The Lucas Laboratory currently focuses on two projects:
Regulation of HSC Niches by Mature Blood Cells
Traditionally it has been assumed that hematopoietic stem cells (HSC) are regulated exclusively by non-hematopoietic (stromal) cells that form the HSC niche. An emerging concept in the field is that HSC can be regulated directly or indirectly (via effects on the niche) by their own progeny. For example, megakaryocytes regulate HSC numbers directly by producing CXCL4 and TGF-beta.
Macrophages regulate HSC release from the bone marrow by targeting LepR+ perivascular cells. These indicate that HSC could be regulated by their own progeny (macrophages and megakaryocytes). These data suggest that there are feedback regulatory loops between mature hematopoietic cells and HSC and their different niches.
We have discovered several cells and molecules involved in these regulatory loops. We are currently defining the mechanisms through which they differentially regulate specific HSC niches. We are also developing methods to utilize these cells to promote recovery after bone marrow transplantation.
Identification of Niches for Progenitors Downstream of HSC
HSC give rise to mature blood cells in a hierarchical manner. They generate short-lived progenitors that progressively differentiate into progenitors that are restricted to a specific lineage (e.g., erythrocyte progenitors that give rise to red blood cells or myeloid progenitors that give rise to neutrophils, macrophages and other leukocytes). Thus, these progenitors are essential for life.
However, very little is known about the signals that regulate how the different progenitors adopt lineage decisions and what populations maintain them in the bone marrow. We have optimized a technique that allows us to perform 5-colorimmunofluorescence in whole-mounted bone marrow. We are using this technique to: 1) map the spatial distribution of different hematopoietic progenitors and 2) determine how these progenitors decide to commit to specific bone marrow lineages.
This research will provide for the first time an integrated and comprehensive view of the cellular networks and regulatory loops that control hematopoiesis. It will also lead to the identification of novel cells, pathways and molecules that can be targeted to treat bone marrow failure syndromes and improve regeneration after transplantation.