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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-02-0564.
HEMATOPOIESIS
From the Immunology Department, Weizmann Institute of
Science, Rehovot, Israel; Gene Therapy Institute, Hadassah University
Hospital, Jerusalem, Israel; Hematology Institute, Tel Aviv Sourasky
Medical Center, Tel Aviv, Israel; Oncological Sciences Department,
Division of Clinical Oncology, Istituto per la Ricerca e la Cura del
Cancro (IRCC) Cancer Institute, Candiolo, Italy; and Bone Marrow
Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel.
Homing and repopulation of nonobese diabetic/severe combined
immunodeficient (NOD/SCID) mice by enriched human CD34+
stem cells from cord blood, bone marrow, or mobilized peripheral blood
are dependent on stromal cell-derived factor 1 (SDF-1)/CXCR4 interactions. Recently, human cord and fetal blood
CD34+CD38 Hematopoietic stem cells migrate during embryonic
development from the fetal liver through the blood circulation, home to the bone marrow (BM) microenvironment, and repopulate it with immature
and maturing blood cells of all lineages. Similarly, in clinical and
experimental stem cell transplantation protocols, hematopoietic stem
cells, which are infused into the blood circulation of patients and
experimental animals, home and repopulate the BM.1 The
molecular mechanisms that regulate the homing and repopulation
processes are crucial for stem cell function and development.2-5
The CXC chemokine stromal cell-derived factor 1 (SDF-1) plays a major
role in migration, proliferation, differentiation, and survival of many
cell types including human and murine hematopoietic stem/progenitor
cells.6,7 SDF-1 is produced by multiple BM stromal cell
types and by epithelial cells in many organs8,9 and is
highly expressed by human and murine BM endothelium.10-12 CXCR4, the 7-transmembrane receptor of SDF-1, is widely expressed by a
variety of hematopoietic cell types, neuronal cells, and different
stromal cells.13 SDF-1 is a chemotactic agent for human
lymphoid, myeloid, and immature CD34+ progenitor
cells.6,7,14,15 This chemokine induces integrin-dependent adhesion of CXCR4+ human T lymphocytes16 and
immature CD34+CXCR4+ cells17 under
shear flow and also mediates transendothelial migration of human
progenitors.18 In vivo cell migration and localization are
also mediated by SDF-1/CXCR4 interactions. Murine T cells
overexpressing human CXCR4 and CD4 accumulated in the BM of transgenic
mice.19 Prevention of CXCR4 expression by introducing SDF-1 intrakine blocked in vitro migration and in vivo dissemination of
a T-cell hybridoma.20 More important, mice reconstituted with progenitor cells expressing SDF-1-intrakine suffered impaired lymphoid and myeloid hematopoiesis, whereas transplantation of progenitors overexpressing SDF-1 led to increased myeloid and B-lymphoid hematopoiesis.21 The key role of SDF-1 and
CXCR4 in embryonic development was demonstrated by knockout studies in
mice. The lack of either SDF-1 or its receptor in murine fetuses results in multiple lethal defects including impaired BM
hematopoiesis.22-25
Recently, Wright and colleagues have demonstrated that SDF-1 is the
sole chemokine mediating in vitro migration of purified adult murine BM
stem cells.26 This important study suggests a major role
for SDF-1/CXCR4 interactions also in adult murine stem cell migration
and development.
