Regulation of hematopoietic stem cell migration and function

Abstract

Hematopoietic stem cell transplantation (HSCT) is an effective treatment for blood disorders and autoimmune diseases. Following HSCT, these cells must successfully migrate to the marrow niche and replenish the blood system of the recipient. This process requires both non-cell and cell-autonomous regulation of hematopoietic stem and progenitor cells (HSPCs). A transgenic reporter line in zebrafish allowed the investigation of factors that regulate HSPC migration and function. To directly observe cells in their endogenous microenvironment, confocal live imaging was used to track runx1:GFP+ HSPCs as they arrive and lodge in the niche. A novel cellular interaction was observed that involves triggered remodeling of perivascular endothelial cells during niche formation. A chemical screen identified the TGF-beta pathway as a regulator of HSPC and niche interactions. Chemical manipulation of HSPCs was used to improve engraftment and repopulation capability following transplantation. Runx1:GFP fish treated with prostaglandin E2 (PGE2) during embryogenesis exhibit increased runx1+ cells in the AGM and CHT, consistent with previous in situ data. This increase in HSPCs is maintained into adulthood, even in the absence of prolonged PGE2 exposure. Kidney marrow from these treated fish can outcompete control marrow in transplantation assays. The ability of PGE2 to confer a long-term advantage on sorted mouse marrow populations in competitive transplantation assays was tested. I found that PGE2-treated short-term (ST)-HSCs, but not long-term (LT)-HSCs show enhanced transplantability in recipients compared to control animals. My studies demonstrate that the effects of PGE2 on HSC function persist over substantial time despite transient exposure. A population of short-term HSCs can engraft and give rise to long-term multilineage reconstitution following PGE2 treatment. Collectively, our studies have led to novel insights regarding the pathways involved in HSC migration, homing, and repopulation.