Exit from quiescence and re-entry into cell cycle is essential for hematopoietic stem cells (HSC) self-renewal and regeneration. Skp2 is the F-box unit of the SCF E3-ligase that targets the Cdk inhibitors (CKI) p21Cip1, p27Kip1, p57Kip2 and p130 for degradation. These CKIs inhibit the G1 to S-phase transition of the cell cycle and their deletion results in increased cell proliferation and decreased stem cell self-renewal. Skp2 deletion leads to CKIs stabilization inducing cell cycle delay or arrest, and conversely, increased Skp2 expression is often found in cancers. Here, we show that SKP2 expression is increased in HSC and progenitors in response to hematopoietic stress from myelosuppression or following transplantation. At steady-state, SKP2 deletion decreased the mitotic activity of HSC and progenitors resulting in enhanced HSC quiescence, increased HSC pool size and maintenance. However, the inability to rapidly enter cell cycle greatly impaired the short-term repopulating potential of SKP2 null HSC and their ability to regenerate following myeloablative stress. Mechanistically, deletion of SKP2 in HSC and progenitors stabilized CKIs in-vivo, particularly p27Kip1, p57Kip2 and p130. Our results demonstrate a previously unrecognized role for SKP2 in regulating HSC and progenitor expansion and hematopoietic regeneration following stress.

  • Submitted November 29, 2010.
  • Accepted March 19, 2011.