A Topological View of Human CD34+ Cell State Trajectories from Integrated Single-Cell Output and Proteomic Data
This week we profile a recent publication in Blood from David Knapp and
Colin Hammond in the laboratory of Dr. Connie Eaves (pictured) at BC Cancer.
Can you provide a brief overview of your lab’s research focus?
The Eaves lab is focused on understanding how normal human blood and mammary cells are produced throughout life and then using this information to determine how malignant properties are acquired. This work has contributed to a foundational understanding of the diversity of blood stem and progenitor cells that exist in humans as well as in mice, and the development of systems to measure and compare their capabilities at the level of individual cells. Importantly, the lab’s work has shown that blood stem cells are similar to snowflakes: despite having many similarities, are each unique. This is proving to be an important consideration for developing ways to induce human blood stem cells to expand ex vivo for therapy, and for obtaining new insights on how to treat leukemic cells.
What is the significance of the findings in this publication?
In this publication, we created highly detailed functional and protein maps of the entire blood stem and progenitor populations that can be isolated from human cord blood. By overlaying these maps using shared landmarks, we showed how they could be used to connect two kinds of properties: one that requires the cells to grow and differentiate, and one that requires fixing and analyzing the cells directly. Interestingly, these maps at single-cell resolution showed that cell populations isolated by methods historically used to enrich for distinct outputs are much more heterogeneous in all their properties than had been previously assumed. This led us to develop new ways of isolating populations that actually are quite “pure” in terms of the cell types they can produce, which then made it possible to analyze some of their related molecular properties. In addition, because we had generated data from hundreds of thousands of single cells drawn randomly from the entire spectrum of progenitor cells, we were able to use our maps to trace the most direct transition pathways from cells that are highly undifferentiated to ones that produce just one type of blood cell as defined by the sequence of molecular changes they undergo. Unexpectedly, the results revealed a broad and shallow landscape of changes rather than narrowly defined pathways, suggesting that the changes that bring about lineage restriction are not rigidly ordered and may be quite small. This is especially important to our understanding of what happens in leukemia, the hallmark of which is a deregulated output of cells that fail to undergo terminal differentiation.
What are the next steps for this research?
It remains unclear exactly how the progression of differentiation decisions is regulated in blood cell progenitors and how this is linked to changes in cell survival and proliferation responses to environmental signals. Ongoing studies in the Eaves lab are now focused on identifying how the outputs of progenitors with relatively homogeneous functional properties are affected by exposing them to different external stimuli and interfering with intrinsic components known to control their differentiation.
This work was funded by:
This work was made possible by a Terry Fox Foundation New Frontiers Program Project grant, a Stem Cell Network of Centres of Excellence grant, grants and studentships from the Canadian Institutes of Health Research, a studentship from the University of British Columbia and core support from the BC Cancer Foundation.