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CD166-CD166 Interaction Enhances Hematopoietic Stem Cell Function

Review of “CD166 engagement augments mouse and human hematopoietic progenitor function via activation of stemness and cell cycle pathways” from STEM CELLS by Stuart P. Atkinson

Previous research from the laboratories of Hal E. Broxmeyer and Edward F. Srour (Indiana University School of Medicine, Indianapolis, Indiana, USA) established CD166, a marker expressed on stem and progenitor cells of all three embryonic lineages, as a marker of immature osteoblasts of the bone marrow stem cell niche [1, 2]. Furthermore, they also defined CD166 as a functional marker of murine and human long-term marrow repopulating hematopoietic stem cells (HSCs) [3]. CD166, or activated leukocyte cell adhesion molecule (Alcam), mediates both homophilic (CD166‐CD166) and heterophilic (CD166‐CD6) interactions [4] and more recent studies from the Broxmeyer and Srour laboratory hoped to understand if homophilic CD166 interactions involving mature murine and human HSCs enhances their hematopoietic potential. 

Excitingly, Zhang et al. now report in STEM CELLS that CD166 interactions activate critical molecular pathways involved in enhancing hematopoietic stem/progenitor cell functions, including activation of the stemness and cell cycle pathways [5]. 

The authors studied mature mouse CD166+ Lineage-Sca‐1+CD117+ (LSK) hematopoietic progenitor cells and CD166+ osteoblasts, finding that interactions between these cells in short term co-culture significantly enhanced the expansion of colony‐forming units when compared to hematopoietic progenitor cells that did not express CD166. Encouragingly, the treatment of CD166+ hematopoietic progenitor cells with recombinant CD166 also prompted colony‐forming unit expansion.

Furthermore, CD34+ human cord blood stem cells that expressed CD166 also produced significantly higher numbers of CFUs following interaction with an immobilized recombinant CD166 when compared to CD166-negative stem cells, providing further proof of the positive effects of CD166 homophilic interactions.

To understand what signaling pathways CD166 homophilic interactions activate or repress, the authors employed single-cell RNA-sequencing to study highly purified hematopoietic progenitor cells from wild type and CD166 knockout mice following interaction with immobilized CD166 protein. Interestingly, cell activated cytokine, growth factor, and hormone signaling, epigenetic pathways, and genes implicated in the maintenance of stem cell pluripotency, and mitochondria‐related signaling pathways.

In summary, the authors provide evidence for homophilic CD166 interactions in the maintenance of hematopoietic stem/progenitor cell function. Moreover, the team’s final reported experiment suggests that this interaction has the ability to enhanced short‐term engraftment in vivo, a finding that may enhance hematopoietic cell transplantation for the treatment of malignant and nonmalignant disorders [6].

For more on hematopoietic stem/progenitor cell function and the role of CD166, stay tuned to the Stem Cells Portal!



  1. Chitteti BR, Cheng Y-H, Poteat B, et al., Impact of interactions of cellular components of the bone marrow microenvironment on hematopoietic stem and progenitor cell function. Blood 2010;115:3239.
  2. Chitteti BR, Cheng Y-H, Streicher DA, et al., Osteoblast lineage cells expressing high levels of Runx2 enhance hematopoietic progenitor cell proliferation and function. Journal of Cellular Biochemistry 2010;111:284-294.
  3. Chitteti BR, Kobayashi M, Cheng Y, et al., CD166 regulates human and murine hematopoietic stem cells and the hematopoietic niche. Blood 2014;124:519.
  4. Bowen MA, Aruffo AA, and Bajorath J, Cell surface receptors and their ligands: In vitro analysis of CD6-CD166 interactions. Proteins: Structure, Function, and Bioinformatics 2000;40:420-428.
  5. Zhang J, Ghosh J, Mohamad SF, et al., CD166 Engagement Augments Mouse and Human Hematopoietic Progenitor Function via Activation of Stemness and Cell Cycle Pathways. STEM CELLS 2019;37:1319-1330.
  6. Singh AK and McGuirk JP, Allogeneic Stem Cell Transplantation: A Historical and Scientific Overview. Cancer Research 2016;76:6445.