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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.

Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC - J. Exp. Med. (1997)

Bottom Line: This is the first chemoattractant reported for human CD34+ progenitor cells.Concentrations of SDF-1 that elicit chemotaxis also induce a transient elevation of cytoplasmic calcium in CD34+ cells.CD34+ cells migrating to SDF-1 include cells with a more primitive (CD34+/CD38- or CD34+/DR-) phenotype as well as CD34+ cells phenotypically committed to the erythroid, lymphoid and myeloid lineages, including functional BFU-E, CFU-GM, and CFU-MIX progenitors.

View Article: PubMed Central - PubMed

Affiliation: Center for Blood Research, Inc., Boston, Massachusetts, USA.

ABSTRACT
Hematopoietic progenitor cells migrate in vitro and in vivo towards a gradient of the chemotactic factor stromal cell-derived factor-1 (SDF-1) produced by stromal cells. This is the first chemoattractant reported for human CD34+ progenitor cells. Concentrations of SDF-1 that elicit chemotaxis also induce a transient elevation of cytoplasmic calcium in CD34+ cells. SDF-1-induced chemotaxis is inhibited by pertussis toxin, suggesting that its signaling in CD34+ cells is mediated by seven transmembrane receptors coupled to Gi proteins. CD34+ cells migrating to SDF-1 include cells with a more primitive (CD34+/CD38- or CD34+/DR-) phenotype as well as CD34+ cells phenotypically committed to the erythroid, lymphoid and myeloid lineages, including functional BFU-E, CFU-GM, and CFU-MIX progenitors. Chemotaxis of CD34+ cells in response to SDF-1 is increased by IL-3 in vitro and is lower in CD34+ progenitors from peripheral blood than in CD34+ progenitors from bone marrow, suggesting that an altered response to SDF-1 may be associated with CD34 progenitor mobilization.

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Mobilized PB CD34+ cells are less responsive to SDF-1 induced chemotaxis than their BM counterparts. PB samples were obtained  from solid tumor patients treated in the hematological recovery phase of  chemotherapy + G-CSF treatment (n = 6, squares), or on day 5 of G-CSF  treatment alone (n = 1, diamond), as described in Materials and Methods.  BM samples were obtained from normal donors (n = 6; circles) or from  solid tumor patient in remission (n = 1; square). Closed circles represent  one set of CD34+ cells purified from BM or PB samples obtained the  same day of treatment from the same tumor patient treated in the hematological recovery phase of chemotherapy + G-CSF treatment. Symbols  indicate the percentage of CD34+ cells migrating to SDF-1 (300 ng/ml)  in a transendothelial assay. Each symbol represents one different preparation from a different donor. The horizontal bars indicate the average percentage of migration for the bone marrow and the mobilized peripheral  blood CD34+cell samples, respectively. Data for PB CD34+ cells are the  following: average 5.1% of input, SEM 0.58. Data for BM CD34+ cells  are the following: average 20% of input, SEM 3.4; P <0.01. The proportion of cells migrating to control media in these transendothelial assays  ranged from 0.05 to 0.5% percent of input, resulting in a low accuracy in  detecting few cells (<1,000) by flow cytometry and a large variability of  chemotactic indexes (CI). Therefore, no statistically significant differences  were found between the CI of BM and PB CD34+ cells to SDF-1, although a tendency was observed for lower CI in PB CD34+ cells (median  CI for BM CD34+, 48 [SEM 8]; for PB CD34+, 24 [SEM 16]).
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Figure 4: Mobilized PB CD34+ cells are less responsive to SDF-1 induced chemotaxis than their BM counterparts. PB samples were obtained from solid tumor patients treated in the hematological recovery phase of chemotherapy + G-CSF treatment (n = 6, squares), or on day 5 of G-CSF treatment alone (n = 1, diamond), as described in Materials and Methods. BM samples were obtained from normal donors (n = 6; circles) or from solid tumor patient in remission (n = 1; square). Closed circles represent one set of CD34+ cells purified from BM or PB samples obtained the same day of treatment from the same tumor patient treated in the hematological recovery phase of chemotherapy + G-CSF treatment. Symbols indicate the percentage of CD34+ cells migrating to SDF-1 (300 ng/ml) in a transendothelial assay. Each symbol represents one different preparation from a different donor. The horizontal bars indicate the average percentage of migration for the bone marrow and the mobilized peripheral blood CD34+cell samples, respectively. Data for PB CD34+ cells are the following: average 5.1% of input, SEM 0.58. Data for BM CD34+ cells are the following: average 20% of input, SEM 3.4; P <0.01. The proportion of cells migrating to control media in these transendothelial assays ranged from 0.05 to 0.5% percent of input, resulting in a low accuracy in detecting few cells (<1,000) by flow cytometry and a large variability of chemotactic indexes (CI). Therefore, no statistically significant differences were found between the CI of BM and PB CD34+ cells to SDF-1, although a tendency was observed for lower CI in PB CD34+ cells (median CI for BM CD34+, 48 [SEM 8]; for PB CD34+, 24 [SEM 16]).

