You are hereMay 10, 2015 | Mammary Stem Cells
Out with the Old and in with the New - The New Stem Cell Mantra
Review of “Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness” from Science by Stuart P. Atkinson
The accumulation of cellular damage with age is proposed to lead to both stem cell and tissue dysfunction. Non-mammalian organisms can segregate damaged cellular components when they asymmetrically divide creating a “pristine” stem cell copy, and a more differentiated daughter cell which carries the damaged cell contents. This is hypothesized to occur in order to maintain a fully functional and healthy stem cell source from where the tissue can faithfully reconstitute itself over time. However, studies have not reached a consensus on the presence of such a mechanism in mammalian stem cells [1-4]. Now, using stem-like cells (SLCs) from cultures of immortalized human mammary epithelial cells , research led by Pekka Katajisto has found that aged mitochondria are indeed differentially apportioned upon stem cell division and this mechanism may be required for the maintenance of stem cell-like characteristics, and may therefore control tissue maintance and ageing .
The group combined light-inducible green fluorescent protein (paGFP) expression with specific targeting signals or proteins in order to study distinct subcellular regions. After light induction, older proteins will be tagged green, although any newly synthesized proteins remain untagged, thereby providing a method to distinguish older proteins contained in the different cellular regions (such as lysosomes, mitochondria etc.). This strategy demonstrated that during SLC asymmetric division, one daughter cell is specifically loaded with higher levels of “older” mitochondria, even though each cell contained roughly the same number of total mitochondria. Interestingly, further labeling analyses found that older mitochondria tended to localize themselves together within the SLC (perinuclear and sometime in distinct punctae), and apart from “newer” mitochondria, a finding that was specific to the stem-like cells. This suggests that SLCs identify older mitochondria, and specifically shuttle them to specific regions in wait for their asymmetric segregation.
Cell sorting of SLCs by the level of older mitochondria through fluorescent labelling demonstrated that a much greater proportion of SLC daughter cells with the newer mitochondria had stem cell characteristics (mammosphere forming potential and further asymmetrical division), while the more differentiated daughter cells tended to contain a higher level of older mitochondria and had lower stem cell potential. Finally, the group found that perturbing normal mitochondrial homeostasis (using siRNAs targeting Parkin or the Drp1 inhibitor mDivi-1 which inhibit mitochondrial fission) led to the loss of the normal mitochondrial apportion during asymmetric SLC division, as there was increase in the number of cells which received both old and new mitochondria, and the spread of old mitochondria throughout the cell from their perinuclear sites. This led to an immediate reduction in the stem cell-like characteristics of these cells, suggesting again that the stem cell nature of SLCs is tightly correlated to the number of new mitochondria.
This exciting study links the assignment of newer cellular components with the maintenance of the stem cell fate in a mammalian model. This again strengthens the hypothesis that any given tissue requires the stem cells to be in a pristine state, in order to maintain said tissue properly over time. The authors do however note that this phenomenon needs to be studied in more depth in other stem cell populations and even in vivo, to ascertain if this phenomenon has a role to play in ageing and tissue maintenance.
- Spokoini R, Moldavski O, Nahmias Y, et al. Confinement to organelle-associated inclusion structures mediates asymmetric inheritance of aggregated protein in budding yeast. Cell Reports 2012;2:738-747.
- Rujano MA, Bosveld F, Salomons FA, et al. Polarised asymmetric inheritance of accumulated protein damage in higher eukaryotes. PLoS biology 2006;4:e417.
- Hernebring M, Fredriksson A, Liljevald M, et al. Removal of damaged proteins during ES cell fate specification requires the proteasome activator PA28. Sci Rep 2013;3:1381.
- Vilchez D, Boyer L, Morantte I, et al. Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature 2012;489:304-308.
- Chaffer CL, Brueckmann I, Scheel C, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proceedings of the National Academy of Sciences of the United States of America 2011;108:7950-7955.
- Katajisto P, Dohla J, Chaffer CL, et al. Stem cells. Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science 2015;348:340-343.