All-lymphoid progenitors (ALPs) yield few myeloid cells invivo, but readily generate such cells invitro. The basis for this difference remains unknown. We hypothesized that ALPs limit responsiveness to invivo concentrations of myeloid-promoting cytokines by reducing expression of the corresponding receptors, potentially through posttranscriptional mechanisms. Consistent with such a mechanism, ALPs express higher levels of CSF1R transcripts than their upstream precursors, yet show limited cell-surface protein expression of colony-stimulating factor 1 receptor (CSF1R). All-lymphoid progenitors and other hematopoietic progenitors deficient in A disintegrin and metalloproteinase domain 17 (ADAM17), display elevated cell surface CSF1R expression. ADAM17--/-- ALPs, however, fail to yield myeloid cells upon transplantation into irradiated recipients. Moreover, ADAM17--/-- ALPs yield fewer macrophages invitro than control ALPs at high concentrations of macrophage colony stimulating factor. Mice with hematopoietic-specific deletion of ADAM17 have normal numbers of myeloid and lymphoid progenitors and mature cells invivo. These data demonstrate that ADAM17 limits CSF1R protein expression on hematopoietic progenitors, but that compensatory mechanisms prevent elevated CSF1R levels from altering lymphoid progenitor potential.
Bibliographical noteFunding Information:
We thank E Lantelme and D Brinja for assistance with flow cytometry and L. Hursey for animal colony maintenance. Dr. D Bhattacharya is a New York Stem Cell Foundation Robertson Investigator. This work was supported by National Institutes of Health grants to Dr AM Becker (no. T32CA009547 ) and Dr. D Bhattacharya (no. K01DK078318 ).
© 2015 ISEH - International Society for Experimental Hematology.