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Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3113-3124
HEMATOPOIESIS
From the MRC Molecular Haematology Unit and from the Neurosciences
Group, Institute of Molecular Medicine, John Radcliffe Hospital,
Headington, Oxford, England; INSERM Unite 506, Groupe Hospitalier Paul
Brousse, Villejuif Cedex, France; Medizinische Universitätsklinik
II, University of Tübingen, Tübingen, Germany; Stem Cell
Laboratory, Peter MacCallum Cancer Institute, Melbourne, Australia;
Hanson Centre for Cancer Research, Adelaide, Australia; StemCells Inc,
Sunnyvale, CA; Miltenyi Biotec, Bergisch Gladbach,
Germany.
Three distinct classes of epitopes on human CD164 have been
identified. Two of these, recognized by the monoclonal antibodies 105A5
and 103B2/9E10, are the CD164 class I and class II functionally defined
epitopes, which cooperate to regulate adhesion and proliferation of
CD34+ cell subsets. In this article, we demonstrate that
these 2 CD164 epitopes are expressed on CD34+ cells
throughout ontogeny, in particular on CD34+ cell clusters
associated with the ventral floor of the dorsal aorta in the developing
embryo and on CD34+ hematopoietic precursor cells in
fetal liver, cord blood, and adult bone marrow. While higher
levels of expression of these CD164 epitopes occur on the
more primitive
AC133hiCD34hiCD38lo/
CD164 is a type 1 integral transmembrane molecule
belonging to the sialomucin family and containing in its extracellular
region 2 O-glycosylated domains (I and II) linked by a cysteine-rich nonmucin subdomain.1-3 These sialomucins encompass a
diverse protein family, exhibiting low levels of amino acid identity to one another.4 They are classified by (a) their high
content of proline, threonine, and serine residues that are
concentrated in 1 or more regions of the molecule, the so-called PTS
domains,4 and (b) O-linked glycosylation of the
serine and threonine residues that constitute the mucin
domains.4
The mucins were initially categorized into 2 classes on the basis of
the cell type from which they were isolated, with the epithelial mucins
encompassing MUC-1 to MUC-8 and the leukocyte/endothelial mucins
including CD34, CD43, CD45RA, glycosylation-dependent cell adhesion
molecule-1 (GlyCAM-1), mucosal addressin (MAd)CAM-1, Tactile (CD96),
and P-selectin glycoprotein ligand-1 (PSGL-1) (CD162).4 For
these and the more recently cloned mucins, such as kidney injury
molecule-1 (KIM-1), podocalyxin-like protein (PCLP), endomucin,
CD42b While these diverse peptide backbones provide the basic structure that
determines their ligand binding capacities, the functions of the mucins
in specific cells are dependent on the differential expression of
variant isoforms that result from differential splicing or sulfation of
specific tyrosine residues or modifications of oligosaccharide side
chains.20-22 The latter are dependent on specific enzymes,
the glycosyltransferases,20,23-25 or PAPS
(3 ' -phosphoadenosine-5 ' -phosphosulfate)
synthetase,26 within specific cells. By genomic analysis,
the leukocyte/endothelial mucins can be subdivided into 2 groups: those
in which the coding sequence is contained in a single exon and
those encoded by multiple exons. The former do not undergo differential
splicing and include CD43, CD42b We have identified 3 classes of epitopes on CD164.27 The
class I and II epitopes recognized by the 105A5 and 103B2/9E10 monoclonal antibodies (Mabs), respectively, are conformationally independent and located within the N-terminal mucin domain I. The
former is associated with long chain sialylated O-linked glycans, while
the class II epitope encompasses both N- and O-linked glycans. The
class III epitopes, defined by the Mabs N6B6 and 67D2, are conformationally dependent and encompass the cysteine-rich subdomain that links mucin domains I and II. These 3 classes of epitopes are
expressed by a subset of CD34+ hematopoietic progenitor
cells and stromal reticular cells from adult bone
marrow.1-3 We have recently demonstrated that interactions of the class I and class II CD164 epitopes with their surrogate ligands, the 105A5 and 103B2/9E10 Mabs, inhibit cytokine-induced recruitment of CD34+CD38lo/ Cell lines and antibodies
