|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
TRANSPLANTATION
From the Department of Pathology and Laboratory
Medicine, University of Pennsylvania School of Medicine, Philadelphia;
Department of Medicine, University of Alberta and Canadian Blood
Services, Edmonton, Alberta, Canada; Department of Transplantology
CMUJ, Krakow, Poland; and James Graham Brown Cancer Center, University
of Louisville, KY.
Because human CD34+ and murine Sca-1+
hematopoietic stem-progenitor cells (HSPCs) express platelet-binding
sialomucin P-selectin (CD162) and integrin Mac-1 (CD11b-CD18) antigen,
it was inferred that these cells might interact with platelets. As a
result of this interaction, microparticles derived from platelets
(PMPs) may transfer many platelet antigens (CD41, CD61, CD62, CXCR4, PAR-1) to the surfaces of HSPCs. To determine the biologic significance of the presence of PMPs on human CD34+ and murine
Sca-1+ cells, their expressions on mobilized peripheral
blood (mPB) and on nonmobilized PB- and bone marrow (BM)-derived
CD34+ cells were compared. In addition, the effects of PMPs
on the proliferation of CD34+ and Sca-1+ cells
and on adhesion of HSPCs to endothelium and immobilized SDF-1 were
studied. Finally, the hematopoietic reconstitution of lethally
irradiated mice receiving transplanted BM mononuclear cells
covered or not covered with PMPs was examined. It was found that PMPs are more numerous on mPB than on BM CD34+
cells, do not affect the clonogenicity of human and murine HSPCs, and
increase adhesion of these cells to endothelium and immobilized SDF-1.
Moreover, murine BM cells covered with PMPs engrafted lethally irradiated mice significantly faster than those not covered, indicating that PMPs play an important role in the homing of HSPCs. This could
explain why in a clinical setting human mPB HSPCs (densely covered with
PMPs) engraft more rapidly than BM HSPCs (covered with fewer
PMPs). These findings indicate a new role for PMPs in stem cell
transplantation and may have clinical implications for the optimization
of transplantations.
(Blood. 2001;98:3143-3149) Peripheral blood mobilized (mPB) by various
means (cytokines, chemotherapy, or both) has become a source of
hematopoietic stem-progenitor cells (HSPC) for autologous and
allogeneic transplantation.1 Hematopoietic recovery after
transplantation with mPB HSPCs is faster than with bone marrow (BM),
but the mechanism(s) responsible for this are not completely
understood.1-3 To explain this, we compared the surface
expression of adhesion molecules in mPB CD34+ cells to that
of BM-derived CD34+ cells. We found to our surprise that
mPB CD34+ cells expressed a significantly higher level of
PMPs are released on the activation of platelets and express functional
adhesion receptors, including We now report evidence suggesting that HSPCs interact with platelets
and subsequently display on their surfaces PMP-derived antigens. PMPs
covering the surfaces of human or murine HSPCs do not affect their
proliferation but increase their adhesion to endothelium and, most
important, significantly improve murine HSPC engraftment after
transplantation into lethally irradiated mice. We suggest that PMPs
displayed on HSPCs may regulate the trafficking and homing of these
cells to hematopoietic organs.
Human CD34+ cells and platelets
Human umbilical vein endothelial cells
Murine BM MNCs, Sca-1+ cells, and platelets Murine MNCs were isolated from BM flushed from the femurs of pathogen-free, 4- to 6-week-old female B.6SJL-Ptprca Pep3b/BoyJ-Ly5.1 mice (The Jackson Laboratory, Bar Harbor, ME), depleted of adherent cells (A ) and enriched for light-density MNC by
Ficoll-Hypaque centrifugation as described.12
Sca-1+ cells were isolated by using paramagnetic mini-beads
(Miltenyi Biotec) according to the manufacturer's protocol. Murine
platelets were prepared using differential centrifugation of whole
anticoagulated blood. Briefly, blood samples obtained by venipuncture
from the inferior vena cava were anticoagulated with 3.8% sodium
citrate and adjusted to a final volume of 8 mL with Tyrode buffer
(containing 1 mg/mL albumin; 5 U/mL apyrase; and 1 mM EGTA, pH 6.5).
Platelet-rich plasma (PRP) was isolated from blood by centrifugation
for 7 minutes at 150g at room temperature. Prostaglandin E1
was added to PRP to a final concentration of 1 µM. Platelets were
pelleted by centrifugation of the PRP (at room temperature for 10 minutes at 800g) and resuspended (in HEPES buffer, pH 7.5, to a concentration of 8 × 108 platelets/mL.
