Differential Effects of Culture Conditions on the Migration Pattern of Stromal Cell–Derived Factor–Stimulated Hematopoietic Stem Cells
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《干细胞学杂志》
a Institute of Immunology and
b Department of Gynecology, Marienhospital, University of Witten/Herdecke, Witten, Germany
Key Words. SDF-1 ? Ex vivo expansion ? Cell migration ? Cytokines ? Hematopoietic stem cells
Correspondence: Corinna Weidt, Institute of Immunology, University of Witten/Herdecke, Stockumer Str. 10, 58448 Witten, Germany. Telephone: 49-2302-669-152; Fax:49-2302-669-158; e-mail: cweidt@uni-wh.de
ABSTRACT
The aptitude of hematopoietic stem cells (HSCs) to migrate is increasingly becoming of interest to researchers and oncologists, not only for the benefit of augmenting the success rate of hematopoietic system regeneration after transplantation of HSCs but also in examining microchimerism , tissue renewal, and disease . In light of technical and ethical issues concerning the usage of embryonic stem cells as a quiescent panacean source, it is all the more important to scrutinize the apparent migrational capacity of facilely available HSCs. Migration is a sine qua non characteristic that enables the homing of HSCs to bone marrow and damaged tissue . The importance of investigating cells in a three-dimensional (3D) surrounding becomes apparent when comparative 2D and 3D experiments are performed. Experiments to this effect have unambiguously shown that a 3D environment brings forth differential results and must therefore be considered.
To investigate the locomotory behavior of HSCs in 3D, we used the highly efficacious migratory stimulant stromal cell–derived factor-1 (SDF-1). This chemokine is constitutively expressed by numerous tissues and serves as a chemoattractant for tumor cells , lymphocytes , monocytes, neutrophil granulocytes, endothelial precursors, and HSCs and has been suggested to play a role as a homeostatic regulator in tissue renewal . SDF-1 belongs to the CXC subgroup of chemokines and binds to the CXCR4 receptor. CXCR4 is a member of the seven-helix receptor family, and signaling induces the migration of HSCs via calcium release and reorganization of actin cytoskeleton structure . The CD34+ population of HSCs is comprised of CXCR4+ and CXCR4– subpopulations. CXCR4 expression and subsequent migration with SDF-1 was seen to be stimulated and enhanced by the addition of stem cell factor (SCF) or SCF and interleukin 6 (IL-6) to the medium .
IL-6 and Flt3-ligand (FL) are common supplements used for HSC expansion . We thus chose to examine cell migration characteristics of HSCs cultivated under these conditions. The study of single-cell migration in a 3D collagen matrix, using video microscopy and computer-aided analysis , enabled us to examine the migration pattern of a population of cord blood–derived cells isolated via the CD133 antigen. A change in the average migration rate can be the result of a permutation of several factors, including the recruitment of immobile cells and a change in the migratory pattern, which is comprised of time active, pauses, and speed. Results of our analysis using FL-incubated HSCs compared with FL/IL-6-incubated HSCs in response to SDF-1 show a differential effect on the recruitment and migration pattern of these cells induced by IL-6. This demonstrates that the inflammatory cytokine IL-6, when present in the culture media, leads to an altered migratory phenotype of these cells.
MATERIALS AND METHODS
Cord blood–derived cells were placed in a collagen-based migration system after cultivation in either FL or a combination of FL and IL-6. Cultivation in IL-6 alone does not allow for such an experiment, because cells are no longer viable after 5 days (data not shown).
Cells previously cultivated in FL alone showed an increase in the average migration rate of 7.4% when stimulated with SDF-1 (Fig. 2A). The average population of moving cells in the control was 63.9%, and the average population of SDF-1–stimulated cells was 78.4%. Additional analysis showed that recruitment of cells alone explained the increase in the average migration rate, because single-cell analysis disclosed no change in the migratory behavior of individual cells (data not shown). In contrast, cells cultivated in FL/IL-6 showed an increase in the average migration rate of 21.7% when stimulated with SDF-1 (Fig. 2B). Actually motile cells comprised 72.2% in the control population and 81.1% in SDF-1–induced cells, whereby recruitment could only explain a minute part of the elevated average migration rate (data not shown).