CD34+ cell isolation
Immunofluorescence labeling and flow cytometric analyses Single-color analysis of cell lines. All immunofluorescence labeling procedures were carried out as described previously.2 Triple-color flow cytometric analysis of CD34+ cells. After Fc receptor blockade (FcR blocking agent, Miltenyi Biotec), CD34+ cells were labeled with the CD164 Mabs, 103B2/9E10, 105A5, or N6B6 Mabs, or isotype-matched negative-control Mabs, CD34-PerCP or mIgG1-PerCP and AC-133-PE or mIgG1-PE for 30 minutes at 4°C in phosphate-buffered saline (PBS)-0.2% (wt/vol) bovine serum albumin followed by FITC-conjugated antimouse isotype-specific antibodies to mIgG3, mIgM, or mIgG2a.2 Four-color flow cytometric analysis of CD34+ cells from fetal liver. CD38-APC or a negative mIgG1-APC Mab were added in addition to the other 3 Mabs above prior to the analysis of fetal liver CD34+ cells. Flow cytometric analysis of
Lin Embryonic tissue processing for histology and immunostaining Human embryos were obtained immediately after voluntary terminations of pregnancy induced using RU 486 with informed consent according to the guidelines and with the approval of both national and institutional ethics committees. The embryos were fixed in 4% (wt/vol) paraformaldehyde (Sigma Chemical Co, St Louis, MO) and processed as described.30 Sections were stained with primary antibody overnight at 4°C, washed in PBS-0.25% (vol/vol) Triton X-100, and incubated for 1 hour at room temperature first with biotinylated rabbit antimouse Ig antibody (Dakopatts) and subsequently with horseradish peroxidase (HRP)-labeled streptavidin (Dakopatts). Peroxidase activity was developed with 0.025% (wt/vol) 3,3-diaminobenzidine (Sigma) in PBS containing 0.015% (wt/vol) hydrogen peroxide. Slides were counterstained with Harris's hematoxylin and mounted in XAM neutral medium.30Tissue specimens Tissues were collected with ethical approval and consent from the hospitals concerned. Tonsils were obtained from the Ear, Nose, and Throat Department of the Radcliffe Infirmary or the John Radcliffe Hospital, Oxford, England. Fresh normal adult tissue samples were provided by the Departments of Histopathology and Paediatric Pathology of the John Radcliffe Hospital. Thymus samples were obtained from 3 patients with myasthenia gravis (2 with thymoma and 1 hyperplastic thymus) and 2 normal thymuses from children undergoing cardiothoracic surgery. Fresh tissues were embedded in OCT (Bright, Huntingdon, England), snap-frozen in isopentane (BDH, Poole, England) in liquid nitrogen, and cryostat sections (5-8 µm) were cut, placed on 3-amino propyl-triethoxy-sialane-coated (Sigma) slides, air-dried overnight, fixed in acetone for 10 minutes, and stored at 20°C or 70°C until
used.31,32
Immunohistochemical staining of tissue sections Sections were blocked with 10% (vol/vol) normal human serum, incubated with Mab, and then incubated with peroxidase-conjugated goat-antimouse Ig (Dakopatts) or biotin-conjugated goat-antimouse Ig (Dakopatts) and streptavidin/HRP (Dakopatts). Staining was developed with diaminobenzidine tetrahydrochloride (DAB; Sigma) and hydrogen peroxide. The slides were then counterstained with hematoxylin (Surgipath, Eynesbury, St. Neots, England) and mounted in Apathy's mountant (BDH, Lutterworth, England).31,32Immunofluorescence staining of tissue sections Sections were FcR-blocked and then stained with CD164 Mabs and isotype-specific FITC-conjugated goat antimouse antibody, followed by CD1, CD3, CD19, CD31, CD33, CD43, CD68, HLA-DR, anticytokeratin, or isotype-matched negative-control antibodies, prior to adding the appropriate isotype-specific fluorescent-conjugated goat antimouse or antirabbit antibodies.31 Slides were mounted in fluorescent mounting medium (Dakopatts) with or without 2% (wt/vol) 4,6-diamidine-2-phenylindole dihydrochloride (DAPI) and viewed under an Olympus BX-60 (Olympus, London, England) or a Zeiss Axioskop (Zeiss, Welwyn Garden City, England) microscope. Images were captured on a JVC 3-CCD color video camera using the Neotech JVC software (Datacell Ltd, London, England) or on a CCD