Platelet microparticles PMPs were prepared from platelets as described earlier.13,14 Before the experiments, platelet concentrates were activated by thrombin (2 U/mL) for 10 minutes and centrifuged at 800g for 20 minutes, and the supernatants enriched in PMPs were collected. Supernatants were examined by flow cytometry analysis using phycoerythrin (PE)-conjugated anti-human IIb 3 antibody (Coulter-Immunotech, Marseilles, France) and were
PE-conjugated anti-human P-selectin (CD62) antibody (Becton Dickinson,
Franklin Lakes, NJ) or PE- or fluorescein isothiocyanate
(FITC)-conjugated anti-mouse IIb3 antibody and anti-mouse CD62P
(P-selectin) antibody (BD PharMingen, San Diego, CA).
Human myeloid, erythroid, and megakaryocytic precursor cells CD34+ cells were cloned in serum-free methylcellulose cultures as previously described.7 Briefly, CD34+ AT MNCs
(104/mL) covered or not covered by PMPs were suspended in
Iscoves MEM (Gibco BRL, Grand Island, NY) supplemented with
50% artificial serum containing 1% delipidated, deionized, and
charcoal-treated bovine serum albumin, 270 µg/mL iron-saturated
transferrin, 20 µg/mL insulin, and 2 mM L-glutamine (all from Sigma,
St Louis, MO) and were cultured in 1% methylcellulose. Granulocyte
macrophage (GM)-colony-forming unit (CFU) growth was stimulated with
10 ng/mL recombinant human (rh) interleukin (IL)-3 and 5 ng/mL
rhGM-CSF. Erythroid burst-forming unit (BFU-E) growth was stimulated
with 2 U/mL rh erythropoietin and 10 ng/mL rh kit ligand (KL).
Megakaryocyte CFU (CFU-Meg) growth was stimulated with 50 ng/mL
rh thrombopoietin and 10 ng/mL rh IL-3. Mixed CFU (CFU-Mix) growth was
stimulated by 10 ng/mL KL, 10 ng/mL IL-3, 50 ng/mL thrombopoietin, 2 U/mL erythropoietin, and 5 ng/mL GM-CSF). All recombinant human
cytokines and growth factors were obtained from R & D Systems
(Minneapolis, MN). Cultures were incubated at 37°C in a fully
humidified atmosphere supplemented with 5% CO2. Colonies
were counted under an inverted microscope on day 11 for CFU-GM and
CFU-Meg and on day 14 for CFU-Mix and BFU-E.
FACS analysis Binding of platelets or PMPs to CD34+, Sca-1+, BFU-E-derived erythroblasts, or UT-7 and HL-60 cells was evaluated using flow cytometry. Cells were incubated with platelets or PMPs for 10 minutes to 2 hours at room temperature and centrifuged at 800 rpm to remove unbound platelets; the resultant cell pellets were resuspended in Tyrode buffer containing 2 mg/mL of PE-anti-IIb3 antibody (anti-CD41 antibody; Coulter-Immunotech).
Expression of IIb3 was evaluated by FACS analysis (FACScan;
Becton Dickinson) as described earlier.8 Fluorescence was
measured in the gate characteristic for CD34+ cells or
Sca-1+ cells. Data are presented as the percentage of cells
labeled with anti-CD41 antibody. Similar experiments were performed for murine BM MNCs isolated from B.6SJL-Ptprca Pep3b/BoyJ-Ly5.1 mice.
Expression of PSGL-1 (CD162), Mac-1 (CD11b-CD18), CD62, CXCR4, and PAR-1 was evaluated on hematopoietic cells by FACS after staining with antigen-specific antibodies. We used the following monoclonal antibodies: PE-anti-PSGL-1 (Research Diagnostic, Flanders, NJ), PE-anti-CD62, and PE-anti-Mac-1 (Becton Dickinson, San Juan, CA), PE-anti-CXCR4 (BD PharMingen), and anti-PAR-1 (Coulter-Immunotech). Adhesion to HUVECs and immobilized SDF-1 Adherence assays of human CD34+ cells that were metabolically labeled by S35-methionine and were incubated for 10 minutes with platelets or PMPs were performed as described.15 Briefly, 96-well microtiter plates (Becton Dickinson, Oak Park, MA) covered with HUVECs (as described above) or immobilized SDF-1 were incubated for 30 minutes at 37°C in culture media. Subsequently, cell suspensions (1 × 105 cells/100 µL) were applied to the wells and incubated for 3 hours at 37°C. The number of adherent cells was estimated in a scintillation counter as described.15Marrow transplantation in lethally irradiated mice Female mice (4-6 weeks old) congenic in murine CD45 at the Ly5 locus (C57BL/6J-Ly 5.2 and B.6SJL-Ptprca Pep3b/BoyJ Ly5.1) were obtained from Jackson Laboratory. For the transplantation experiments, C57BL/6J-Ly 5.2 mice were irradiated with a lethal dose of -irradiation (900 cGy [900 rads]). After 24 hours, the mice
received transplanted cells by tail vein injection with
5 × 105 BM MNCs from B.6SJL-Ptprca Pep3b/BoyJ-Ly5.1 mice
covered or not covered with PMPs. Mice receiving transplanted
cells were bled at various intervals from the retro-orbital
plexus to obtain samples for leukocyte, platelet, and hematocrit counts
using Unopette Microcollection (Becton Dickinson, Rutherford, NJ) and
heparinized microhematocrit capillary tubes (Oxford Labware, St Louis,
MO) as described.12
