Gene expression pattern in individual multipotent hematopoietic progenitor cells: population dynamics in cell fate decision
Date
2015-01-14
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Abstract
Cell fate decisions in multipotent progenitor cells are believed to be regulated by gene regulatory networks in a deterministic way. However, observation of cell fate behavior of individual cells point to stochastic process. Stochasticity is manifested as heterogeneity in clonal cell populations. According to dynamical systems framework, cell fates are stable attractor states and fate commitment is the exit from the progenitor attractor into a differentiated lineage attractor. As experimental system we studied the multipotent CMPs with the capability to commit to the erythroid (ERY) or myeloid (MYL) lineages and used single-cell RT-qPCR technique to measure in individual cells the expression of a set of TFs important in CMP multipotency and differentiation. We asked: how does the state of an individual cell as a dynamical system, change when the cell makes a binary decision? First, we confirmed that the heterogeneity of transcript expression of these TFs is the basis of priming otherwise identical cells for the downstream lineages of ERY and MYL. The cells that happen to be at opposite “borders” of the progenitor attractor basin displayed a bias towards the opposite prospective lineages. Second, analysis of transcript expression change following exposure to differentiation factors in multiple individual cells and over multiple time points revealed signs of a destabilization of the progenitor state. This indicates that cells undergo a bifurcation, or “critical phase transition”, in which the progenitor attractor state is converted into an instability that forces cells into the attractors of the committed lineage, ERY and MYL. Specifically, we found, as indicative of a critical phase transition, that gene-gene correlation increased (a sign of GRN activity), while cell-cell correlation decreased (a sign of state diversification due to instability). Third, a more detailed dissection of the MYL differentiation process along the axis of CD11b marker revealed the transient splitting of the uniform population into three discrete subpopulations of destabilized progenitor state, intended MYL and unintended ERY fates, in agreement with a progenitor state destabilization. This finding reveals that cytokines operate by selecting a latently present, rather than instructing the de novo establishment of the gene expression program of the desired lineage. Finally, to further dissect the role of selection and instruction, we explored the response of the progenitor cells to simultaneous exposure to both the ERY and MYL cytokines. We discovered evidence for both mechanisms in the lineage commitment process.
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Biology--Molecular
Citation
Mojtahedi, M. (2015). Gene expression pattern in individual multipotent hematopoietic progenitor cells: population dynamics in cell fate decision (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26264