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RED CELLS
From the Division of Hematology/Oncology, Children's
Hospital; the Department of Pediatrics, Harvard Medical School; and the
Howard Hughes Medical Institute, Boston, MA; and the Department of
Biology, Massachusetts Institute of Technology, Cambridge, MA.
Mammalian erythrocytes undergo a unique maturation process in which
they discard their nuclei and organelles and assume a flexible
biconcave shape. We found that altered plasma lipoprotein metabolism
can profoundly influence these events. Abnormal erythrocyte morphology
was observed in hypercholesterolemic mice lacking the high-density
lipoprotein receptor SR-BI. This was exacerbated by feeding mice a
high-cholesterol diet or, more dramatically, by inactivating the
apolipoprotein E gene. Erythrocytes from
SR-BI Red blood cells are descended from multipotential
hematopoietic progenitor cells in the bone marrow. Lineage commitment
establishes an erythroid differentiation program in which differential
gene expression leads to high-level hemoglobin production, nuclear condensation and expulsion from the cell, and the shutdown of most
cellular functions. The erythroid precursors generated by the expulsion
of nuclei from bone marrow erythroblasts are called reticulocytes.
Early reticulocytes, which are rarely found in the peripheral blood,
are irregular in shape and contain cytoplasmic organelles and
polyribosomes.1 As reticulocyte maturation progresses, RNA, mitochondria, and ribosomes are degraded; protein synthesis ceases; and cell-surface transferrin receptors (Trfrs)
disappear. Finally, cytoskeletal remodeling transforms reticulocytes
into compact, biconcave, discoid corpuscles devoid of organelles and translational apparatus. The earliest steps in erythroid commitment and
differentiation have been the subject of extensive study (reviewed in
Bungert and Engel2). However, maturational events
subsequent to nuclear expulsion have been only partially characterized
by morphologic studies.1,3,4 Some patients with severe
anemia syndromes, especially those whose spleen has been removed, have a small fraction of circulating erythrocytes containing
autophagosomes.1 Because these autophagosomes contain
mitochondria and ribosomes that are absent from mature erythrocytes, it
has been proposed that they represent intermediates in the final stages
of red cell maturation.1 Furthermore, splenic macrophages
have been postulated to participate in the removal of autophagosomes
from such precursors, but the mechanism of autophagosome extraction in
the bone marrow was not addressed.1 We show here that
hypercholesterolemic mice with abnormal lipoproteins due to
inactivation of the high-density lipoprotein (HDL) receptor
SR-BI gene (SR-BI SR-BI mediates cellular uptake of cholesterol and plays a key role in
the transport of cholesterol from peripheral tissues to the liver by
HDL (reviewed in Krieger6). During studies of the role of
SR-BI in atherosclerosis,7 SR-BI In the current study, we observed that
SR-BI Animals
Erythrocyte analysis
Detection of lysosomes and RNA in reticulocytes We visualized lysosomes by washing fresh red blood cells and diluting them 1:1000 in Eagle modified minimum essential medium with low calcium and without L-glutamine (BioWhittaker, Walkersville, MD) and then incubating them with Lysotracker (Molecular Probes, Eugene, OR), a pH-specific marker for lysosomes, or with fluorescein di-( -D-galactopyranoside) (FDG) (Sigma, St Louis, MO), a substrate of -galactosidase that yields a fluorescent cleavage product. We
visualized fluorescence by confocal imaging on a Kr/Ar Zeiss Axio Vert
s100 microscope.