Evaluation of chimerism after transplantation Hematologic engraftment in mice that received transplanted cells was evaluated by staining bone marrow cells with Ly5.1 (clone A20) and Ly5.2 (clone 104) donor- and host-specific antibodies, respectively (PharMingen) as described.16CFU-S assay For the splenic colony-forming unit (CFU-S) assays, C57BL/6J-Ly 5.2 mice received transplanted 2 × 105 marrow cells from B.6SJL-Ptprca Pep3b/BoyJ-Ly5.1 mice covered or not covered with murine PMPs. At day 9 or 12, spleens were removed and fixed in Tellysyniczky fixative, and CFU-S were counted on the surface of the spleen using magnification glass as described.17Statistical analysis Arithmetic means and standard deviations of our FACS data were calculated on a Macintosh computer PowerBase 180 (Apple, Cupertino, CA), using Instat 1.14 (GraphPad, San Diego, CA) software. Data were analyzed using the Student t test for unpaired samples. Statistical significance was defined as P < .05.
Human mPB CD34+ cells highly express platelet-characteristic antigens We found that human CD34+ cells isolated from mobilized PBs, in contrast to CD34+ cells obtained from nonmobilized PBs (collected from whole blood without leukapheresis), highly expressed antigens characteristic for platelets such as CD41 and CD61 integrins (Figure 1, Table 1) and the thrombin receptor PAR-1 (data not shown). Only 23% ± 7% of nonmobilized PB CD34+ cells expressed the CD41 antigen compared with 83% ± 18% of the mPB CD34+ cells (P = .0017). Hence, we asked whether these mPB CD34+ cells were covered by platelets activated during leukapheresis. We performed electron-microscopic studies to address this issue and to assess the presence of platelets on the CD34+ cells. To our surprise, no intact platelets were found on the surfaces of either mobilized or nonmobilized PB CD34+ cells (data not shown).
Human BM-derived CD34+ cells display platelet-binding ligands on their surfaces, activate platelets, and subsequently incorporate PMPs Because we could not demonstrate intact platelets on the surfaces of human CD34+ cells, we hypothesized that the high expression of platelet-characteristic antigens on these cells results from binding of PMPs to their membranes. It is known that PMPs are released from platelets activated by platelet agonists.6,8,18,19 We confirmed that human CD34+ cells express CD162 and Mac-1 (CD11b-CD18) (Figure 2), both of which may potentially bind or activate platelets after binding to platelet selectin (CD62P) and platelet glycoprotein (Ib), respectively.
Consistent with previous findings, we observed that human BM
CD34+ cells also expressed CD414; however, in
contrast to mPB CD34+ cells, expression of CD41 on these
cells was significantly lower (19% ± 4% versus 83% ± 18%;
P = .0011) (Table 1). This could be explained by the fact
that, in steady state hematopoiesis, BM CD34+ cells reside
in bone marrow niches and probably interact with platelets and PMPs
circulating in the peripheral blood to a lesser extent and thus have
fewer PMPs on their surfaces. To test the hypothesis that
CD34+ cells interact with platelets and that PMPs
subsequently bind to their surfaces, we compared the expression of CD41
on the surfaces of BM-derived CD34+ cells before and after
incubation with platelets. Accordingly, we incubated BM-derived MNCs
with platelets freshly isolated from PB (5 × 109
platelets/µL). We found that after incubation with platelets, BM
CD34+ cells expressed significantly more CD41
(73% ± 21% for cells incubated vs 27% ± 8% for cells not
incubated with platelets; P < .0001). We also found that
CD41 expression could be partly inhibited after pre-incubating
CD34+ cells with monoclonal antibodies blocking CD162
(73% ± 21% for cells not exposed and 42% ± 19% for cells
exposed to anti-CD162 antibody; P < .002). Figure
3 shows the expression of CD41 and CD61
antigens on BM CD34+ cells that have been pre-incubated
with platelets.
Human erythroblasts, HL-60, and UT-7 cells may interact with platelets and bind PMPs Next we tested whether, in addition to human CD34+ cells, other hematopoietic cells may bind PMPs to their membranes. Because we found that human erythroblasts, HL-60 cells, and UT-7 cells expressed CD162 on their surfaces, we incubated these cells with platelets and found that after incubation they expressed CD41 on their surfaces (Figure 4). This interaction was again partly inhibited by anti-CD162 blocking monoclonal antibody (data not shown). Hence, platelet binding on hematopoietic cell surfaces, followed by the binding of PMPs to the cell membranes, seems to be a common mechanism for platelet interaction with hematopoietic cells of various lineages.
