3. Parihar R, Nadella P, Lewis A, et al. A phase I studyof interleukin 12 with trastuzumab in patients with hu-man epidermal growth factor receptor-2-overexpressingmalignancies: analysis of sustained interferon gammaproduction in a subset of patients. Clin Cancer Res. 2004;10:5027-5037.

4. Cherukuri A, Dykstra M, Pierce SK. Floating the rafthypothesis: lipid rafts play a role in immune cell activation.Immunity. 2001;14:657-660.

5. Jiang K, Zhong B, Gilvary DL, et al. Pivotal role ofphoshoinositide-3 kinase in regulation of cytotoxicity innatural killer cells. Nat Immunol. 2000;1:419-425.

● ● ● HEMATOPOIESIS & STEM CELLS

Comment on Jokubaitis et al, page 4055

BB9 ACEs the HSC compartment----------------------------------------------------------------------------------------------------------------

Mervin C. Yoder INDIANA UNIVERSITY SCHOOL OF MEDICINE

In an effort to discover specific markers to isolate human hematopoietic stem cells,Jokubaitis and colleagues report that the monoclonal antibody BB9 reacts with he-matopoietic cells displaying morphologic, phenotypic, and/or functional proper-ties of stem and progenitor cells throughout human ontogeny.

Why the continued search for a stem-cellmarker? In the murine system, hemato-

poietic stem cells (HSCs) can be isolated tonear homogeneity, permitting detailed com-parative analysis throughout ontogeny, andrecent data suggest that there may be distinctdifferences in clonal HSC behavior in vivo.1 Incontrast, the human HSC is less well defined;although several cell-surface molecules haveprovided a tool for HSC enrichment, use ofthese molecules has not yet been translated

into novel cell therapies.2 In this issue ofBlood, Jokubaitis and colleagues report thatBB9 identifies severe combined immunodefi-cient (SCID)–repopulating cells (SRCs) inCD34� human umbilical cord blood with a3-fold enrichment (SRC frequency: 1 in 2984cells) over CD34�BB9� cells (1 in 8376 cells).Furthermore, the highest level of BB9 expres-sion in human umbilical cord blood and fetalliver CD34� cells was detected in those cellscoexpressing CD90 and CD133 with low or

undetectable levels ofCD38, a phenotypic popu-lation known to be enrichedin HSC activity. In addi-tion, CD34�BB9� cellswere identified as clusteredcells protruding into thelumen from the ventralaortic endothelium ofthe day 34 human fetuswithin the aorta-gonad-mesonephros region (seefigure), a site known to beenriched in the earliestemerging precursors for thedefinitive hematopoieticsystem. Since BB9 had pre-viously been identified onCD34� bone marrow andmobilized peripheral-bloodcells,3 the present datasuggest that BB9 marks asubpopulation of CD34�

hematopoietic cellsthroughout human ontog-

eny and may serve as a reagent to furtherinterrogate the human HSC compartment.

But what is the antigen recognized byBB9? Jokubaitis and colleagues reportthat BB9 binds to the somatic form ofangiotensin-converting enzyme (ACE/CD143), a key regulator in the renin-angiotensin system (RAS). This well-recognized system that plays important rolesin blood pressure regulation, renal physiol-ogy, and reproduction is now known to par-ticipate in the pathophysiology of diabetes,cancer, and cardiovascular dysfunction.ACE and other members of the RAS havepreviously been reported to play a role inavian yolk sac erythropoiesis,4 and the no-tion of a local RAS functioning within thebone marrow compartment was proposed adecade ago.5 Although a role for ACE inHSC physiology was not delineated in thepresent study, Jokubaitis and colleaguesspeculate that the potential substrates forACE may be broader than those typicallyrestricted to the RAS system, as ACE isknown to target numerous non-RAS mol-ecules. These exciting possibilities add tothe increasing recognition that HSCs playan active role in niche homeostasis, and sug-gest that some systems, such as the RAS,may need to be further explored as possiblecommon regulatory pathways that transcendthe multiple sites of hematopoiesis through-out ontogeny and function to maintain HSCbiological properties required at each stageof development.

Conflict-of-interest disclosure: The authoris a cofounder and consultant for EndGenitorTechnologies (Indianapolis, IN), whose poten-tial product was not described in thiscommentary. ■

REFERENCES1. Muller-Sieburg CE, Sieburg HB. Clonal diversity of thestem cell compartment. Curr Opin Hematol. 2006;13:243-248.

2. Bryder D, Rossi DJ, Weissman IL. Hematopoietic stemcells: the paradigmatic tissue-specific stem cell. Am JPathol. 2006;169:338-346.

3. Ramshaw HS, Haylock D, Swart B, et al. Monoclonalantibody BB9 raised against bone marrow stromal cellsidentifies a cell-surface glycoprotein expressed by primitivehuman hemopoietic progenitors. Exp Hematol. 2001;29:981-992.

4. Savary K, Michaud A, Favier J, Larger E, Corvol P,Gasc JM. Role of the renin-angiotensin system in primi-tive erythropoiesis in the chick embryo. Blood. 2005;105:103-110.

5. Hubert C, Savary K, Gasc JM, Corvol P. The hemato-poietic system: a new niche for the renin-angiotensin sys-tem. Nat Clin Pract Cardiovasc Med. 2006;3:80-85.

Expression of BB9 in the AGM region of the developing human embryo.See the complete figure in the article beginning on page 4055.

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