Jin Hur,1,2,9 Jae-Il Choi,1,2,9 Hwan Lee,1,2,9 Pniel Nham,1,2 Tae-Won Kim,1,2 Cheong-Whan Chae,1,2 Ji-Yeon Yun,1,2 Jin-A Kang,1,2 Jeehoon Kang,1 Sang Eun Lee,1 Chang-Hwan Yoon,3 Kyungjin Boo,4 Seokjin Ham,5 Tae-Young Roh,5 Jong Kwan Jun,6 Ho Lee,7 Sung Hee Baek,4,* and Hyo-Soo Kim1,2,8,*
1National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul 110-744, Republic of Korea
2Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-744, Republic of Korea
3Cardiovascular Center and Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do 463-707, Republic of Korea
4Creative Research Initiative Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea
5BK21PLUS Fellowship Program, Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 790-784, Republic of Korea
6Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea
7Division of Convergence Technology, National Cancer Center, Gyeonggi-do 410-769, Republic of Korea
8Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 110-744, Republic of Korea
9Co-first author
*Correspondence: Sung Hee Baek, Hyo-Soo Kim
Summary
Hematopoiesis is regulated by crosstalk between long-term repopulating hematopoietic stem cells (LT-HSCs) and supporting niche cells in the bone marrow (BM). Here, we examine the role of CD82/KAI1 in niche-mediated LT-HSC maintenance. We found that CD82/KAI1 is expressed predominantly on LT-HSCs and rarely on other hematopoietic stem-progenitor cells (HSPCs). In Cd82-/- mice, LT-HSCs were selectively lost as they exited from quiescence and differentiated. Mechanistically, CD82-based TGF-β1/Smad3 signaling leads to induction of CDK inhibitors and cell-cycle inhibition. The CD82 binding partner DARC/CD234 is expressed on macrophages and stabilizes CD82 on LT-HSCs, promoting their quiescence. When DARC+ BM macrophages were ablated, the level of surface CD82 on LT-HSCs decreased, leading to cell-cycle entry, proliferation, and differentiation. A similar interaction appears to be relevant for human HSPCs. Thus, CD82 is a functional surface marker of LT-HSCs that maintains quiescence through interaction with DARC-expressing macrophages in the BM stem cell niche.
Keywords : LT-HSCs, stem cell niche, CD82/KAI1, tetraspanin, quiescence, DARC/CD234, macrophage, bone marrow