Flow cytometry Trfr was detected with a phycoerythrin-conjugated monoclonal anti-Trfr antibody (Pharmingen, San Jose, CA), and RNA was detected with thiazole orange (Becton Dickinson, San Jose, CA) as previously described.12 SR-BI was detected with a polyclonal rabbit anti-SR-BI antibody13 and a 488 fluorophore-labeled antirabbit antibody (Molecular Probes). We detected circulating erythroid cells at all stages of maturity with a phycoerythrin-conjugated antimouse TER-119 antibody (Pharmingen).Induced reticulocytosis Reticulocytosis was induced in wild-type mice by daily removal of 0.3 to 0.5 mL blood for a period of 7 days, maintaining the hematocrit above 20%. Iron dextran (5 mg) (Sigma) was administered intraperitoneally on day 3. Final reticulocyte counts in these animals ranged from 45% to 55%.In vitro incubation of blood cells We washed red blood cells once with phosphate-buffered saline (PBS) and once with minimum essential medium (BioWhittaker) augmented with 1 g/L glucose (5.5 mM), 25 mM Hepes, 20% fetal calf serum, 2 mM L-glutamine, 200 U/mL penicillin, and 200 µg/mL streptomycin, (GibcoBRL, Grand Island, NY), pH 7.4. We then counted cells and diluted them to 2 × 107/mL in this medium. We immediately harvested an aliquot of cells by centrifugation as the zero time sample. We monitored the medium pH regularly and maintained the medium at pH 7.4 with small additions of NaOH as previously described.14 We took samples at 24-hour intervals and prepared them for electron microscopy and flow cytometric analysis. In some experiments, we treated duplicate samples of 2 × 107 red cells per milliliter for 5 minutes prior to the in vitro incubation with 0.1% methyl B cyclodextrin (Sigma) in the incubation medium at 37°C.In vivo biotin labeling and reinfusion of red blood cells We labeled red blood cells with biotin in vivo as previously described.15 We prepared 16 µg NHS-Biotin (Calbiochem, La Jolla, CA) per gram of body weight dissolved in 30 µL dimethylacetamide (Calbiochem) and diluted to 0.5 mL in PBS, and injected it through the tail vein of donor mice. At 2 hours after infusion, we collected blood in tubes containing EDTA as an anticoagulant and then transfused 0.5 mL into each recipient mouse. At 24 and 48 hours after transfusion, we bled the mice and analyzed cells by live confocal microscopy to detect biotin (with phycoerythrin-streptavidin; Molecular Probes) and autophagolysosomes (with Lysotracker as described above). We further analyzed the samples by flow cytometry as described above. We determined biotin-labeling efficiency by diluting cells and incubating 1 × 106 red cells with 15 micrograms of 1 mg/mL phycoerythrin-streptavidin.Filipin detection of cholesterol We preserved blood in vitro in Karnovsky fixative (2.5% paraformaldehyde, 2% glutaraldehyde, 0.2 M cacodylate buffer). The cells were then incubated for 2 hours in 50 µg/mL (from stock solution of 12 mg/mL in dimethylsulfoxide) of filipin (Sigma) in PBS to label cholesterol and generate a fluorescent signal. Fluorescence was observed by means of 4'6-diamidino-2-phenylindole-2 HCl filters for confocal microscopy and UV filters for flow cytometry.Quantitative cholesterol analysis We prepared erythrocytes for cholesterol quantitation by first centrifuging whole blood and removing plasma and buffy coat. The cells were then washed 3 times with PBS and diluted 1:1 in deionized water to cause cell lysis. Total cholesterol was extracted by adding 100 µL the internal standard epicoprostamol (1 mg/mL in methanol) (EPIC, Sigma Chemicals) either to 100 µL red blood cell lysate or to the positive control, human plasma. Human plasma was used as the positive control instead of pure cholesterol to compensate for any extraction effect. The samples were then saponified by adding 1 mL 10% potassium hydroxide/90% ethanol (Fisher Scientific, Fair Lawn, NJ) to each sample and incubating for 60 minutes at 60°C. The samples were cooled to room temperature and extracted with 2 mL hexane (Fisher Scientific) by mixing for 1 minute and then aspirating off the hexane layer. We repeated this 3 times and then combined the hexane extracts and evaporated them to dryness under nitrogen at 40°C. Finally, we resuspended the samples in 100 µL pyridine and 100 µL N, O-Bis(trimethylsilyl)-trifluoroacetamide/trimethylchlorosilane (Alltech Associates, Folsom, CA) and heated them for 60 minutes at 60°C.16,17 After cooling the extract, we injected 1 µL into a gas chromatograph mass spectrometer and measured the cholesterol levels (Hewlett Packard Model 5890/5972 [Atlanta, GA] equipped with a DB-1 column of 30 cm length, 0.25 mm inner diameter, and 0.25 µm film thickness [Alltech Associates]). Unesterified cholesterol was determined as above except that saponification was omitted.
Mice lacking SR-BI and apoE develop an unusual anemia SR-BI //apoE/
mice fed a standard chow diet had low hematocrits and hemoglobin
values, which differed significantly from wild-type controls (Table
1) (P < .0001). The
SR-BI//apoE/ red
blood cells were abnormally large as compared with wild-type cells
(MCV, P < .0001), but had normal or near-normal cellular hemoglobin content. All circulating
SR-BI//apoE/ red
blood cells were reticulocytes. Unlike wild-type and
apoE/ mice, whose red blood cells appeared
normal in blood smears (Figure 1A, B),
the SR-BI//apoE/ mice had a
nonuniform population of macrocytic red blood cells (Figure 1D) with a
targetlike appearance. However, these targetlike cells sometimes
appeared to have multiple intracellular inclusions and were often
spiculated. They were more irregular than classical target forms (eg,
the targetlike erythrocytes from homozygous hbd
mice18 in Figure 1E). Spiculated cells could be seen in smears from the SR-BI/ mice fed a standard
chow diet (Figure 1C), but their abnormalities were not as striking as
those from the SR-BI//apoE/
mice. We also observed morphologic abnormalities in
SR-BI/ and
SR-BI//apoE/ mice
using DIC microscopy. Unlike the normal morphologies of erythrocytes
from wild-type and apoE/ mice (Figure
1F,G), many erythrocytes from SR-BI/
mice had irregularities within their cytoplasms, suggesting the presence of small, membrane-enclosed intracellular inclusions (Figure
1H). Virtually all the erythroid cells from
SR-BI//apoE/ mice (Figure
1I) had one or more large, membrane-enclosed intracellular inclusions
that were considerably larger than those seen in
SR-BI/ animals. Their appearance was
distinctly different from that of the target cells of hbd
mice (Figure 1J). Furthermore, these cells from
SR-BI//apoE/ mice stained
strongly with both acridine orange and thiazole orange,19,20 indicating that they retained a high RNA
content, a characteristic of reticulocytes but not mature erythrocytes (Figure 4T and data not shown).
