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One of the most fascinating questions for me, since I entered the field of stem cell biology, has been how a stem cell chooses what to do when it divides. I’ve looked down the microscope at single cells, which look like little air bubbles for the most part, watched them divide into two more or less similar little air bubbles, and then put them both separately into stem cell assays with only one of them retaining stem cell potential. This has always made me wonder: what does one sack of air contain that the other has lost?
One of the most thought-provoking illustrations I came across during my training was by Tim Brummendorf and Peter Lansdorp, which contemplated the multiple ways a stem cell might partition its various constituent parts. Much work over the last 10-15 years has focused on isolating stem cells and non-stem cells and asking what makes them different. Such efforts are often hampered by impure cell populations (e.g., non-stem cells mixed in with stem cells) and, in many tissues, a lack of stringent functional assays to detect stem cell properties.
Practically, the lowest hanging fruit for scientists is the set of molecules most easily observed via new technologies. Molecular tools to amplify and compare DNA and RNA make it possible to study the global changes in genes expressed in one cell type compared to another and antibody technologies have allowed for the assessment of different protein segregation, including observation by time lapse imaging.
However, very little work in mammalian cell systems has focused on the second of the Brummendorf/Lansdorp suggestions – the asymmetric partitioning of cellular organelles. While some work has been done in worms and flies, virtually nothing has been done in higher order mammals when it comes to assessing where the bits inside cells get distributed, until now. A recent study has emerged from Science magazine where scientists have explored organelle partitioning in human mammary cell lines.
In their study, Katajisto et al., from the Whitehead Institute at the Massachusetts Institute of Technology in Boston, use light activated marker proteins to monitor the age of cell organelles in human breast tissue derived cell lines and track their distribution into daughter cells. As expected, organelle distribution was not different in the majority of cells, but a subset of daughter cells showed differences. Those daughters that retained more newly generated organelles and fewer older organelles were also endowed with more stem cell-like properties (in this case, the ability to make colonies of mammary cells in culture).
I would note that this study is pitched as a stem cell story and implies that stem cell fate could be governed by asymmetric partitioning of one such organelle type (e.g., mitochondria). However, these studies are undertaken in an immortalized cell line and the readout is a colony assay, which many non-stem cells would also successfully pass, so the relevance of these studies to actual human stem cell biology is questionable. Still, it is incredibly interesting to see this kind of work being undertaken in mammalian cell systems of any sort since, if true, manipulating the distribution of organelles could be the key to controlling stem cell fate choice. I hope to see more such studies in the future, in an effort to understand what makes one sack of air different to the other.
David Kent
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