The Endothelial Antigen ESAM Monitors Hematopoietic Stem Cell Status between Quiescence and Self-Renewal

Abstract

Whereas most hematopoietic stem cells (HSC) are quiescent in homeostasis, they actively proliferate in response to bone marrow (BM) injury. Signals from the BM microenvironment are thought to promote entry of HSC into the cell cycle. However, it has been cumbersome to assess cycle status of viable HSC and thus explore unique features associated with division. In this study, we show that expression of endothelial cell-selective adhesion molecule (ESAM) can be a powerful indicator of HSC activation. ESAM levels clearly mirrored the shift of HSC between quiescence and activation, and it was prominent in comparison with other HSC-related Ags. ESAMhi HSC were actively dividing, but had surprisingly high long-term reconstituting capacity. Immunohistochemical analyses showed that most ESAMhi HSC were located near vascular endothelium in the BM after 5-fluorouracil treatment. To determine the importance of ESAM in the process of BM recovery, ESAM knockout mice were treated with 5-fluorouracil and their hematopoietic reconstruction was examined. The ESAM deficiency caused severe and prolonged BM suppression, suggesting that ESAM is functionally indispensable for HSC to re-establish homeostatic hematopoiesis. With respect to intracellular regulators, NF-κB and topoisomerase II levels correlated with the ESAM upregulation. Thus, our data demonstrate that the intensity of ESAM expression is useful to trace activated HSC and to understand molecular events involved in stem cell states.

The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

“…Among the candidate genes present within the Chr9L interval, but not in the Chr9S interval, we found Crtam, which has been associated with diabetes induction in a mouse model of induced autoimmune diabetes and is expressed on some T cell populations (57). Esam, involved in hematopoiesis (58), is also of interest considering that DN T cell proportion is regulated by bone marrow-intrinsic factors (24). Tirap and Tbrg1 are two other genes within the Chr9L interval known to play significant roles in the immune system, which could be candidate genes for defining the proportion of DN T cells and susceptibility to diabetes.…”

A Proteomics and Transcriptomics Approach to Identify Leukemic Stem Cell (LSC) Markers

“…Parathyroid hormone receptors are typically associated with formation of the stem cell niche (57), but we find them to be up-regulated in AML CD34 ϩ cells as well. ESAM was recently reported as a marker that identifies actively cycling human stem cells that do retain long-term reconstitution activity (58), and it will be interesting to determine its role in myeloid leukemias. The hepatocyte growth factor receptor MET has been shown to play an essential role in numerous cancers (59), and it was recently shown that autocrine activation of MET is frequently observed in AML (60).…”

Inhibition of endothelial ERK signalling by Smad1/5 is essential for haematopoietic stem cell emergence

“…Endothelial-specific adhesion molecule (ESAM) is a novel HSC-specific marker in mice 37,38 . Expression level of ESAM reflects the HSC transition status between quiescence and self-renewal 39 . It is also involved in the VEGFtriggered vascular permeability and Rho-mediated endothelial cell contacts 40 .…”