Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells

Abstract

A central issue in stem cell biology is to understand the mechanisms that regulate the self-renewal of haematopoietic stem cells (HSCs), which are required for haematopoiesis to persist for the lifetime of the animal¹. We found that adult and fetal mouse and adult human HSCs express the proto-oncogene Bmi-1. The number of HSCs in the fetal liver of Bmi-1^-/- mice² was normal. In postnatal Bmi-1^-/- mice, the number of HSCs was markedly reduced. Transplanted fetal liver and bone marrow cells obtained from Bmi-1^-/- mice were able to contribute only transiently to haematopoiesis. There was no detectable self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi-1^-/- mice. A gene expression analysis revealed that the expression of stem cell associated genes³, cell survival genes, transcription factors, and genes modulating proliferation including p16^Ink4a and p19^Arf was altered in bone marrow cells of the Bmi-1^-/- mice. Expression of p16^Ink4a and p19^Arf in normal HSCs resulted in proliferative arrest and p53-dependent cell death, respectively. Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs.