title: CD82/KAI1 Maintains the Dormancy of Long-Term Hematopoietic Stem Cells through Interaction with DARC-Expressing Macrophages.
abstract: 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.
authors.affiliation: National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Hur
authors.affiliation: National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Choi
authors.affiliation: National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Hwan
authors.initials: H
authors.lastname: Lee
authors.affiliation: National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Pniel
authors.initials: P
authors.lastname: Nham
authors.affiliation: National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kim
authors.affiliation: National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Cheong-Whan
authors.initials: CW
authors.lastname: Chae
authors.affiliation: National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Yun
authors.affiliation: National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Jin-A
authors.initials: JA
authors.lastname: Kang
authors.affiliation: National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Jeehoon
authors.initials: J
authors.lastname: Kang
authors.affiliation: National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Cardiovascular Center and Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do 463-707, Republic of Korea.
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yoon
authors.affiliation: Creative Research Initiative Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Boo
authors.affiliation: BK21PLUS 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.
authors.forename: Seokjin
authors.initials: S
authors.lastname: Ham
authors.affiliation: BK21PLUS 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.
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Roh
authors.affiliation: Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea.
authors.forename: Jong Kwan
authors.initials: JK
authors.lastname: Jun
authors.affiliation: Division of Convergence Technology, National Cancer Center, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Ho
authors.initials: H
authors.lastname: Lee
authors.affiliation: Creative Research Initiative Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: sbaek@snu.ac.kr.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Baek
authors.affiliation: National Research Laboratory for Stem Cell Niche, Center for Medical Innovation, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-744, Republic of Korea; Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 110-744, Republic of Korea. Electronic address: hyosoo@snu.ac.kr.
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D004375:Duffy Blood-Group System / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D051861:Kangai-1 Protein / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011956:Receptors, Cell Surface / Q000378:metabolism
chemical_list: C497689:Cd82 antigen, mouse; D004375:Duffy Blood-Group System; D051861:Kangai-1 Protein; D011956:Receptors, Cell Surface; C483025:Ackr1 protein mouse
keywords: CD82/KAI1; DARC/CD234; LT-HSCs; bone marrow; macrophage; quiescence; stem cell niche; tetraspanin