When a marble is rolling down from the top of the hill…

by on August 17, 2008 · 1 comment

in Journal club

Blogging on Peer-Reviewed ResearchIn the May 22 issue of Nature, Huang and his colleagues published their surprising discovery about built-in variability in stem cell population which used to be called “experimental noise”.

When they labeled a well-defined hematopoietic progenitor cell population with Sca-1 (stem cell antigen 1), the fluorescence distribution appears to be bell-shaped, a famous shape for “normal school”. This “school” is highly heterogeneous, like all the public schools in the US, made up of “good” students and “bad” students. I mean high Sca-1 positive cells and low expression ones. The amazing part of their work is that the bell-shaped Sca-1 distribution came back again when they sorted high or low Sca-1 sub-populations out of the total cell population and cultured them for several days! The group further pinpointed more cell surface markers for high and low Sca-1 cell subpopulation.

Innate Sca-1 Protein Concentration in a Population of Stem Cells
(A) The concentration Sca-1 protein, a marker of “stemness,” varies greatly in a population of stem cells, though the most common concentration is toward the middle of the range. (B) If the population of stem cells is divided into three groups (low, medium and high Sca-1 level), and those cells are allowed to divide and grow, (C) each group of descendents will reproduce the original range of Sca-1 concentrations. This suggests that populations of stem cells, though genetically identical, have an innate variability that may provide the basis for stem-cell differentiation. This variability could be tapped to increase the efficiency of stem-cell differentiation for therapeutic purposes.

Credit: Graham Paterson, Children’s Hospital Boston

It turned out GATA-1 (transcription factor, characterized erothroid lineage) is high in the Sca-1low population while PU.1 (transcription factor, characterized myeloid lineages) is high on the Sca-1high side. The reasonable biological consequence is Sca-1low population is poised for erythrocyte differentiation and the other for myeloid destination.

Within a clonal population, heterogeneous gene expression patterns prime multipotent cells toward different fates. Here, each green marble represents a single cell within a “cloud” of temporary cellular states. Outliers are more inclined to commit to different lineages.

Credit: Sui Huang

1. Hi, boss, this is not my fault!!! About heterogeneity of a “pure” cell population
This may be the most important significance of this paper which shows even in some “cell lines”, cells possess high heterogeneity.

It reminds me about my Ph.D. project when I had to make ectopic tumor xenografts in immunodeficient mice. I needed at least 1 million cells for each mouse. The cancer stem cell theory perfectly fits into the situation. Remember, I used Hep3B CELL LINE. Even in a cell line, the tumorigenecity of each cell is totally different. When we are working with much more sophisticated cell populations, especially sorted cell populations from primary cells, we have no idea what will happen next.Bosses are all good for trouble shooting. But what they are shooting for? Are they barking up the wrong tree sometimes? Don’t let my boss know I said that.

The other issue proposed by the paper is that we may take every individual cell as a population of cell surface markers. A single cell in a suspension of millions of its friends is unique and it decides where it’ll go. We are working so hard to get the “driving force” behind it.

2. Once a thief, always a thief?
Presumably, you have watched a certain amount of martial movies. It’s always extremely hard for the hero to get rid of the tongs, one must fight really hard to transform to a new life style. Oh, Zohan is different. That is exactly the destiny of a stem cell or progenitor cell with pluripotency or multipotency. The curse sounds like either keep the differerntiation potential or differentiate, the latter way leads to the end of life. To stay as a stem cell, its responsibility is to divide asymmetrically again and again. When other members in the population are gone, the left-over must rebuild the heterogeneity. That’s the way to survive.

3. Good school district is a myth?
Everyone is heading for a good school district for his/her kids even if it costs you a fortune. Swarthmore around Philly is a perfect example. So many Chinese are flooding into the area and are increasing the real estate price. They are moving to a prestigious school district just for their kids. Is that true for the cell population? According to Huang’s finding, it’s a myth. Cells are heterogenous as for Sca-1 antigen expression level in the first place. When they segregated the cells with this standard and culture the sorted cells for just 9 days, the heterogeneity came back. Sca-1 expression level is “normal school” again.

4. Can we have a talk?
Finally, Dr. Huang’s results clearly showed that there is cross-talking among cells. They discussed their present tasks and future directions in a mysterious way. What is the media of the communication? Absolutely not something like internet, but a much, much more complicated network. Cytokine? Chemokine? Or extracellular matrix? That’s another way we definitely should pursue. I don’t really know how, though.

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Nature 2008;453:544
Children’s Hospital Boston press-release
Metarandom states push cell fate (by Nature Reports Stem Cells)
Chance and the single cell (by Nature Reports Stem Cells)

{ 1 comment… read it below or add one }

Alex August 27, 2008 at 7:06 pm

nice post, thank you Lei!
i like your metaphors

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