A novel model of human hematopoietic stem cell (HSC) hierarchy in cord blood with CD34-negative (CD34<sup>−</sup>) HSC at the apex, revealed from single-cell-based analyses of human HSC

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  • Sumide Keisuke
    Department of iPS Stem Cell Regenerative Medicine, Kansai Medical University
  • Matsuoka Yoshikazu
    Department of iPS Stem Cell Regenerative Medicine, Kansai Medical University
  • Sonoda Yoshiaki
    Department of iPS Stem Cell Regenerative Medicine, Kansai Medical University

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  • ヒト臍帯血由来CD34抗原陰性造血幹細胞の1細胞解析から見えた新たなヒト造血幹細胞の階層制
  • ヒト サイタイケツ ユライ CD34 コウゲン インセイ ゾウケツ カンサイボウ ノ 1 サイボウ カイセキ カラ ミエタ アラタ ナ ヒト ゾウケツ カンサイボウ ノ カイソウセイ

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<p>Human hematopoietic stem cells (HSCs), which form the basis of human hematopoietic cell transplantation therapies, have long been empirically believed to exist only in the CD34-positive (CD34+) fraction in the all human HSC sources. We have challenged this long-standing dogma and succeeded to identify CD34-negative (CD34−) severe combined immunodeficiency (SCID)-repopulating cells (SRC) as primitive HSC in human CB. However, because of quite low incidence of the SRC in human CB-derived CD34− cell fractions, it was difficult to characterize the human CD34− SRC (HSC) and to accurately compare between the characteristics of the CD34− HSC and that of CD34+ HSC. Through the series of our studies, we finally achieved to develop the ultra-high-resolution purification methods for prospectively isolation of the human CD34− HSCs from human CB, as well as CD34+ HSCs, using two positive markers, CD133 and GPI-80, as well as CD34+ HSCs. Using this method, we succeeded to detect long-term human hematopoietic cell repopulation in the recipient mice translated with single-human CD34− SRC (HSC). As evidenced by the single-cell-initiated serial transplantation analyses, human CD34− HSC possess self-renewing capability to expand HSC pool. And this method enables detailed comparison between human CD34+ and CD34− HSC. We demonstrated that the purified human CD34− HSC show a potent megakaryocyte/erythrocyte (MegE) differentiation potentials in vivo and in vitro. According to the results of single-cell-initiated colony forming cell assay, human CD34− HSC dominantly differentiated into MegE lineage in semi-solid culture. But CD34− HSC also showed multi-Lineage hematopoietic cell repopulation in the recipient mice. Thus, in human CB, MegE progenitors may be generated directly from the CD34− HSC via a bypass route. On the other side of analyses, the human CD34− HSC could generate both CD34+ and CD34− SRC (HSC) but CD34+ HSC could not generate CD34− SRC (HSC). These facts strongly suggested that CD34− HSC resides at the apex of human HSC hierarchy. Based on these data, we propose a novel human HSC hierarchy model and a revised road map for the commitment of human CD34− HSC in CB.</p>

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