Murine Sca-1+ cells activate platelets and incorporate PMPs into cell membranes Next we investigated whether similar effects occur in murine hematopoietic cells, and we isolated HSPCs expressing the Sca-1 antigen from murine bone marrow. We found that these cells weakly express CD41 on their surfaces (10% ± 4%) (Figure 5A). Subsequently, Sca-1+ cells were incubated with the murine platelets. As in human CD34+ cells, we found that murine Sca-1+ cells expressed CD41 highly on the surface after incubation with platelets (62% ± 8%) (Figure 3B). This binding was inhibited after the pre-incubation of cells with monoclonal antibodies against platelet CD62P (after pre-incubation with anti-CD62 antibody, 47% ± 12% of cells expressed CD41; P < .0002), suggesting that in murine, as in human, HSPCs, there is at least some involvement of the CD162-CD62P axis in platelet binding. In addition, though murine Sca-1+ cells highly expressed CD41 antigen on their surfaces, electron microscopy revealed the absence of intact platelets (not shown). This supports our assumption that high expression of CD41 antigen on Sca-1+ cells, as for human mPB CD34+ cells, is the result of PMP binding to the cell membranes.
PMPs do not affect proliferation of either human
CD34+ or murine A BM
MNCs (data not shown).
Human CD34+ cells covered with PMPs adhere better to endothelium and immobilized SDF-1 Our data suggest that PMPs transfer various platelet-endothelium attachment receptors (glycoprotein [GP] IIb/IIIa [CD41], GPIb, GPIaIIa, P-selectin, chemokine CXCR4) to the cell membranes of CD34+ cells.5,6 This has an important role in the adhesion of CD34+ cells to the endothelial cells in bone marrow.5 Because the SDF-1 chemokine is preferentially expressed by bone marrow endothelium,3,20,21 we investigated whether cells covered with PMPs adhere better to endothelial cells and immobilized SDF-1 cells and found that human BM CD34+ cells covered with PMPs adhered significantly better to HUVECs and immobilized SDF-1 cells than those that were not covered (Figure 6).
Murine BM HSPCs covered with PMPs engraft faster We found that HSPCs covered with PMPs expressed several new platelet-expressed adhesion molecules and, as shown above, adhered significantly better to endothelial cells and immobilized SDF-1. Thus, we asked whether the presence of PMPs on the HSPC surface has any effect on their engraftment and on the kinetics of hematopoietic reconstitution after transplantation. To address this, we performed transplantations between congenic C57BL mice that differed in the Ly5 locus, a murine homolog of the CD45 antigen. Ly5.2 mice received transplanted BM cells derived from congenic Ly5.1 animals covered or not covered with PMPs. After transplantation, the recovery of peripheral blood cells was observed in these mice (Figure 7). Mice receiving transplanted cells covered with PMPs showed a statistically significant shorter recovery time for leukocytes and platelets by 3 to 4 days than mice receiving transplanted cells not covered. This difference was statistically significant (P < .0001 for days 7 and 11 for leukocytes; P < .0001 for days 7, 11, and 16 for platelets). We also observed faster hematocrit recovery (P < .0001 for day 7).
We also looked for the number of day 9 and day 12 CFU-S colonies after
transplantation of murine A
Moreover, the changes in the number of CFU-S colonies paralleled the
changes in the degree of chimerism detected in the bone marrows of Ly
5.1+ animals receiving transplanted
Ly5.2+ marrow cells. Accordingly, we found that Ly
5.1+ mice receiving transplanted cells covered
with PMPs had significantly more Ly5.2+ cells in their bone
marrow cavities at day 12 after transplantation (Figure
8, Table
3).
Finally, at day 30, we evaluated hematopoietic reconstitution after the transplantation of 5 × 105 BM MNCs per mouse. By this time, there were no differences in hematopoietic chimerism, suggesting that both types of cells (covered and not covered with PMPs) reconstituted mice in a similar way.
