Mechanism of KAI1 that regulated cell cycle in hematopoietic stem cell

Abstract

Hematopoiesis is regulated by quiescent long term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow (BM) niche. KAI1 belongs to tetraspanin superfamily and is known as suppressor of tumor metastasis. In this study, KAI1 was expressed selectively in LT-HSCs located in the BM, but not in other stem-progenitor cells. We generated KAI1-/- mice and observed that LT-HSCs selectively decreased in number because LT-HSCs lost quiescence. KAI1 repressed cell cycle by induction of TGF-β1/Smad3 signaling via PKC, leading to induction of CDK inhibitors and cycle arrest. After ablation of BM by 5-fluorouracil treatment, recovery of cells in the BM was significantly retarded in KAI1-/- mice. Mice that received KAI1-/- HSCs showed a decrease in LT-HSCs compared with those receiving WT-HSCs. KAI1 was expressed also in human LT-HSCs, and the majority of KAI1+ LT-HSCs were quiescent. Thus, KAI1 is a previously unidentified functional surface marker of LT-HSCs and maintains LT-HSC quiescence.