CD9 phones home with a TEM of its own

Tetraspanins are small molecule proteins known to impact cellular migration and signaling. In this issue of Blood, Leung and colleagues uncover a novel function of the tetraspanin molecule CD9 as a potential mediator of CD34⁺ cell homing.¹ 

Signaling between CXCR4 and its ligand—stromal-derived factor 1 (SDF-1/CXCR12)—is clearly important in hematopoietic stem cell (HSC) homing and engraftment, but the precise mediators involved are unclear. Recently, attempts to exploit this axis for benefit in the clinic have led to the development of the CXCR4 inhibitor, plerixafor,²  and several other similar agents are in development. Given the catastrophe of engraftment failure in hematopoietic stem cell transplantation (HSCT), and the increased rates of such an outcome with cord blood HSCT in adults, attempts to maximize engraftment by enhancing homing are tantalizing.

The use of microarray screening technology in the elucidation of essential mechanistic targets led to many exciting discoveries in the past decade; in this issue, Leung and colleagues explore the role of CD9, a tetraspanin protein found in a screen, as one in a series of genes preferentially induced by SDF-1 in human CD34⁺ cord blood cells.

Cell-surface proteins of the tetraspanin family have 4 transmembrane domains, intracellular N and C termini, and 2 extracellular domains. Tetraspanins are thought to act as scaffold proteins: multimolecular organizers which anchor proteins to one area of the cell membrane thereby forming structures known as tetraspanin-enriched microdomains (TEMs).³  Tetraspanins are therefore often considered molecular facilitators modulating the activities of their associated molecules depending upon the TEM composition. Interestingly, a TEM formed by CD9 often includes HSC homing proteins B1 integrin,⁴  MTI-MMP,⁵  and CD26.^6,7 

Leung et al transplanted CD34⁺CD9⁻ cells and whole CD34⁺ cells (CD9 antibodies used to positively select CD34⁺CD9⁺ cells had neutralizing effect and were not used for this reason) into NOD.CB.17-Prkdc^scid/J (NOD-Scid) mice, both with and without anti-CD122 antibody. After establishing a clear increase in homing among CD34⁺CD9⁺ cells in the bone marrow and spleen of mice 20 hours after transplantation, the authors elegantly put several known pharmacologic inhibitors of the effectors of the SDF-1/CXCR4 pathway to use to suggest a signaling pathway leading to CD9 expression via activation of the transcription factor STAT. Interestingly, phosphatidylinositol 3-kinase was not involved in signaling of CD9 transcription as it is with other factors involved in homing via mediated SDF-1.⁸ 

Enhancement of stem cell engraftment has significant clinical relevance in the era of cord blood transplantation. Leung and colleagues are the first to demonstrate that CD9 enrichment improves homing of CD34⁺ cells to the bone marrow in the in vivo xenograft assay. It will be interesting to explore potential relationships between CD9 and other SDF-1–induced proteins—regardless of their association with the CD9 TEM—known to impactHSC homing such as CD44⁹  and CD26.⁶  And, of course, the question remains open as to the effect this improved homing will have on HSC engraftment.