camera or Leaf micro lumina camera (Scitex Corp Ltd, Herzlia, Israel) using Improvision Openlab software (Improvision, Coventry, England) and analyzed in Adobe Photoshop. The exposure times were the same for the positive- and negative-control experiments.2Immunoblotting of cell and tissue lysates The equivalent of 8 × 104 of each exponentially growing cell line was resuspended in 1× nonreducing Laemmli loading buffer3 containing 1× Complete protease inhibitors (Boehringer-Mannheim, Mannheim, Germany) plus 5-mM DTT. A range of human tissues (heart, pancreas, colon, kidney, and spleen) were obtained from Clontech (Palo Alto, CA) and diluted in 1× Laemmli loading buffer containing 5-mM DTT and 1× Complete protease inhibitors (Boehringer-Mannheim). After boiling for 5 minutes, 2- to 10-µg lysate proteins or the equivalent of 8 × 104 were fractionated by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), transferred to polyvinylidine difluoride immobilon membranes, and probed with the CD164 or isotype-matched negative-control Mabs followed by HRP-conjugated antimouse Ig or antimouse Ig isotype-specific Mabs (Southern Biotechnology Associates Inc). Blots were developed using the ECL system (Amersham International, Amersham, Bucks, England).27
Expression of functional CD164 epitopes on CD34+ hematopoietic cells during ontogeny Because the interaction of class I and II CD164 Mabs 105A5 and 103B2/9E10, with their epitopes on bone marrow CD34+ cells,3 inhibits the adhesion of CD34+ cells to stroma or negatively regulates CD34+ cell proliferation, we examined the expression of these CD164 epitopes on CD34+ cells throughout ontogeny.CD164 epitopes are expressed on primitive
CD34+ intraaortic cell clusters in human
embryos.
The sialomucin CD34 was used to identify intraaortic cell clusters and
their associated ventral endothelium (Figure
1A, 1B), with the panleukocyte marker CD45
distinguishing hematopoietic from endothelial cells (Figure 1C) in
human embryo sections. We compared the expression of the homing
receptor, CD44 (Figure 1G), with that of CD43 (Figure 1D) and the CD164
epitopes 103B2/9E10 and 105A5 (Figure 1E and 1F, respectively). Our
results show clusters of positively stained hematopoietic
CD34+ cells adhering to the endothelium on the ventral side
of the dorsal aorta and vitelline artery, with these cells also
expressing CD45, CD43, CD44, and the CD164 epitopes 103B2/9E10 and
105A5.
The class I, II, and III CD164 epitopes are expressed on the surface
of primitive CD34+ cells from fetal liver,
cord blood, and adult bone marrow.
Although most CD34+ cells in fetal liver, cord blood, and
adult bone marrow expressed the CD164 functional epitopes, the level of
staining varied from high to low (Figure
2). In 3 separate CD34+
preparations from fetal liver, 70% ± 34%, 93% ± 3%, and
96% ± 1% of cells were stained with 105A5, 103B2/9E10, and N6B6
Mabs, respectively, above background levels (2% ± 0%,
2% ± 0%, and 3% ± 1% for mIgM, mIgG3, and mIgG2a,
respectively). In addition, 55% ± 12%, 93% ± 3%, and
89% ± 9% of CD34+ cord blood cells (4 independent
experiments) were positive for these same epitopes, respectively.
Similarly, 82% ± 10% of CD34+ human bone marrow
cells expressed higher than background levels of the N6B6 epitope,
whereas 70% ± 26% and 63% ± 26% of these cells reacted
with the 103B2/9E10 and 105A5 Mabs, respectively.
The highest cell surface expression of the 3 CD164 epitopes occurs
on
CD34hiAC133hiCD38lo/
The CD164 class I and II epitopes are expressed on the surface of
Lin
Class I, II, and III CD164 epitopes are differentially expressed in adult tissues in vivo Although the CD164 epitopes are highly expressed on primitive CD34+AC133+CD38lo/
hematopoietic progenitor cells, we have demonstrated that CD164 expression also occurs on subsets of more mature hematopoietic cells.2,3 We investigated the expression patterns of
the class I, II, and III epitopes in a set of normal adult tissues. In
contrast to the more uniform expression of CD164 epitopes on hematopoietic progenitor cells, the class I and II epitopes in diverse
tissue specimens were often differentially expressed.
Postnatal lymphoid tissues.
