Cell cycle quiescence of early lymphoid progenitors in adult bone marrow.

Abstract

Lymphocyte production in bone marrow (BM) requires substantial cell division, but the relationship between largely quiescent stem cells and dividing lymphoid progenitors is poorly understood. Therefore, the proliferation and cell cycle status of murine hematopoietic progenitors that have just initiated the lymphoid differentiation program represented the focus of this study. Continuous bromo-2'-deoxyuridine (BrdU) incorporation and DNA/RNA analysis by flow cytometry revealed that a surprisingly large fraction of RAG-1(+)c-kit(hi) early lymphoid progenitors (ELPs) and RAG-1(+)c-kit(lo) pro-lymphocytes (Pro-Ls) in adult BM were in cell cycle quiescence. In contrast, their counterparts in 14-day fetal liver actively proliferated. Indeed, the growth fraction (cells in G(1)-S-G(2)-M phases) of fetal ELPs was on average 80% versus only 30% for adult ELPs. After 5-fluorouracil treatment, as many as 60% of the adult ELP-enriched population was in G(1)-S-G(2)-M and 34% incorporated BrdU in 6 hours. Transcripts for Bcl-2, p21Cip1/Waf1, and p27 Kip1 cell cycle regulatory genes correlated inversely well with proliferative activity. Interestingly, adult lymphoid progenitors in rebound had the high potential for B lymphopoiesis in culture typical of their fetal counterparts. Thus, lymphocyte production is sustained during adult life by quiescent primitive progenitors that divide intermittently. Some, but not all, aspects of the fetal differentiation program are reacquired after chemotherapy.