PMPs generated from peripheral blood platelets activated by agonists are believed to play an important role in various physiological processes, such as facilitating the interaction of leukocytes or monocytes with endothelial cells5,6 and in the aggregation and accumulation of leukocytes on selectin-expressing substrates,14 or in many pathologic states including heparin-induced thrombocytopenia.18,19 In this study we report that both human and murine HSPCs are covered with PMPs after incubation with platelets, and we discuss mechanisms and biologic consequences of this phenomenon. In view of the observations by others22-24 that PB CD34+ cells express PSGL-1 (CD162) and to explain the high expression of CD41/CD61 on these cells, we initially hypothesized that PB CD34+ cells bind platelets to their surfaces. In fact, we were able to confirm the presence of platelet-activating and -binding PSGL-1 on these cells; in addition, we demonstrated that they express another platelet-binding molecule, Mac-1 (CD11b-CD18). The fact that monoclonal antibodies against CD162 partly prevented the interaction of platelets with human CD34+ cells and that antibodies against murine CD62P selectin partly inhibited the interaction of murine Sca-1 cells with platelets suggests that the CD162-CD62P axis does indeed play an important role in platelet binding to human and murine HSPCs.25 Because we could not detect platelets on the surfaces of CD34+ cells by electron microscopy, we postulate that the expression of platelet-derived antigens such as CD41, CD62, CXCR4, and PAR-1 is related to the presence of PMPs on CD34+ cells rather than intact platelets. Given that platelets are exposed to many platelet agonists (eg, chemokines, cytokines) during mobilization and that platelets in mPB are additionally activated while they circulate in the plastic tubing used during leukapheresis, we set out to demonstrate that CD34+ cells isolated from the leukapheresis products of mPB are more highly covered with PMPs than their counterparts harvested from nonmobilized PB or BM. Moreover, it has been reported that during leukapheresis platelets not only become activated but also release PMPs,5,6 so it is likely that mobilized CD34+ cells bind circulating PMPs to their surfaces. The other major observation emanating from our work is that
hematopoietic cells covered with PMPs adhere more efficiently to
endothelial cells and immobilized SDF-1, which suggests that PMP-derived molecules expressed on CD34+ cells increase
these effects. Potential candidates for these interactions are
PMP-derived molecules such as the platelet-endothelium attachment
receptors GPIIb/IIIa, GPIb, and GPIa/IIa and the chemokine receptor
CXCR4.27-29 Moreover, we postulate that because not all HSPCs express endogenous CXCR4 on the surfaces,30
PMP-derived CXCR4 may regulate the homing of such CXCR4 Most important, we demonstrated in our in vivo animal model that murine bone marrow-derived HSPCs covered with PMPs engraft significantly faster after transplantation into lethally irradiated mice than marrow cells not covered with PMPs. This observation may explain why in a clinical setting we observe faster early-hematopoietic recovery after transplantation of mPB stem-progenitor cells than of BM.1 In this study, we found that human HSPCs obtained from mPB are more densely covered with PMPs than their nonmobilized BM counterparts. Because murine HSPCs covered with PMPs showed faster homing after transplantation, we suggest that "painting" of human HSPCs with PMPs could potentially accelerate early engraftment. The activation/binding of platelets on the surfaces of human CD34+ cells we describe here is an interesting biologic phenomenon and represents an example of cross-talk between platelets and hematopoietic cells. We suggest that incorporation of PMPs into the membranes of mobilized CD34+ cells can be important in directing these cells from the peripheral blood back to the bone marrow and possibly in other physiological processes. For example, a similar mechanism may direct PMP-covered lymphocytes from areas of inflammation to the lymphopoietic organs in which they would proliferate and expand. This possibility is under investigation in our laboratory. There are potential disadvantages associated with PMP-binding to human CD34+ cells. First, in patients with immunothrombocytopenia, it is possible that some platelet-associated antigens may be displayed by PMPs on the surfaces of HSPCs and thus may be recognized by the antiplatelet antibodies. Second, PMPs rich in phosphatidylserine may "mark" CD34+ cells as apoptotic cells that may then become targets for immune response.31 Both these questions require further study. It has been reported recently that activation of PSGL-1 (CD162) expressed on human CD34+ cells by CD62P delivers negative signals in human hematopoietic progenitors26 and could result in inhibition of the growth of these cells. In our work, however, the addition of platelets or PMPs to cultured in vitro human or murine progenitors did not affect their proliferation. We believe that these discrepancies can be explained by the fact that CD162 expressed on CD34+ cells interacts with platelet- or PMP-derived CD62P differently than with purified recombinant CD62P protein.26 In conclusion, our study demonstrated that CD34+ cells interact with platelets and bind PMPs to their cell membranes, and we present evidence that such PMPs increase HSPC homing into bone marrow. We postulate that the so-called painting of CD34+ cells with PMPs may prove to be a strategy for accelerating engraftment after transplantation. The potential role of PMPs in the homing of lymphohematopoietic cells to lymphohematopoietic organs may also be of great importance and requires further investigation.
Submitted February 7, 2001; accepted July 5, 2001.
Supported by National Institutes of Health grant R01 HL61796-01 (M.Z.R.) and by a Canadian Blood Services Research and Development grant (A.J.-W.).
A.J.-W. and M.M. contributed equally to this work.
