Hematopoietic Microenvironment

Our experimental approach combines phenotypic and functional studies in clinically-relevant mouse models, intra-vital imaging, genomics and single cell transcriptomics. Our lab is a part of the Stem Cell and Gene Therapy Program in the Clinical Research Division, and has close links with the Integrated Immunotherapy Research Center at Fred Hutch.

Our previous studies used a combination of single cell RNA-Seq and imaging of freshly isolated bone tissue sections to identify novel regulators of hematopoietic stem cell (HSC) quiescence and self-renewal. By interrogating the molecular profile of individual osteolineage cells in close proximity to transplanted HSC, we found that these “proximal” cells were enriched for transcripts encoding molecules previously unrecognized for their ability to regulate HSC/progenitor quiescence and self-renewal (Embigin, IL18, angiogenin) (Silberstein et al, Cell Stem Cell 2016, Goncalves, Silberstein et al, Cell 2016).  Moreover, we have shown that modulating the activity of these molecules enhances post-transplant reconstitution in mice.

Current Projects

Investigating the regulation of blood cell production by the bone marrow niche

Our current work focuses on investigating Neutrophil derived Sema4A as a regulator of emergency myelopoiesis and stemness preservation of HSC.

Previous Projects

Non-cell autonomous regulation of HSC lineage bias

Our recent preliminary observations suggest that niche-derived factors may preferentially regulate myeloid-biased HSC and thus contribute towards age-related HSC dysfunction and the emergence of myeloid malignancy.

Restoration of HSC quiescence and self-renewal by extrinsic factors as a therapeutic strategy in bone marrow failure and myelodysplasia

Given that HSC proliferative stress is a prominent feature in these conditions, we hypothesize that treatment of diseased HSC with niche-derived quiescence-inducing molecules will improve their function and boost mature blood cell production. 

Collaborators

We are very fortunate to have a wide network of outside collaborators, both in the USA (Scadden lab, Harvard; Spencer lab, UC Merced) and abroad (Scialdone lab, University of Munich; Maes lab, KU Leuven; Slush lab, Weitzmann Institute).