Mentions: Mobilized PBPCs were collected by leukapheresis from seven patients being treated on protocols at the Dana-Farber Cancer Institute (14). Donor patients were being treated for advanced breast cancer (n = 6) or non-Hodgkin's lymphoma (n = 1) (stage III to stage IV). Mobilization regimens consisted of single-agent doxorubicin 90 mg/m2 (n = 3) or cyclophosphamide 6 g/m2 (n = 3) followed in either case by subcutaneous injection of 5 μg/kg of granulocyte–colony-stimulating factor (G-CSF) daily for 5 d (Neupogen, Amgen, Thousand Oaks, CA). PBPCs were collected on consecutive days at the time of hematological recovery after the chemotherapy-induced leukopenia. One patient had PBPC, collected at the beginning the fifth day of G-CSF treatment (5 μg/kg), which was given daily by subcutaneous injection without chemotherapy (labeled as a diamond in Fig. 4). PBPCs used in this study were all obtained from different subjects and from products collected either on the first (n = 1), second (n = 4), or third (n = 3) day of leukapheresis. All samples were obtained from the Dana Farber Cancer Institute blood component laboratory with the exception of one set of BM or PB from the same patient which was obtained from the hematology/oncology staff of The Hospital Universitario de Alcala and The Centro Ramon y Cajal (Madrid, Spain).


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.

Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC - J. Exp. Med. (1997)

Mobilized PB CD34+ cells are less responsive to SDF-1 induced chemotaxis than their BM counterparts. PB samples were obtained  from solid tumor patients treated in the hematological recovery phase of  chemotherapy + G-CSF treatment (n = 6, squares), or on day 5 of G-CSF  treatment alone (n = 1, diamond), as described in Materials and Methods.  BM samples were obtained from normal donors (n = 6; circles) or from  solid tumor patient in remission (n = 1; square). Closed circles represent  one set of CD34+ cells purified from BM or PB samples obtained the  same day of treatment from the same tumor patient treated in the hematological recovery phase of chemotherapy + G-CSF treatment. Symbols  indicate the percentage of CD34+ cells migrating to SDF-1 (300 ng/ml)  in a transendothelial assay. Each symbol represents one different preparation from a different donor. The horizontal bars indicate the average percentage of migration for the bone marrow and the mobilized peripheral  blood CD34+cell samples, respectively. Data for PB CD34+ cells are the  following: average 5.1% of input, SEM 0.58. Data for BM CD34+ cells  are the following: average 20% of input, SEM 3.4; P <0.01. The proportion of cells migrating to control media in these transendothelial assays  ranged from 0.05 to 0.5% percent of input, resulting in a low accuracy in  detecting few cells (<1,000) by flow cytometry and a large variability of  chemotactic indexes (CI). Therefore, no statistically significant differences  were found between the CI of BM and PB CD34+ cells to SDF-1, although a tendency was observed for lower CI in PB CD34+ cells (median  CI for BM CD34+, 48 [SEM 8]; for PB CD34+, 24 [SEM 16]).
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Related In: Results  -  Collection