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: Mariusz Z. Ratajczak, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 405A Stellar Chance Labs, 422 Curie Blvd, Philadelphia, PA 19104; e-mail: mariusz{at}mail.med.upenn.edu.
1. Champlin RE, Schmitz N, Horowitz MM, et al. Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. Blood. 2000;5:3702-3709.
2.
Janowska-Wieczorek A, Marquez LA, Nabholtz J-M, et al.
Growth factors and cytokines up-regulate gelatinase expression in bone marrow CD34+ cells and their transmigration through reconstituted basement membrane.
Blood.
1999;93:3379-3390 3. Ponomaryov T, Peled A, Petit I, et al. Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest. 2000;106:1331-1339[Medline] [Order article via Infotrieve].
4.
Gomez-Espuch J, Corral J, Gonzalez-Conejero R, Ortuno F, Moraleda JM, Vicente V.
Glycoprotein IIb/IIIa expression on hematopoietic stem cells: constitutive expression or platelet adhesion?
Blood.
1999;94:3271-3273 5. Barry OP, FitzGerald GA. Mechanisms of cellular activation by platelet microparticles. Thromb Haemost. 1999;82:794-800[Medline] [Order article via Infotrieve]. 6. Barry OP, Pratico D, Savani RC, FitzGerald GA. Modulation of monocyte-endothelial cell interaction by platelet microparticles. J Clin Invest. 1998;102:136-144[Medline] [Order article via Infotrieve].
7.
Ratajczak MZ, Kuczynski WI, Sokol LD, Moore J, Pletcher C, Gewirtz AM.
Expression and physiologic significance of Kit ligand and stem cell tyrosine kinase-1 receptor ligand in normal human CD34+, c-Kit R+ marrow cells.
Blood.
1995;86:2161-2167
8.
Majka M, Janowska-Wieczorek A, Ratajczak J, et al.
Stromal derived factor-1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis.
Blood.
2000;96:4142-4151
9.
Majka M, Rozmyslowicz T, Lee B, et al.
Bone marrow CD34+ cells and megakaryoblasts secrete
10.
Kowalska MA, Ratajczak MZ, Majka M, Brass LW, Poncz M.
SDF-1 and MDC: complementary chemokines at the crossroads between inflammation and thrombosis.
Blood.
2000;96:50-57 11. Kowalska MA, Ratajczak J, Hoxie J, et al. Megakaryocyte precursors, megakaryocytes and platelets express the HIV co-receptor CXCR4 on their surface: determination of response to stromal derived factor-1 by megakaryocytes and platelets. Br J Haematol. 1999;104:220-229[CrossRef][Medline] [Order article via Infotrieve]. 12. Ratajczak MZ, Ratajczak J, Machalanski B, Mick R, Gewirtz AM. In vitro and in vivo evidence that ex vivo cytokine priming of donor marrow cells may ameliorate post-transplant thrombocytopenia. Blood. 1998;1:353-359.
13.
Mesri M, Altieri DC.
Leukocyte microparticles stimulate endothelial cell cytokine release and tissue factor induction in a JNK1 signaling pathway.
J Biol Chem.
1999;274:23111-23118
14.
Forlow SB, McEver RP, Nollert MU.
Leukocyte-leukocyte interactions mediated by platelet microparticles under flow.
Blood.
2000;95:1317-1323
15.
Qi W, Loh E, Vilaire G, Bennett JS.
Regulation of aIIb/b3 function in human B lymphocytes.
J Biol Chem.
1998;273:15271-15278
16.
Fisher RC, Lovelock JD, Scott EW.
A critical role for PU.1 in homing and long-term engraftment by hematopoietic stem cells in the bone marrow.
Blood.
1999;94:1283-1290 17. Jedrzejczak WW, Pojda Z, Ahmed A, Ratajczak MZ. Hematological compensation of microphthalmic mice with congenital osteoporosis. Bone. 1987;8:315-317[Medline] [Order article via Infotrieve].
18.
Nieuwland R, Berckmans RJ, McGregor S, et al.
Cellular origin and procoagulant properties of microparticles in meningococcal sepsis.
Blood.
2000;95:930-935
19.
Hughes M, Hayward CPM, Warkentin TE, Horsewood P, Chomeyko KA, Kelton JG.
Morphological analysis of microparticle generation in heparin-induced thrombocytopenia.
Blood.
2000;96:188-194 20. Peled A, Grabovsky V, Habler L, et al. The chemokine SDF-1 stimulates integrin-mediated arrest of CD34+ cells on vascular endothelium under shear flow. J Clin Invest. 1999;104:1199-1211[Medline] [Order article via Infotrieve].
21.
Peled A, Kollet O, Ponomaryov T, et al.
The chemokine SDF-1 activates the integrins LFA-1, VLA-4 and VLA-5 on immature human CD34+ cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice.
Blood.
2000;95:3289-3296
22.
