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TISSUE-SPECIFIC STEM CELLS

Quiescent Human Hematopoietic Stem Cells in the Bone Marrow Niches Organize the Hierarchical Structure of Hematopoiesis

^aDivision of Hematopoiesis, Research Center for Regenerative Medicine;
^bDepartment of Hematology;
^cDepartment of Cell Transplantation and Regenerative Medicine; Tokai University School of Medicine, Kanagawa, Japan;
^dCentral Institute for Experimental Animals, Kawasaki, Japan

Key Words. Cell cycle • Clonal assays • Hematopoietic stem cell transplantation • Long-term repopulation • Mesenchymal stem cells • Stem cell-microenvironment interactions • Human hematopoietic stem cells • Severe combined immunodeficient repopulating cell

Correspondence: Correspondence: Kiyoshi Ando, M.D., Ph.D., Division of Hematopoiesis, Research Center for Regenerative Medicine and Department of Hematology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. Telephone: 81-463-93-1121; Fax: 81-463-92-4511; e-mail: andok{at}keyaki.cc.u-tokai.ac.jp

Received on June 11, 2008; accepted for publication on September 3, 2008.

First published online in STEM CELLS EXPRESS  September 11, 2008.

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.

Disclosure of potential conflicts of interest is found at the end of this article.