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Figure 4: Mobilized PB CD34+ cells are less responsive to SDF-1 induced chemotaxis than their BM counterparts. PB samples were obtained from solid tumor patients treated in the hematological recovery phase of chemotherapy + G-CSF treatment (n = 6, squares), or on day 5 of G-CSF treatment alone (n = 1, diamond), as described in Materials and Methods. BM samples were obtained from normal donors (n = 6; circles) or from solid tumor patient in remission (n = 1; square). Closed circles represent one set of CD34+ cells purified from BM or PB samples obtained the same day of treatment from the same tumor patient treated in the hematological recovery phase of chemotherapy + G-CSF treatment. Symbols indicate the percentage of CD34+ cells migrating to SDF-1 (300 ng/ml) in a transendothelial assay. Each symbol represents one different preparation from a different donor. The horizontal bars indicate the average percentage of migration for the bone marrow and the mobilized peripheral blood CD34+cell samples, respectively. Data for PB CD34+ cells are the following: average 5.1% of input, SEM 0.58. Data for BM CD34+ cells are the following: average 20% of input, SEM 3.4; P <0.01. The proportion of cells migrating to control media in these transendothelial assays ranged from 0.05 to 0.5% percent of input, resulting in a low accuracy in detecting few cells (<1,000) by flow cytometry and a large variability of chemotactic indexes (CI). Therefore, no statistically significant differences were found between the CI of BM and PB CD34+ cells to SDF-1, although a tendency was observed for lower CI in PB CD34+ cells (median CI for BM CD34+, 48 [SEM 8]; for PB CD34+, 24 [SEM 16]).
Mentions: Mobilized PBPCs were collected by leukapheresis from seven patients being treated on protocols at the Dana-Farber Cancer Institute (14). Donor patients were being treated for advanced breast cancer (n = 6) or non-Hodgkin's lymphoma (n = 1) (stage III to stage IV). Mobilization regimens consisted of single-agent doxorubicin 90 mg/m2 (n = 3) or cyclophosphamide 6 g/m2 (n = 3) followed in either case by subcutaneous injection of 5 μg/kg of granulocyte–colony-stimulating factor (G-CSF) daily for 5 d (Neupogen, Amgen, Thousand Oaks, CA). PBPCs were collected on consecutive days at the time of hematological recovery after the chemotherapy-induced leukopenia. One patient had PBPC, collected at the beginning the fifth day of G-CSF treatment (5 μg/kg), which was given daily by subcutaneous injection without chemotherapy (labeled as a diamond in Fig. 4). PBPCs used in this study were all obtained from different subjects and from products collected either on the first (n = 1), second (n = 4), or third (n = 3) day of leukapheresis. All samples were obtained from the Dana Farber Cancer Institute blood component laboratory with the exception of one set of BM or PB from the same patient which was obtained from the hematology/oncology staff of The Hospital Universitario de Alcala and The Centro Ramon y Cajal (Madrid, Spain).

Bottom Line: This is the first chemoattractant reported for human CD34+ progenitor cells.Concentrations of SDF-1 that elicit chemotaxis also induce a transient elevation of cytoplasmic calcium in CD34+ cells.CD34+ cells migrating to SDF-1 include cells with a more primitive (CD34+/CD38- or CD34+/DR-) phenotype as well as CD34+ cells phenotypically committed to the erythroid, lymphoid and myeloid lineages, including functional BFU-E, CFU-GM, and CFU-MIX progenitors.

View Article: PubMed Central - PubMed

Affiliation: Center for Blood Research, Inc., Boston, Massachusetts, USA.

ABSTRACT
Hematopoietic progenitor cells migrate in vitro and in vivo towards a gradient of the chemotactic factor stromal cell-derived factor-1 (SDF-1) produced by stromal cells. This is the first chemoattractant reported for human CD34+ progenitor cells. Concentrations of SDF-1 that elicit chemotaxis also induce a transient elevation of cytoplasmic calcium in CD34+ cells. SDF-1-induced chemotaxis is inhibited by pertussis toxin, suggesting that its signaling in CD34+ cells is mediated by seven transmembrane receptors coupled to Gi proteins. CD34+ cells migrating to SDF-1 include cells with a more primitive (CD34+/CD38- or CD34+/DR-) phenotype as well as CD34+ cells phenotypically committed to the erythroid, lymphoid and myeloid lineages, including functional BFU-E, CFU-GM, and CFU-MIX progenitors. Chemotaxis of CD34+ cells in response to SDF-1 is increased by IL-3 in vitro and is lower in CD34+ progenitors from peripheral blood than in CD34+ progenitors from bone marrow, suggesting that an altered response to SDF-1 may be associated with CD34 progenitor mobilization.

Show MeSH
Related in: MedlinePlus