This week we profile a recent publication in Nature Communications from Dr. Brandon Hadland and the laboratory of Dr. Irwin Bernstein at Fred Hutch and UW.
Can you provide a brief overview of your lab’s current research focus?
Our lab’s focus is in understanding the origin of blood and immune cells during development. We are particularly interested in determining the mechanisms by which hematopoietic stem cells (HSCs) arise and how they acquire their unique properties, such as the capacity for life-long self-renewal and multilineage hematopoietic reconstitution following transplantation. We are also interested in understanding the developmental origins of pediatric leukemias and how the pathways that regulate HSC development are co-opted by leukemic stem cells, contributing to disease resistance and relapse. Our long-term objective is to apply knowledge of embryonic HSC development toward de novo HSC engineering in vitro, for the purposes of disease modeling, drug discovery, gene editing, and cellular therapies in blood and immune disorders.
What is the significance of the findings in this publication?
We believe this work represents a significant step toward addressing a longstanding challenge in the field of hematopoiesis by identifying specific niche signals responsible for orchestrating the formation of multilineage, long-term engrafting HSCs. Briefly, we used single-cell RNA-sequencing to simultaneously study the transcriptomes of newly forming embryonic HSC and HSC-supportive niche endothelial cells, generating a transcriptional atlas of HSC development and identifying ligand-receptor interactions regulating HSC development. We then applied this knowledge to rationally design a stromal cell-independent engineered niche sufficient to generate engrafting HSCs from embryonic hemogenic precursors in vitro. Altogether, these studies offer new insight into the specific signals required to support HSC formation, with implications for translational applications in engineering HSC, and create a resource for further discovery of the transcriptional regulation of HSC development.
What are the next steps for this research?
Building on the atlas of ligand-receptor interactions identified by this study, we hope to further elucidate how various signal pathways are integrated temporally during the embryonic specification and emergence of HSCs and leverage this knowledge to generate HSCs de novo from sources such as pluripotent stem cells for future applications in disease modeling and cellular therapies.
If you’d like us to mention your funding sources, please list them.
Funding for this research was provided by the NIH (NIDDK and NHLBI) and the American Society of Hematology (Scholar Award).