We demonstrated the essential role of SDF-1/CXCR4 interactions in
both homing and high-level multilineage repopulation of nonobese diabetic/severe combined immunodeficient (NOD/SCID)
and NOD/SCID/B2mnull mice that have received primary and
secondary serial transplants of enriched human
CD34+ stem and progenitor cells derived from cord blood
(CB), BM, and mobilized peripheral blood.10,27,28 The
antihuman CXCR4-neutralizing monoclonal antibody (mAb; clone 12G5)
binds CXCR4 on the first and second extracellular domain as its ligand
SDF-1, interfering with SDF-1 binding and signaling.29,30
Coinjecting enriched human CD34+ cells with neutralizing
anti-CXCR4 mAb blocked homing and repopulation of human
SCID-repopulating stem cells. Similar inhibition was achieved by using
neutralizing anti-SDF-1 antibody or desensitizing CD34+
cells with high doses of SDF-1.27,28 Increasing SDF-1
levels within the recipient BM by either preconditioning the murine
hosts with DNA-damaging agents or by direct injection of human SDF-1 led to increased homing and repopulation.10,28 Short-term
(24-48 hours) stimulation with stem cell factor (SCF) and interleukin 6 (IL-6) up-regulated surface CXCR4 expression by immature human CD34+ cells and increased in vitro migration toward a
gradient of SDF-1 and in vivo homing and
repopulation,27,28 demonstrating functional dynamic
expression of CXCR4. We therefore recharacterized human SCID
repopulating stem cells as CD38 The aim of the present study was to elucidate the regulation of CXCR4
expression in sorted human CB CD34+CXCR4 Human cells
Mice
Human cell engraftment Where indicated, human cells (1-2 × 105 cells/mouse) were preincubated with nonconjugated neutralizing antihuman CXCR4 mAb (10 µg or 50 µg/mouse, clone 12G5, R&D Systems) before transplantation. Incubated cells were not washed and the entire dose of anti-CXCR4 mAb was coinjected with the cells. In other experiments, 10 µg anti-CXCR4 mAb was injected intraperitoneally at different time points after transplantation as indicated. Two or 6 weeks later, a single-cell suspension was prepared from the BM and spleen of mice that underwent transplantation. Human cell engraftment was assayed by flow cytometry (FACSCalibur, Becton Dickinson), using specific antihuman CD45-FITC mAb (Immuno Quality Products, Groningen, The Netherlands), anti-CD19-PE (Coulter, Miami, FL), or anti-CXCR4-PE (12G5, Pharmingen). Human plasma and mouse IgG were used to block Fc receptors. Isotype control antibodies and cells obtained from mice that did not undergo transplantation were used as negative controls and human cells were used as a positive control.Intracellular CXCR4 staining CXCR4 expressed on the cell surface was blocked with nonconjugated antihuman CXCR4 mAb (clone 12G5, 10 µg/mL, 1 hour, 4°C). Cells were fixed with paraformaldehyde (4%, 20 minutes at room temperature; BDH, Poole, England) and then permeabilized with Triton X-100 (0.5%-1%,10 minutes at room temperature; Sigma, St Louis, MO). Antihuman CXCR4-PE mAb was used to label the cells for flow cytometry for 30 minutes, 4°C. The cells were washed with phosphate-buffered-saline without Mg++/Ca++ after each step.Homing assay Human CD34+CXCR4 sorted cells
( 7 × 105 cells/mouse) and human
CD34+-enriched cells (5 × 105 cells/mouse)
from the same donors were injected into sublethally (375 cGy)
irradiated mice 24 hours after irradiation. Where indicated, cells were
incubated with antihuman CXCR4 mAb (10 µg/mouse) and coinjected
without washing. Cells were recovered from the BM and spleen of mice
that underwent transplantation 16 or 29 hours after transplantation and
analyzed for the presence of human cells by using human-specific
anti-CD34-FITC (Becton Dickinson), antihuman CD38-PE (Coulter), and
anti-CXCR4-PE antibodies acquiring at least 106
cells/sample. Mouse IgG and human plasma were used to block Fc receptors. Cells obtained from mice that did not undergo
transplantation or labeled with mouse isotype control antibodies were
used as negative controls. Human cells were used as a positive control and propidium iodide (PI) staining was used to exclude
dead cells.
Migration assay Human CB-enriched CD34+ cells were allowed to migrate toward a gradient of SDF-1 as previously described.27 Briefly, 125 ng/mL SDF-1 was added to the lower chamber of a Costar 24-well transwell (Corning, NY). CD34+ cells (1-2 × 105) or R4
cells (1 × 105 cells, 2, 24, and 48 hours after sorting
and incubation with the indicated cytokines) were loaded to the
upper chamber and were allowed to migrate for 4 hours at 37°C.
CD34+ migrating cells (which are about 25% of the total
CD34+ population) were collected from the lower chamber,
washed, and transplanted (1-2 × 105 cells/mouse) into
NOD/SCID mice as indicated.