Laszik Z, Jansen PJ, Cummings RD, Tedder T, McEver RP, Moore KL.
P-selectin glycoprotein ligand-1 is broadly expressed in cells of myeloid, lymphoid, and dendritic lineage and in some nonhematopoietic cells.
Blood.
1996;88:3010-3021
23.
Zannettino ACW, Berndt MC, Butcher C, Butcher EC, Vadas MA, Simmons PJ.
Primitive human hematopoietic progenitors adhere to P-selectin (CD62P).
Blood.
1995;85:3466-3477
24.
Simon DI, Chen Z, Xu H, et al.
Platelet glycoprotein Ib
25.
Snapp KR, Ding H, Atkins K, Warnke R, Luscinskas FW, Kansas GS.
A novel P-selectin glycoprotein ligand-1 monoclonal antibody recognizes an epitope within the tyrosine sulfate motif of human PSGL-1 and blocks recognition of both P- and L-selectin.
Blood.
1998;91:154-164 26. Levesque JP, Zannettino ACW, Pudney M, et al. PSGL-1-mediated adhesion of human hematopoietic progenitors to P-selectin results in suppression of hematopoiesis. Immunity. 1999;11:369-378[CrossRef][Medline] [Order article via Infotrieve]. 27. Nagasawa T, Hirota S, Tachibana K, et al. Defects of B-cell lymphopoiesis and bone marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996;382:635-638[CrossRef][Medline] [Order article via Infotrieve]. 28. Zou Y, Kottman AH, Kuroda M, Taniuchi I, Littman DR. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature. 1998;393:595-599[CrossRef][Medline] [Order article via Infotrieve].
29.
Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC.
The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood.
J Exp Med.
1997;185:111-120 30. Rosu-Lyles M, Gallacher L, Murdoch B, et al. The human hematopoietic stem cells compartment is heterogenous for CXCR expression. Proc Natl Acad Sci U S A. 2000;97:15626-14631. 31. Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature. 2000;407:784-788[CrossRef][Medline] [Order article via Infotrieve].
© 2001 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  M. Prokopi, G. Pula, U. Mayr, C. Devue, J. Gallagher, Q. Xiao, C. M. Boulanger, N. Westwood, C. Urbich, J. Willeit, et al. Proteomic analysis reveals presence of platelet microparticles in endothelial progenitor cell cultures Blood, July 16, 2009; 114(3): 723 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Bruno, C. Grange, M. C. Deregibus, R. A. Calogero, S. Saviozzi, F. Collino, L. Morando, A. Busca, M. Falda, B. Bussolati, et al. Mesenchymal Stem Cell-Derived Microvesicles Protect Against Acute Tubular Injury J. Am. Soc. Nephrol., May 1, 2009; 20(5): 1053 - 1067. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Z. Ratajczak Megakaryocyte-derived microvesicles, please stand up! Blood, January 29, 2009; 113(5): 981 - 982. [Full Text] [PDF]
|
|
|
|
|
|
M. Z. Ratajczak Microvesicles as immune orchestra conductors Blood, May 15, 2008; 111(10): 4832 - 4833. [Full Text] [PDF]
|
|
|
|
|
|
D. L. Sprague, B. D. Elzey, S. A. Crist, T. J. Waldschmidt, R. J. Jensen, and T. L. Ratliff Platelet-mediated modulation of adaptive immunity: unique delivery of CD154 signal by platelet-derived membrane vesicles Blood, May 15, 2008; 111(10): 5028 - 5036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Deregibus, V. Cantaluppi, R. Calogero, M. Lo Iacono, C. Tetta, L. Biancone, S. Bruno, B. Bussolati, and G. Camussi Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA Blood, October 1, 2007; 110(7): 2440 - 2448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Xu, J. Sui, H. Tao, Q. Zhu, and W. A. Marasco Human Anti-CXCR4 Antibodies Undergo VH Replacement, Exhibit Functional V-Region Sulfation, and Define CXCR4 Antigenic Heterogeneity J. Immunol., August 15, 2007; 179(4): 2408 - 2418. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Morel, F. Toti, B. Hugel, B. Bakouboula, L. Camoin-Jau, F. Dignat-George, and J.-M. Freyssinet Procoagulant Microparticles: Disrupting the Vascular Homeostasis Equation? Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2594 - 2604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Sapet, S. Simoncini, B. Loriod, D. Puthier, J. Sampol, C. Nguyen, F. Dignat-George, and F. Anfosso Thrombin-induced endothelial microparticle generation: identification of a novel pathway involving ROCK-II activation by caspase-2 Blood, September 15, 2006; 108(6): 1868 - 1876. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Langer, A. E. May, K. Daub, U. Heinzmann, P. Lang, M. Schumm, D. Vestweber, S. Massberg, T. Schonberger, I. Pfisterer, et al. Adherent Platelets Recruit and Induce Differentiation of Murine Embryonic Endothelial Progenitor Cells to Mature Endothelial Cells In Vitro Circ. Res., February 3, 2006; 98(2): e2 - e10. