title: Quiescent human hematopoietic stem cells in the bone marrow niches organize the hierarchical structure of hematopoiesis.
abstract: Hematopoiesis is a dynamic and strictly regulated process orchestrated by self-renewing hematopoietic stem cells (HSCs) and the supporting microenvironment. However, the exact mechanisms by which individual human HSCs sustain hematopoietic homeostasis remain to be clarified. To understand how the long-term repopulating cell (LTRC) activity of individual human HSCs and the hematopoietic hierarchy are maintained in the bone marrow (BM) microenvironment, we traced the repopulating dynamics of individual human HSC clones using viral integration site analysis. Our study presents several lines of evidence regarding the in vivo dynamics of human hematopoiesis. First, human LTRCs existed in a rare population of CD34(+)CD38(-) cells that localized to the stem cell niches and maintained their stem cell activities while being in a quiescent state. Second, clonally distinct LTRCs controlled hematopoietic homeostasis and created a stem cell pool hierarchy by asymmetric self-renewal division that produced lineage-restricted short-term repopulating cells and long-lasting LTRCs. Third, we demonstrated that quiescent LTRC clones expanded remarkably to reconstitute the hematopoiesis of the secondary recipient. Finally, we further demonstrated that human mesenchymal stem cells differentiated into key components of the niche and maintained LTRC activity by closely interacting with quiescent human LTRCs, resulting in more LTRCs. Taken together, this study provides a novel insight into repopulation dynamics, turnover, hierarchical structure, and the cell cycle status of human HSCs in the recipient BM microenvironment.
authors.affiliation: Division of Hematopoiesis, Research Center for Regenerative Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yahata
authors.forename: Yukari
authors.initials: Y
authors.lastname: Muguruma
authors.forename: Shizu
authors.initials: S
authors.lastname: Yumino
authors.forename: Yin
authors.initials: Y
authors.lastname: Sheng
authors.forename: Tomoko
authors.initials: T
authors.lastname: Uno
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Matsuzawa
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
authors.forename: Shunichi
authors.initials: S
authors.lastname: Kato
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Hotta
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D018952:Antigens, CD34 / Q000096:biosynthesis; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology*; D018929:Cell Culture Techniques / Q000379:methods; D002453:Cell Cycle; D005312:Fetal Blood / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006706:Homeostasis; D006801:Humans; D016086:Lentivirus / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology; D033581:Stem Cell Transplantation; D013997:Time Factors
chemical_list: D018952:Antigens, CD34; D051997:ADP-ribosyl Cyclase 1