Sorted CB CD34+CXCR4+ and
CD34+CXCR4 (R4) purified
subsets, yielding a purity of more than 97% (Figure 1Bi,ii,iii,
respectively). Because R4+ cells required staining with
neutralizing anti-CXCR4 mAb for their sorting, a process that also
blocks SDF-1 signaling, enriched CD34+ cells from the same
donors were kept untreated as a positive control. In addition, enriched
CD34+ cells from the same donors were allowed to migrate
toward a low gradient of SDF-1 in transwells, to functionally select
CXCR4+ cells based on their responsiveness to SDF-1,
without blocking SDF-1 binding and signaling, and with only minimal
CXCR4 internalization. Equal numbers of all CD34+ subsets
were then transplanted into sublethally irradiated NOD/SCID mice
(1-2 × 105 cells/mouse) that were assayed for the
level of human/mouse chimerism 2 weeks (only for control, total
CD34+ cells) or 5 or 6 weeks later, as indicated. Enriched
CD34+ cells and CD34+ cells migrating to a
gradient of SDF-1 demonstrated significantly higher levels of human
cell engraftment (26.7% and 34.8%, respectively) compared to
R4+ and R4 sorted cells (3.1% and 4.4%,
respectively; Figure 1C). These data demonstrate that the use of
neutralizing antibodies to sort R4+ cells significantly
impairs their repopulating potential by preventing SDF-1 binding and
signaling. Repopulation levels by R4+ sorted cells are thus
similarly reduced to the low levels obtained with R4
cells. However, the low but significant repopulation ability of
R4 and neutralized R4+ cells required further
investigation.
Sorted CB CD34+CXCR4 cells (4.4%) were also
significantly reduced by coinjection with 10 µg neutralizing
anti-CXCR4 (1.3%), providing evidence for CXCR4-dependent engraftment
also by the R4 cells (Figure 1C). Moreover, the in vivo
inhibition capacity of the neutralizing anti-CXCR4 mAb is
dose-dependent. Coinjection of 50 µg/mouse neutralizing anti-CXCR4
mAb significantly reduced further BM repopulation by both control,
total CD34+ cells (0.1% ± 0.03%) and by sorted
CD34+CXCR4 cells (0.2% ± 0.05%) similar
to the minimal background levels detected by isotype control mAb
staining (0.1%; Figure 1D). This high dose was used to demonstrate
that BM repopulation could be totally blocked with a single treatment
of anti-CXCR4 mAb (Figure 1D).
A similar pattern of CXCR4-dependent repopulation by the different
human CD34+ subsets was also observed in the spleen of mice
that received transplantations, which is a hematopoietic organ as well
(Figure 2). Repopulation by
CD34+ subset coinjected with neutralizing anti-CXCR4 mAb,
was also significantly reduced (to 0.26% by using 10 µg/mouse and
0.05% with 50 µg/mouse) compared to their untreated counterparts
(3.5%; Figure 2). Similarly, repopulation by
CD34+CXCR4
Sorted CD34+CXCR4 cells as well can rapidly express functional cell
surface CXCR4 that, in turn, mediates their limited SDF-1-dependent
repopulation capacity. To investigate this hypothesis, the levels of
cell surface and intracellular CXCR4 expressed by the cells were
determined immediately after sorting and following 24 hours of in vitro
incubation with cytokines that are known to support SCID repopulating
cells.31,33 We documented low intracellular CXCR4 levels
in sorted R4 cells (Figure
3Aib), whereas almost no detectable CXCR4
was expressed on the cell surface (Figure 3Bi). R4 sorted
cells that were cultured with a 5-cytokine combination (SCF, FLT3-L,
IL-6, IL-3, and G-CSF)31,33 demonstrated limited cell
surface CXCR4 expression after 24 and even more so after 48 hours,
similar to normal levels, (Figure 3Biii and vi, respectively), which
was associated with increased expression of intracellular CXCR4 (Figure
3Aiid). Similarly, spontaneous up-regulation of surface CXCR4
expression within 24 hours was also observed when R4
cells were cultured in serum-free media without additional cytokines, suggesting autocrine secretion of cytokines capable of CXCR4
up-regulation, although cell viability was significantly reduced (56%
viability, Figure 3Bv). Most notably is the fact that short-term
cytokine-stimulated R4 sorted cells express similar
levels of intracellular CXCR4 compared to freshly isolated
CD34+ cells (Figure 3Aic and iid, respectively), indicating
the potential of both subsets to rapidly express surface CXCR4 within
24 hours.
