Journal Article

Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche

Nakauchi, Hiromitsu, Seita, Jun, Chen, James Y., Wang, Sean K., Miyanishi, Masanori, Weissman, Irving L., Sinha, Rahul, Kao, Kevin S., Yamazaki, Satoshi, Sahoo, Debashis

2016

Overview

Until recently, complex multi-parameters were required for the isolation and identification of haematopoietic stem cells, complicating study of their biology in situ ; here the authors have found that expression of a single gene, Hoxb5 , defines haematopoietic stem cells with long-term reconstitution capacity, and that these cells are mainly found in direct contact with endothelial cells. Haematopoietic stem cell niche characterized Until recently, the isolation and recognition of haematopoietic stem cells (HSCs) has been a complex process involving the manipulation of multiple parameters, and this complicates the study of HSC biology in situ . In particular, it has been difficult to establish their relationship to the HSC niche, and how their self-renewal and differentiation properties are modulated by their environment. Here Irving Weissman and colleagues demonstrate that expression of a single gene, Hoxb5 , defines cells with long-term reconstitution capacity, and show that these cells are mainly found directly in contact with endothelial cells. Haematopoietic stem cells (HSCs) are arguably the most extensively characterized tissue stem cells. Since the identification of HSCs by prospective isolation 1 , complex multi-parameter flow cytometric isolation of phenotypic subsets has facilitated studies on many aspects of HSC biology, including self-renewal 2 , 3 , 4 , differentiation, ageing, niche 5 , and diversity 6 , 7 , 8 . Here we demonstrate by unbiased multi-step screening, identification of a single gene, homeobox B5 ( Hoxb5 , also known as Hox-2.1 ), with expression in the bone marrow that is limited to long-term (LT)-HSCs in mice. Using a mouse single-colour tri-mCherry reporter driven by endogenous Hoxb5 regulation, we show that only the Hoxb5 + HSCs exhibit long-term reconstitution capacity after transplantation in primary transplant recipients and, notably, in secondary recipients. Only 7–35% of various previously defined immunophenotypic HSCs are LT-HSCs. Finally, by in situ imaging of mouse bone marrow, we show that >94% of LT-HSCs (Hoxb5 + ) are directly attached to VE-cadherin + cells, implicating the perivascular space as a near-homogenous location of LT-HSCs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/532/1542 / 631/532/2139 / Animals / Antigens, CD - metabolism / Biomarkers - analysis / Blood / Bone marrow / Bone Marrow - metabolism / Cadherins - metabolism / Cell cycle / Cell interaction / Cell Self Renewal / Flow cytometry / Gene expression / Gene Expression Regulation / Genes, Reporter - genetics / Health aspects / Hematopoietic Stem Cell Transplantation / Hematopoietic stem cells / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - metabolism / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Humanities and Social Sciences / Immunophenotyping / letter / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Niches / Observations / Science / Stem Cell Niche / Stem cells / Transplants & implants