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Oki, J. Kitaura, K. Eto, Y. Lu, M. Maeda-Yamamoto, N. Inagaki, H. Nagai, Y. Yamanishi, H. Nakajina, H. Kumagai, et al. Integrin {alpha}IIb{beta}3 Induces the Adhesion and Activation of Mast Cells through Interaction with Fibrinogen J. Immunol., January 1, 2006; 176(1): 52 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Lapidot, A. Dar, and O. Kollet How do stem cells find their way home? Blood, September 15, 2005; 106(6): 1901 - 1910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Mause, P. von Hundelshausen, A. Zernecke, R. R. Koenen, and C. Weber Platelet Microparticles: A Transcellular Delivery System for RANTES Promoting Monocyte Recruitment on Endothelium Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1512 - 1518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Brill, O. Dashevsky, J. Rivo, Y. Gozal, and D. Varon Platelet-derived microparticles induce angiogenesis and stimulate post-ischemic revascularization Cardiovasc Res, July 1, 2005; 67(1): 30 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zernecke, A. Schober, I. Bot, P. von Hundelshausen, E. A. Liehn, B. Mopps, M. Mericskay, P. Gierschik, E. A. Biessen, and C. Weber SDF-1{alpha}/CXCR4 Axis Is Instrumental in Neointimal Hyperplasia and Recruitment of Smooth Muscle Progenitor Cells Circ. Res., April 15, 2005; 96(7): 784 - 791. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Weber Platelets and Chemokines in Atherosclerosis: Partners in Crime Circ. Res., April 1, 2005; 96(6): 612 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Martinez, A. Tesse, F. Zobairi, and R. Andriantsitohaina Shed membrane microparticles from circulating and vascular cells in regulating vascular function Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1004 - H1009. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wysoczynski, R. Reca, J. Ratajczak, M. Kucia, N. Shirvaikar, M. Honczarenko, M. Mills, J. Wanzeck, A. Janowska-Wieczorek, and M. Z. Ratajczak Incorporation of CXCR4 into membrane lipid rafts primes homing-related responses of hematopoietic stem/progenitor cells to an SDF-1 gradient Blood, January 1, 2005; 105(1): 40 - 48. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ratajczak, K. Miekus, M. Kucia, P. Dvorak, and M. Ratajczak A New Mechanism of Communication between Stem Cells Involving Vertical Transfer of mRNA by Its Intracellular Delivery within Membrane-Derived Microvesicles. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 460 - 460. [Abstract]
|
|
|
|
|
|
L. A. Marquez-Curtis, M. Wysoczynski, M. Z. Ratajczak, and A. Janowska-Wieczorek Microvesicles Derived from Activated Platelets Enhance the Invasive Potential of Breast Cancer Cells. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 3904 - 3904. [Abstract]
|
|
|
|
|
|
T. J. Rabelink, H. C. de Boer, E. J.P. de Koning, and A.-J. van Zonneveld Endothelial Progenitor Cells: More Than an Inflammatory Response? Arterioscler Thromb Vasc Biol, May 1, 2004; 24(5): 834 - 838. [Abstract] [Full Text]
|
|
|
|
|
|
J. Ratajczak, R. Reca, M. Kucia, M. Majka, D. J. Allendorf, J. T. Baran, A. Janowska-Wieczorek, R. A. Wetsel, G. D. Ross, and M. Z. Ratajczak Mobilization studies in mice deficient in either C3 or C3a receptor (C3aR) reveal a novel role for complement in retention of hematopoietic stem/progenitor cells in bone marrow Blood, March 15, 2004; 103(6): 2071 - 2078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Reca, D. Mastellos, M. Majka, L. Marquez, J. Ratajczak, S. Franchini, A. Glodek, M. Honczarenko, L. A. Spruce, A. Janowska-Wieczorek, et al. Functional receptor for C3a anaphylatoxin is expressed by normal hematopoietic stem/progenitor cells, and C3a enhances their homing-related responses to SDF-1 Blood, May 15, 2003; 101(10): 3784 - 3793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. Burger and D. D. Wagner Platelet P-selectin facilitates atherosclerotic lesion development Blood, April 1, 2003; 101(7): 2661 - 2666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Kollet, I. Petit, J. Kahn, S. Samira, A. Dar, A. Peled, V. Deutsch, M. Gunetti, W. Piacibello, A. Nagler, et al. Human CD34+CXCR4- sorted cells harbor intracellular CXCR4, which can be functionally expressed and provide NOD/SCID repopulation Blood, September 26, 2002; 100(8): 2778 - 2786. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