The potential of newly expressed receptors to function in vitro was
assessed by SDF-1 transwell migration assay, comparing R4 Slower and reduced CXCR4-dependent homing of sorted
CD34+CXCR4 sorted cells to
express functional CXCR4 during transplantation, in vivo experiments
were performed. In one set of experiments we introduced anti-CXCR4 mAb
into the recipients at multiple time points up to 10 hours after
transplantation to provide R4 cells with time to regulate
cell surface CXCR4 expression in vivo. Engraftment of R4
cells was significantly reduced regardless of whether mAb was injected
together with the cells (Figure 1C) or separately 1, 5, or 10 hours
later by intraperitoneal injection (Figure
4A, left panel; P < .005).
Moreover, the partial up-regulation of both intracellular and cell
surface CXCR4 induced by cytokine stimulation within 24 and 48 hours
(Figure 3Aii,Biii,vi) correlated well with improved CXCR4-dependent
engraftment capacities (1.4- and 4.2-fold increase, Figure 4A, middle
and right panels). Fluorescence-activated cell-sorter scanner (FACS)
analyses of highly engrafted mice that received transplants of
R4 cells that were cultured with 5 cytokines for 48 hours
reveals that once the cells engraft the murine BM, they give rise to
normally distributed multilineage differentiation as indicated by the
presence of myeloid and B-lymphoid human cells (Figure 4Bi).
Interestingly, these cells expressed variable levels of surface CXCR4
(Figure 4Bii) demonstrating the ability of R4
transplanted cells to give rise to a heterogeneous, normal cell profile
in the murine BM. No human cell engraftment could be determined when
the cultured cells were coinjected with neutralizing anti-CXCR4 mAb
(Figure 4Biii).
We previously showed that freshly isolated human CB
CD34+-enriched cells home rapidly in a CXCR4-dependent
manner and can be detected in the BM and spleen of NOD/SCID recipient
mice as early as 2 to 4 hours after transplantation.28 The
potential function of cell surface CXCR4, expressed by transplanted
R4 Taken together, these results corroborate the notion that following in
vitro cytokine incubation and subsequent in vivo stimulation of
R4 In vitro and in vivo dynamic CXCR4 expression on CXCR4+ sorted cells As shown in Figure 1C, binding of anti-CXCR4 mAb used for sorting (in which the excess of conjugated mAb was washed) did not fully abolish the SDF-1-dependent repopulating potential of sorted R4+ cells. We considered the possibility that CXCR4 expression by R4+ sorted cells is not constant and is dynamically regulated during the sorting process and moreover while circulating in vivo, enabling partial recovery of receptor function and homing/repopulation activities. Thus, R4+ cells were incubated in the same cytokine combination as R4 cells.
Unexpectedly, the expression of cell surface CXCR4 was reduced
following 24 and furthermore 48 hours of cytokine stimulation with SCF,
FLT3-L, IL-6, IL-3, and G-CSF (Figure
5Ai-iii). Interestingly, cells incubated
with SCF and IL-6 alone maintained higher levels of CXCR4 on the
cell surface compared to the 5-cytokine combination (Figure
5Aiv). Moreover, viable sorted R4+ cells cultured
in serum-free media without cytokines preserved the highest level of
CXCR4 surface expression (Figure 5Av), suggesting involvement of an
autocrine loop of cytokine signaling. However, human cytokine
deprivation led to reduced cell viability (40% viable cells compared
to 97% with cytokines). Similarly, CXCR4 down-regulation was
previously documented by primitive
CD34+CD38CXCR4+ sorted cells
within 24 hours of cytokine stimulation in an SDF-1-responsive manner.31 Intracellular CXCR4 levels expressed by
R4+ cells could not be documented due to the high
background contributed by the cell surface receptors stained with the
conjugated antibody used for sorting.
