A New Paradigm
“For years, we have defined bone marrow stem cells in terms of their ability to differentiate along a specific lineage, but we missed the possibility that the bone marrow could be a resource to generate adult tissues,” says Richard A. Lerner, M.D., professor of immunochemistry at The Scripps Research Institute.
Investigators in Dr. Lerner’s lab recently reported the possibility to transdifferentiate CD34+ human myeloid bone marrow stem cells into neural progenitor cells using antibodies, in an approach different from those employed to date. To identify a large number of agonist antibodies that each can bind to a different region of the G-CSF receptor (G-CSFR) molecule, Dr. Lerner and colleagues designed a two-step selection strategy.
First, antibodies derived from a phage combinatorial library, which had been converted to a plasma membrane-binding format, are selected based on their ability to bind a membrane-bound version of G-CSFR. Second, based both on binding and function, selected agonists are enriched for those possessing unusual or rare functions.
This strategy favors the selection of antibodies that are generally not identified in solution and provides the opportunity to explore a large number of agonists, each of them binding to a different region of the receptor. Additional strengths of this approach are the presentation of the receptor in its natural environment, where it assumes physiologically relevant conformations, and its ability to test for direct binding.
Among the antibodies they generated, Dr. Lerner and his colleagues identified one that, unlike the natural ligand G-CSF, was also able to activate CD34+ stem cells and initiate neurogenesis.
“What we found is a special antibody to a known receptor whose activation generates more white blood cells but, in this case, the antibody stimulated differentiation into brain cells,” Dr. Lerner explains.
This revealed a new paradigm, an agonist antibody binding, in a population of identical cells, the same receptor as the ligand, but inducing a distinct cell fate, by biasing signaling to specific downstream pathways. While antibodies that can generate other cell types, such as red blood cells, platelets, or dendritic cells, have previously been described, in each of those examples the respective differentiated cells represented a known potential of that specific cell lineage. “In this case, what we observed is not a known potential, and the broad question that emerges is whether we have missed the overall capacity of the bone marrow,” he says.