We further characterized the intracellular inclusions using electron
microscopy. Wild-type and apoE Membrane-enclosed inclusions within erythrocytes increase with cholesterol feeding and are correlated with cellular cholesterol content Because of the possibility that increased hypercholesterolemia accounted for the increased severity of defects in SR-BI//apoE/ mice relative
to SR-BI/ mice, we compared the red blood
cells from wild-type and SR-BI/ mice
maintained for 3 months on diets consisting either of normal, low-cholesterol chow or chow supplemented with 1% cholesterol. In
wild-type mice, the high-cholesterol diet did not appear to influence
the hematocrit, the MCV (Table 1; P not significant), or the
morphology of the cells (Figure 2A,B). In
contrast, SR-BI/ mice fed cholesterol had
exacerbation of a mild anemia (Table 1) (change in
SR-BI/ hematocrit significant;
P = .0007) and marked macrocytosis (Table 1) (change in
SR-BI/ MCV significant;
P = .0004). Electron microscopy showed that SR-BI/ mice fed cholesterol had larger and
more frequent intracellular inclusions than the controls fed normal
chow (Figure 2C,D). However, the cholesterol-feeding-induced
abnormalities in hematocrit, MCV, and erythroid cell morphology in
SR-BI/ mice were not as severe as those seen
in SR-BI//apoE/ mice.
To determine if the morphological abnormalities of the erythrocytes
correlated with their cholesterol compositions, we stained red blood
cells from the different mouse strains with the cholesterol-binding fluorescent dye filipin and measured the filipin staining. Flow cytometric analysis showed that wild-type erythrocytes and
reticulocytes contained less cholesterol (filipin stain) than
erythrocytes from animals with mutations in apoE, SR-BI, or
both genes (Figure 3A; the box in each
panel indicates the approximate distribution of wild-type
erythrocytes). Cholesterol levels were highest in
SR-BI
The abnormal inclusions are autophagolysosomes The inclusions in SR-BI//apoE/ red blood cells
had the appearance of autophagolysosomes, vesicles that result from
sequestration of cytoplasmic contents in a membrane-enclosed
compartment that has low internal pH and contains lysosomal
enzymes.21,22 To explore this possibility, we incubated
red blood cells with Lysotracker, a fluorescent dye that accumulates in
low pH compartments, and with FDG, a substrate for lysosomal
-galactosidase. Wild-type and apoE/
erythrocytes (Figure 4A,B)
rarely contained fluorescent inclusions (Figure 4E-F,I-J,M-N). In
contrast, erythrocytes from SR-BI/ and
SR-BI//apoE/ mice (Figure
4C,D) were stained with these phagolysosomal dyes in overlapping
patterns (Figure 4G,H,K,L,O,P) that were similar to those of the
inclusions described above. Thus, the inclusions are probably
autophagolysosomes.
Erythroid differentiation is reversibly disrupted in
SR-BI / mice (lower left quadrant of cytograms
in Figure 4Q,R). In keeping with the morphologic studies,
SR-BI/ mice had a larger fraction of
immature cells (RNA+ and Trfr+, upper
right quadrant, Figure 4S) than the wild-type and
apoE/ mice, but most of the cells were
double negative. Strikingly, virtually all of the
SR-BI//apoE/ cells retained
a high RNA content, and most, but not all, expressed substantial levels
of Trfr (Figure 4T). This suggests that in SR-BI//apoE/ mice, some
steps in reticulocyte maturation are completely blocked (normal
cytoskeletal remodeling, clearance of organelles, and RNA) while others
can proceed at least partially (loss of cell-surface Trfr).