To evaluate whether the cells, which express the highest CXCR4 levels also gain the highest stem cell activity, we next examined the repopulating potential of cytokine-stimulated R4+ cells. Despite reduction in the total level of surface CXCR4 expression detected during the culture period (Figure 5Ai-iii), 5-cytokine-treated R4+ cells had significantly increased engraftment capacities compared to nonstimulated R4+ sorted cells (Figure 5B, P < .03). This contradiction between decreasing CXCR4 expression and increasing NOD/SCID repopulation led us to re-examine the cytokine-treated cells for newly expressed CXCR4 receptors. Still binding the labeled, neutralizing anti-CXCR4 antibodies used for sorting, the cultured cells were analyzed with and without restaining for CXCR4. Figure 5C shows the fold increase of CXCR4 re-expression calculated by dividing nonrestained by restained values. A strong correlation between new surface CXCR4 re-expression (C) and the potential to repopulate NOD/SCID (B) can be clearly observed. These results imply a dynamic expression of CXCR4: highly expressed receptors, which bind neutralizing anti-CXCR4 mAb, are down-regulated with time most probably mimicking interactions mediated by the ligand. On the other hand, new receptor molecules free of inhibitory mAb are expressed in vitro and in vivo and mediate SDF-1-dependent repopulation. These newly expressed functional receptors can also be efficiently blocked by coinjecting 10 µg neutralizing anti-CXCR4 mAb leading to significantly reduced engraftment levels (Figure 5B, P < .03).
The study reported here shows that the mechanism whereby
SDF-1/CXCR4 interactions regulate the homing and repopulation of human
stem cells is a dynamic process. We demonstrate that despite the
absence of CXCR4 on the cell surface,
CD34+CXCR4 The low repopulation capacity of CD34+CXCR4+
sorted cells results from the neutralizing activity of anti-CXCR4 mAb
that was used for sorting. This mAb (12G5) binds conformation-dependent epitopes34 comprised of the first and second extracellular
loops of CXCR4, a site that also serves for SDF-1 binding and
signaling.29,30 Thus, conjugated 12G5 mAb used to sort
CD34+CXCR4+ cells also neutralizes receptors
expressed on the cell surface, leading to reduced potential of
positively labeled cells to respond to SDF-1. Homing of enriched human
CB CD34+ cells was not impaired by either antihuman CD34
antibody or by in vivo infusion of isotype control antibody (data not
shown). Nevertheless, an indirect effect of infused neutralizing
anti-CXCR4 mAb has to be considered as well. Recently, Tanaka et al
produced a new antihuman CXCR4 mAb, A80, which binds the third
extracellular loop of CXCR4. A80 did not interfere with SDF-1
signaling, but triggered agglutination of T cells.35
Therefore, the possibility of using nonneutralizing anti-CXCR4 mAb such
as A80 to sort CXCR4 subsets of CD34+ cells without
interfering with their SDF-1 signaling will be evaluated in future
studies. As long as neutralizing mAbs are used, the repopulating
potential of CD34+ subsets sorted on the basis of CXCR4
expression have to be compared with unmanipulated CD34+
cells. In the present study 2 crucial control cell subsets were added:
unmanipulated enriched CD34+ cells and CD34+
cells migrating toward a relatively low concentration of SDF-1, that
is, CXCR4+ cells that retain the potential to respond to
murine SDF-1 in vivo. Both control populations demonstrated
significantly high levels of engraftment as opposed to the low levels
obtained with sorted R4+ and R4 We demonstrate that freshly isolated R4 In contrast to R4 Our results show that in parallel to down-regulation of antibody bound surface CXCR4 by highly expressing R4+ cells in a process that mimics receptor-ligand interactions, newly expressed receptors were documented, which could compensate for antibody-bound internalized receptors by facilitating an increased repopulation potential. Different cytokine combinations might differently regulate the turnover of cell surface CXCR4. We found that SCF plus IL-6 better induce surface CXCR4 up-regulation.27 These studies support the notion of dynamic regulation of both CXCR4 expression and function, which are rapid, and moreover stress the important role of using biologic assays to assess cell function based on specific activities rather than surface markers