Junctional Adhesion Molecule-A Is Highly Expressed on Human Hematopoietic Repopulating Cells and Associates with the Key Hematopoietic Chemokine Receptor CXCR4

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• 作者：Chao-Hui Chang ; Sarah J Hale ; Charlotte V. Cox ; Allison Blair ; Barbara Kronsteiner ; Rita Grabowska ; Youyi Zhang ; David Cook ; Cheen P. Khoo ; Jack B. Schrader ; Suranahi Buglass Kabuga ; Enca Martin-Rendon and Suzanne M. Watt
• 刊名：STEM CELLS
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：34
• 期：6
• 页码：1664-1678
• 全文大小：1080K
• ISSN：1549-4918

文摘

Hematopoietic stem/progenitor cells (HSPCs) reside in specialized bone marrow microenvironmental niches, with vascular elements (endothelial/mesenchymal stromal cells) and CXCR4-CXCL12 interactions playing particularly important roles for HSPC entry, retention, and maintenance. The functional effects of CXCL12 are dependent on its local concentration and rely on complex HSPC-niche interactions. Two Junctional Adhesion Molecule family proteins, Junctional Adhesion Molecule-B (JAM)-B and JAM-C, are reported to mediate HSPC-stromal cell interactions, which in turn regulate CXCL12 production by mesenchymal stromal cells (MSCs). Here, we demonstrate that another JAM family member, JAM-A, is most highly expressed on human hematopoietic stem cells with in vivo repopulating activity (p < .01 for JAM-A^high compared to JAM-A^{Int or Low} cord blood CD34⁺ cells). JAM-A blockade, silencing, and overexpression show that JAM-A contributes significantly (p < .05) to the adhesion of human HSPCs to IL-1β activated human bone marrow sinusoidal endothelium. Further studies highlight a novel association of JAM-A with CXCR4, with these molecules moving to the leading edge of the cell upon presentation with CXCL12 (p < .05 compared to no CXCL12). Therefore, we hypothesize that JAM family members differentially regulate CXCR4 function and CXCL12 secretion in the bone marrow niche. Stem Cells 2016;34:1664–1678