Erythrocytes from SR-BI To examine the role of the extracellular environment in erythrocyte
maturation in vivo, we transfused biotin-labeled erythrocytes from
SR-BI
Expulsion of autophagolysosomes from
SR-BI //apoE/ reticulocytes
in vitro, we harvested red blood cells from
SR-BI//apoE/ mice and
incubated them in medium containing normolipidemic fetal calf serum
under conditions that support cell metabolism and cell survival for
several days. For positive controls, we harvested reticulocyte-rich red
blood cells from wild-type mice that had been repeatedly phlebotomized.
Expulsion of autophagolysosomes was assessed by transmission electron
microscopy before (0 hours) and after 72 hours of incubation in
vitro (Figure 6).
At 0 hours, many of the erythrocytes from the phlebotomized wild-type
mice contained small vesicles (Figure 6A, arrowheads). We interpret
this to be the result of marked erythropoietic stress, due to
phlebotomy, that led to the release of immature cells into the
circulation. This observation is consistent with an earlier report
postulating autophagocytosis in patients with severe anemia syndromes.1 At 0 hours, the inclusions in the
SR-BI We considered the possibility that excess cellular cholesterol directly
interfered with expulsion of the autophagolysosomes. To investigate
this, we briefly treated
SR-BI
Investigation of an unusual anemia in mice with defective
lipoprotein metabolism has provided a unique window into late erythroid maturation. Abnormal erythrocyte morphology was observed in mice lacking the HDL receptor SR-BI. This was exacerbated by feeding SR-BI Do the autophagolysosome-containing, Trfr+, and RNA-rich
erythrocytes in SR-BI Although our results are perhaps not surprising given the
intriguing role that cholesterol is thought to play in regulated trafficking and sorting (reviewed in Hoekstra and van
IJzendoorn25), the details of the mechanisms by which
erythrocytes expel autophagolysosomes and by which dyslipidemia and
excess cholesterol arrest this expulsion remain to be determined. We do
not yet know if the mechanisms for nuclear expulsion from early
erythrocyte precursors26 and phagolysosomal expulsion from
reticulocytes are similar. Nuclei were no longer present in the
SR-BI In vivo, reticuloendothelial macrophages of the liver and spleen play
an important role in removing particulate matter (eg, nuclear remnants,
precipitated hemoglobin) from circulating erythroid cells.27,28 As the erythrocytes pass through narrow
vascular spaces, macrophages are thought to aid in cellular remodeling by actively removing membrane-enclosed vesicles containing cellular debris. Although autophagolysosome expulsion from
SR-BI In conclusion, the novel abnormalities of
SR-BI
We thank Helena Miettinen for critical suggestions, advice, and help with cholesterol-feeding experiments; Mark Fleming and Antonio Perez-Atayde for assisting us in the interpretation of pathology slides; and Mohandas Narla, Ellis Neufeld, David Clapham, Sam Lux, Joanne Levy, and Robert Levy for helpful discussions. We thank Jeff Macklis and Lisa Catapano for assisting us with differential interference contrast microscopy. Howard Mulhern in the Department of Pathology carried out electron microscopy at Children's Hospital, Boston. Michelle Lowe in the Confocal and Multiphoton Core Facility at the Brigham and Women's Hospital performed confocal microscopy. Lynne Montross kindly performed all mouse tail vein injections.
Submitted August 10, 2001; accepted October 25, 2001.
Supported by grants from the National Institutes of Health (M.K. and N.C.A.). A.B. was a European Molecular Biology Organization and Human Frontiers Science Program postdoctoral fellow. B.L.T. was a Medical Research Council of Canada postdoctoral fellow. N.C.A. is an Associate Investigator of the Howard Hughes Medical Institute.
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: Nancy C. Andrews, HHMI/Hematology, Enders 720, Children's Hospital, 300 Longwood Ave, Boston, MA 02115; e-mail: nandrews{at}enders.tch.harvard.edu.
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M. Vinals, S. Xu, E. Vasile, and M. Krieger Identification of the N-Linked Glycosylation Sites on the High Density Lipoprotein (HDL) Receptor SR-BI and Assessment of Their Effects on HDL Binding and Selective Lipid Uptake J. Biol. Chem., February 7, 2003; 278(7): 5325 - 5332. [Abstract] [Full Text] [PDF]
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T. J. F. Nieland, M. Penman, L. Dori, M. Krieger, and T. Kirchhausen Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI PNAS, November 26, 2002; 99(24): 15422 - 15427. [Abstract] [Full Text] [PDF]
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B. Liu and M. Krieger Highly Purified Scavenger Receptor Class B, Type I Reconstituted into Phosphatidylcholine/Cholesterol Liposomes Mediates High Affinity High Density Lipoprotein Binding and Selective Lipid Uptake J. Biol. Chem., September 6, 2002; 277(37): 34125 - 34135. [Abstract] [Full Text] [PDF]
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| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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Abstract
Introduction
indicates normal mouse chow diet, and + indicates
3 months on the high-cholesterol diet.