that reveal only a frozen snapshot and can rapidly be changed with time. Other surface markers expressed on hematopoietic stem cells, such as CD34, also oscillate on both human and murine stem cells.48,49 Oscillated CXCR4 expression is also observed when stem and progenitor cells egress from the BM into the blood circulation. Recently others and we demonstrated that SDF-1/CXCR4 interactions are also implicated in both human and murine G-CSF-induced mobilization.50-53 Interestingly, G-CSF administration, associated with SDF-1 decrease, induced a pattern of CXCR4 oscillation; a rapid reduction was followed by increased expression within 0.5 to 1 hour after each G-CSF injection,50 demonstrating that dynamic regulation of CXCR4 expression is involved in cell migration and localization in vivo. Proteolytic enzymes such as neutrophil elastase are actively involved in SDF-1 degradation and surface CXCR4 inactivation by cleavage of the signaling N-terminus of the receptor.50,54 Matrix metalloproteinase-9 (MMP-9) secretion, induced by SDF-1 within the BM, regulates the shedding of c-kit ligand (SCF) from the BM during stem cell mobilization.55 Interestingly, mobilized peripheral blood CD34+ cells express reduced levels of surface c-kit, demonstrating dynamic regulation of this receptor on migrating stem and progenitor cells.56 The key role of CXCR4 signaling in stem cell activity was demonstrated
by documenting in vitro and in vivo effects of SDF-1 on repopulating
cells. SDF-1 is a survival factor for both human and mouse stem
cells.57,58 It was previously shown that the majority of
human CD34+-enriched cells, the more mature
CD34+CD38+ cells, which include
CXCR4+ cells, also secrete low levels of
SDF-159,60 and therefore are less sensitive or dependent
on exogenous SDF-1 compared with the more primitive
CD34+CD38 In summary, our data provide further evidence for the key role of CXCR4 regulation and cell surface expression in motility and tissue localization of human stem and progenitor cells in a preclinical, small animal model. CXCR4 expression is a dynamic process, which is regulated by environmental factors such as cytokines, chemokines, stromal cells, and adhesion molecules. Our findings that CXCR4 oscillation has biologic roles in regulating human stem and progenitor cell migration, homing, and repopulation, suggest in vitro stimulation of human progenitors prior to clinical stem cell transplantation to improve human SDF-1-dependent stem cell homing and repopulation.
Special thanks to Drs John Dick and Dov Zipori for fruitful discussions and for critically reviewing this manuscript.
Submitted February 21, 2002; accepted June 5, 2002.
Prepublished online as Blood First Edition Paper, June 21, 2002; DOI 10.1182/blood-2002-02-0564.
Supported in part by grants from the Israel Academy of Science, The Ares Serono group, and MINERVA Foundation. T.L. is Incumbent of the Pauline Recanati Career Development Chair of Immunology.
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.
Reprints: Tsvee Lapidot, Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel; e-mail: tsvee.lapidot{at}weizmann.ac.il.
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| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
sorted cells harbor
intracellular CXCR4, which can be functionally expressed and provide
NOD/SCID repopulation
Top
Abstract
Introduction
SCF, FLT-3 ligand (FLT3-L 300 ng/mL each), G-CSF
(50 ng/mL), IL-3 (10 ng/mL), all from R & D Systems (Minneapolis, MN)
and IL-6 (10 ng/mL; Interpharm Laboratories, Ares-Serono Group, Ness
Ziona, Israel); 2-cytokine combination
) or with (
) anti-CXCR4
mAb (10 µg/mouse). Each dot represents one mouse. Data summarize
results of 3 independent experiments. P values are
indicated. (B) CB enriched CD34+ cells (Bi) were further
sorted with neutralizing antihuman CXCR4 mAb to R4+ (Bii),
and R4
indicates untreated
CD34+ cells. 
indicates coinjection of 10 µg/mouse.
indicates coinjection of 50 µg/mouse or background levels
determined by staining with isotype control mAb, as indicated.
P values are indicated. Data present values of 3 experiments.
.005). Comparing in vivo surface CXCR4
expression by total human CD34+ BM-homed cells 16 hours
after transplantation (Figure 4Diii), with R4
/low)CXCR4(+) stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2m(null) mice.
Blood.
2001;97:3283-3291