The class I and class II functional epitopes were often distributed on
reciprocal cell subsets, whereas the class III epitopes defined by N6B6
and 67D2 Mabs were expressed on both the 105A5+ and
103B2/9E10+ subsets (Table 3
and Figure 5). A sub-pan-reactive pattern
of staining with strong labeling of T and B lymphocytes and an absence of endothelial labeling was evident for the class I Mab 105A5 in tonsil
(Figure 5A), with the macrophage population exhibiting particularly
high levels of 105A5 epitope expression (Table 3; Figure 5L and 5K).
The class II Mab 103B2/9E10 stained CD31+ endothelium
(Figure 5P) in tonsil and thymus, basal-layer epithelium in tonsil
(Figure 5G), and subcapsular epithelium in thymus (Figure 5I) but not
lymphoid cells (Figures 5F and 6O; Table 3). Most thymic
CD1+ cortical lymphoid cells stained very weakly with the
class I Mab, with weak coexpression of the 105A5 epitope observed with CD43+ T cells in the thymic cortex and medulla (Figure 5N).
105A5 did not stain thymic epithelial cells (Figure 5D and 5E). Thymic
macrophages stained with 105A5 (Figure 5L) and 103B2/9E10 (Figure 5J).
The CD31+ thymic blood vessel endothelia was
105A5
Adult nonhematopoietic tissues.
The differential patterns of CD164 epitope expression observed in
hematopoietic tissues were observed in nonhematopoietic tissues,
particularly those with a glandular element, such as salivary gland,
thyroid, and colon (Table 3). While all of the Mabs labeled the
secretory lobules of salivary gland, the class II 103B2/9E10 Mab
labeled the apical membranes of secretory ducts, which were negative
for the class I 105A5 epitope. In sections of colon, Mab 105A5 stained
the infiltrating CD68+ macrophages, CD3+ T
cells, and CD19+ B cells (Table 3) in the laminar propria
(Figure 6A). In contrast, 103B2/9E10
labeled the goblet cell vacuolar membranes of the colon and endothelial
cells within the laminar propria (Figure 6B, 6H, 6J, 6K, and 6L). This
was confirmed by colabeling with 9C4, which stains epithelial cells in
many tissues (S.M.W., unpublished data; Figure 6E and 6F). The N6B6 and
67D2 class III Mabs reacted with both the 105A5+ and
103B2/9E10+ cells in the colon sections (Figure 6C and 6D).
The basal layer of the skin was 103B2/9E10 class II+
(Figure 6M). The splenic sinus endothelia were strongly
103B2/9E10+ while, in brain, the specialized
endothelia34 were both class I 105A5+ and class
II 103B2/9E10+ (Table 3).
Immunoblot analysis of CD164 epitopes in tissues and cell lines.
CD164 messenger RNA can be detected in a variety of cell lines and
tissues. To confirm that the CD164 Mabs were recognizing molecules of
similar apparent molecular weights in these tissues, a set of
whole-cell lysates were immunoblotted with each CD164 Mab after
SDS-PAGE separation (Figure 7). The Mab
105A5 detected an 80- to 100-kd protein in kidney and spleen on short
exposures (Figure 7A) and, on longer exposures, proteins within this
molecular weight range were also seen in colon and pancreas. The
expression in heart was very weak and only detectable on very long
exposures. Equivalent proteins of 80- to 100-kd were detected in each
tissue examined using the class III Mab N6B6 (Figure 7B). However,
particularly strong reactivity was found with spleen and, as with 105A5
detection, the protein appeared to possess a slightly higher molecular
weight than that found in other tissues. The class II Mab, 103B2/9E10, although able to detect this slightly higher-molecular-weight protein
in spleen, did not appear to detect any protein bands in the other
tissues examined (data not shown), presumably due to the limited
cellular expression of this epitope in these tissues. The size and
intensities of the bands detected with the different CD164 Mabs are
very likely the result of differential/partial glycosylation generated
by differential splicing of the CD164 molecule or during processing.
