoietic system, skin, olfactory sensory epithelium). In other tissues, most stem cells are quiescent throughout life (nervous system, ovary). The long-term control mechanisms are not well known.