Angiotensin-converting enzyme (CD143) marks hematopoietic stem cells in human embryonic, fetal, and adult hematopoietic tissues

Abstract

Previous studies revealed that mAb BB9 reacts with a subset of CD34(+) human BM cells with hematopoietic stem cell (HSC) characteristics. Here we map BB9 expression throughout hematopoietic development and show that the earliest definitive HSCs that arise at the ventral wall of the aorta and surrounding endothelial cells are BB9(+). Thereafter, BB9 is expressed by primitive hematopoietic cells in fetal liver and in umbilical cord blood (UCB). BB9(+)CD34(+) UCB cells transplanted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice contribute 10-fold higher numbers of multilineage blood cells than their CD34(+)BB9(-) counterparts and contain a significantly higher incidence of SCID-repopulating cells than the unfractionated CD34(+) population. Protein microsequencing of the 160-kDa band corresponding to the BB9 protein established its identity as that of somatic angiotensin-converting enzyme (ACE). Although the role of ACE on human HSCs remains to be determined, these studies designate ACE as a hitherto unrecognized marker of human HSCs throughout hematopoietic ontogeny and adulthood.

Generation of T Cells from Human Embryonic Stem Cell-Derived Hematopoietic Zones

“…An extensive flow cytometric analysis of the gated populations is shown in supplemental Table S1. 4 We could confirm, as was previously described (6), that the R1 CD34 high CD43 Ϫ population depicted in Fig. 2A comprises CD31 ϩ CD146 ϩ CD45 Ϫ endothelial cells, whereas the CD34 Ϫ CD43 ϩ cells (R4 in Fig.…”

“…2C), suggesting T/NK lineage commitment of these CD34 ϩ cells on OP9-DL1 monolayers (18). Importantly, prolonged culture of the HZs on the initial OP9 cells 4 The online version of this article contains supplementary material. The gated R2 (CD34 high CD43 low ) and R3 (CD34 low CD43 high ) populations generated on OP9 cells in A (day 12 on OP9) are sorted on OP9-DL1 monolayers (5000 cells each) to allow T cell differentiation.…”

“…The three-dimensional embryoid body system and coculture systems on stromal cell lines such as murine OP9 cells or aorta-gonad-mesonephros-derived stromal cells are often used (2,3). In both systems, multipotent HPC with self-renewing activity were demonstrated (4,5). Vodyanik et al (6) performed an extensive analysis of precursors generated from hESC in OP9 coculture and described a CD34 ϩ CD43 ϩ population, with precursor activity for B, NK, and myeloid cells.…”

Embryonic origin of human hematopoiesis

“…2) emerging on the ventral aortic endothelium at 4-5-weeks, as well as the neighboring endothelial cells (Jokubaitis et al, 2008). In addition, BB9 identified a few cells scattered among the subaortic mesoderm, on which no colocalization of CD34 or CD45 was observed, suggesting the angiohematopoietic potential of BB9-positive mesodermal progenitors (Jokubaitis et al, 2008). An analysis conducted at even earlier stages of human development is consistent with this hypothesis (Sinka et al, submitted).…”

“…enzyme (ACE/CD143), exhibits reactivity with primitive hematopoietic cells at all stages of hematopoietic ontogeny including in the umbilical cord blood (UCB) and fetal liver. Transplantations into NOD/SCID mice demonstrated that CD34 + BB9 + cells from UCB, but not CD34 + cells lacking expression of BB9, sustained multilineage human hematopoietic cell engraftment and, therefore, clearly established BB9/ACE as a bona fide marker of human HSC (Jokubaitis et al, 2008).…”