The other class III Mab, 67D2, detected the 80- to 100-kd proteins in
pancreas, colon, kidney, and spleen as well as much
higher-molecular-weight molecules (> 220 kd) in heart and kidney
(Figure 7C). On filters of hematopoietic cell lines representing
CD34+ progenitor cells (KG1A), monocytic cells (U937), and
B cells (RPMI-1788) and of epithelial cell lines derived from the colon (Calu-1), uterus (HeLa), and kidney (293T), the class I Mab 105A5 (Figure 7D), the class II Mab 103B2/9E10 (Figure 7E), and the class III
Mab N6B6 (Figure 7F) detected proteins of 80 to 100 kd, while the class
III Mab 67D2 detected the 80- to 100-kd and greater than 220-kd protein
bands (data not shown). These studies confirm our preliminary
observation that the higher-molecular-weight band is found in the SDS
solubilized cell and tissue lysates but not in the cell lysates
solubilized in Triton X-100, NP-40, or CHAPS detergents. Explanations
for these results are that the CD164 molecule may associate with
cytoskeletal elements in a complex that is not solubilized by Triton
X-100 or that the 67D2 Mab may detect a Triton X-100-insoluble CD164
isoform containing a glycosaminoglycan attachment or CD164
tetramers.27
Hematopoiesis in mammals and birds originates from the extra-embryonic mesoderm of the yolk sac and autonomously from the paraaortic splanchnopleural mesoderm, the presumptive aorta-gonad-mesonephros (AGM) region of the embryo proper.35,36 The observation that hematopoietic and endothelial cells are closely associated during embryonic development, particularly in the blood islands of the yolk sac and in dorsal aorta and vitelline artery, has led to the hypothesis that a common hematopoietic-endothelial precursor, termed the hemangioblast, exists. In this respect, elegant transplantation experiments in birds have suggested the existence of 2 distinct endothelial lineages. The first is derived from the somites and generates the sides and roof of the aorta. The second, which has both endothelial and hematopoietic potentialities, forms the floor of the aorta.37 This may represent a common mechanism for hematopoietic/endothelial development in birds and mammals. In the human 4- to 5-week-old embryo, the largest accumulation of CD45+CD31+CD34+ putative hematopoietic stem cells has been found associated with the ventral endothelium of the aorta and the vitelline artery.30,38-40 Here, the endothelial layer is disorganized and replaced by cell clusters that bud into the lumen and express hematopoietic markers such as CD45.32,39 These cells have also recently been shown to coexpress SCL, c-myb, GATA-2, GATA-3, c-kit, flk-1, HCA (CD166), and KG1-kinase.39,40 From murine gene knockout studies, several of these molecules (eg, GATA-2, SCL, and flk-1) appear to be essential for definitive hematopoiesis.36
The authors thank Drs K. Micklem, R. Roberts-Gant, M. Jones, R. Bicknell, and Professors K. Gatter and N. Willcox for their advice on the section staining, and Professors D. J. Weatherall, L. Kanz, and M. J. Watt for their support.
Submitted August 25, 1999; accepted January 12, 2000.
Supported by the Leukaemia Research Fund and the Medical Research Council UK, INTAS/RFBR and EU Biotechnology grants and Smith-Kline Beecham (S.M.W., L.H.B., I.R., R.D., J.Y.-H.C.), Deutsche Forschungsgemeinschaft (SFB 510; project A1; H.-J.B.), National Health and Medical Research Council of Australia (P.J.S., A.C.W.Z., J.-P.L.), State Scholarships Foundation of Greece (I.R.) and, in part, the European Commission (M.T., B.P.).
B.P. and I.R. are joint senior authors of this paper.
Reprints: Suzanne M. Watt, MRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, England; e-mail: swatt{at}enterprise.molbiol.ox.ac.uk.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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S. Forde, B. J. Tye, S. E. Newey, M. Roubelakis, J. Smythe, C. P. McGuckin, R. Pettengell, and S. M. Watt Endolyn (CD164) modulates the CXCL12-mediated migration of umbilical cord blood CD133+ cells Blood, March 1, 2007; 109(5): 1825 - 1833. [Abstract] [Full Text] [PDF]
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L. Rossi, R. Manfredini, F. Bertolini, D. Ferrari, M. Fogli, R. Zini, S. Salati, V. Salvestrini, S. Gulinelli, E. Adinolfi, et al. The extracellular nucleotide UTP is a potent inducer of hematopoietic stem cell migration Blood, January 15, 2007; 109(2): 533 - 542. [Abstract] [Full Text] [PDF]
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M. A. Vodyanik, J. A. Bork, J. A. Thomson, and I. I. Slukvin Human embryonic stem cell-derived CD34+ cells: efficient production in the coculture with OP9 stromal cells and analysis of lymphohematopoietic potential Blood, January 15, 2005; 105(2): 617 - 626. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
, CD68, and CD107, this classification is not absolute. For
example, MUC-1 can be found on hematopoietic cells,
