Reduced EBF expression underlies loss of B-cell potential of hematopoietic progenitors with age

Aging Cell. 2010 Jun;9(3):410-9. doi: 10.1111/j.1474-9726.2010.00566.x. Epub 2010 Mar 13.

Abstract

Aging is accompanied by a reduction in the generation of B lymphocytes leading to impaired immune responses. In this study, we have investigated whether the decline in B lymphopoiesis is due to age-related defects in the hematopoietic stem cell compartment. The ability of hematopoietic stem cells from old mice to generate B cells, as measured in vitro, is decreased 2-5-fold, while myeloid potential remains unchanged. This age-related decrease in B-cell potential is more marked in common lymphoid progenitors (CLP) and was associated with reduced expression of the B-lineage specifying factors, EBF and Pax5. Notably, retrovirus-mediated expression of EBF complemented the age-related loss of B-cell potential in CLP isolated from old mice. Furthermore, transduction of CLP from old mice with a constitutively active form of STAT5 restored both EBF and Pax5 expression and increased B-cell potential. These results are consistent with a mechanism, whereby reduced expression of EBF with age decreases the frequency with which multipotent hematopoietic progenitors commit to a B-cell fate, without altering their potential to generate myeloid cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / metabolism*
  • Cell Differentiation*
  • Cell Lineage
  • Down-Regulation
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • PAX5 Transcription Factor / genetics
  • PAX5 Transcription Factor / metabolism
  • STAT5 Transcription Factor / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*

Substances

  • Ebf1 protein, mouse
  • PAX5 Transcription Factor
  • Pax5 protein, mouse
  • STAT5 Transcription Factor
  • Trans-Activators