Figure 2. Average migration of FL- and FL/IL-6–cultivated CD133 cells response to SDF-1. (A): The average migration rate of FL-cultivated CD133 cells in response to SDF-1 (1 μg/ml) showed an average increase of 7.4% due to a recruitment of nonmoving cells. (B): CD133 cells cultivated in FL/IL-6 responded to SDF-1 (1 μg/ml) stimulation, with an average increased migration rate of 21.3%. Each diagram represents the results of cells isolated from three independent cord blood donors. Abbreviations: FL, Flt3-ligand; IL-6, interleukin 6; SDF-1, stromal cell–derived factor-1.
Based on the observation that cells do not move constantly, we calculated the percent time in which cells were active. Control cells were active on average 21.1% of the time, and SDF-1–stimulated cells were active 42.6% of the time (Fig. 3A; p < .0001). For more detailed analysis, we decided to differentiate distance over time. Velocity denotes distance over time of each individual cell omitting pauses. Conjointly, speed denotes distance over time including pauses made. Control cells showed an average velocity of 3.16 and 2.68 μm/minute (Fig. 3B; p < .05) for SDF-1–stimulated cells. Average speed of the cells was 0.75 μm/minute for unstimulated cells and 1.26 μm/minute (Fig. 3C; p < .001) for stimulated cells. Pause characteristics, such as pause frequency, showed that, on average, control cells put in 8.8 pauses and stimulated cells put in 13.8 pauses (Fig. 3D; p < .0001). This observation is at first contradictory to the increased time active but could be explained by a marked reduction in the length of each individual pause. Pause length was on average 16.7 minutes for unstimulated cells and 8.3 minutes for the SDF-1–activated cells (Fig. 3E; p < .001). The combined effect of the aforementioned precipitates into an increase in the average distance migrated, which was 86.2 μm for control cells and 134.6 μm (Fig. 3F; p < .001) for stimulated cells.
Figure 3. Migration pattern of FL/IL-6–cultivated CD133 cells in response to SDF-1. Time-lapse video microscopy combined with computer-assisted cell tracking allows for detailed analysis of the migration pattern on a single-cell level. The following parameters were analyzed in this study: time active (%) (A), velocity (excluding pauses; μm/min) (B), speed (including pauses; μm/min) (C), pause frequency (D), pause length (min) (E), and distance migrated (μm) (F). Stimulation of FL/IL-6–cultivated CD133 cells with SDF-1 resulted in a decrease in velocity. In contrast, there was a significant increase in the time active, speed, pause frequency, and distance migrated. Abbreviations: FL, Flt3-ligand; IL-6, interleukin 6; SDF-1, stromal cell–derived factor-1.
To investigate whether the migration effect seen was caused by the differential conditions, FL and FL/IL-6 per se, we analyzed the migration pattern of these cells without SDF-1 stimulation. Upon comparing the migration pattern of FL- and FL/IL-6-incubated cells, we found no significant difference. For a summary of the results, see Table 1.
Table 1. Culture conditions used and migration analysis results
DISCUSSION
These data are of particular relevance in light of obligatory HSC expansion before therapy, whereby SDF-1 plays a significant role in maintaining and reinstating the hematopoi-etic system and also conceivably in tissue regeneration. Parameters such as recruitment, speed, and pauses made are elementary in characterizing migration and demonstrably play a significant role in the migration of IL-6–incubated, SDF-1–stimulated HSCs. This level of qualitative and quantitative analysis bares potential to help interpret repopulation data with HSCs and gives reason to carefully consider the supplements of expansion media, which may enhance or even compromise the efficacy of therapy involving HSC migration.
ACKNOWLEDGMENTS
Tutschek B, Reinhard J, Kogler G et al. Clonal culture of fetal cells from maternal blood. Lancet 2000;356:1736–1737.
Kale S, Karihaloo A, Clark PR et al. Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. J Clin Invest 2003;112:42–49.
Kayali AG, Van Gunst K, Campbell IL et al. The stromal cell-derived factor-1/CXCR4 ligand-receptor axis is critical for progenitor survival and migration in the pancreas. J Cell Biol 2003;163:859–869.
Krause DS, Theise ND, Collector MI et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001;105:369–377.
Camargo FD, Green R, Capetenaki Y et al. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med 2003;9:1520–1527.
Cao B, Zheng B, Jankowski RJ et al. Muscle stem cells differentiate into haematopoietic lineages but retain myogenic potential. Nat Cell Biol 2003;5:640–646.
Askari AT, Unzek S, Popovic ZB et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 2003;362:697–703.
Tran SD, Pillemer SR, Dutra A et al. Differentiation of human bone marrow-derived cells into buccal epithelial cells in vivo: a molecular analytical study. Lancet 2003;361:1084–1088.
Wang F, Weaver VM, Petersen OW et al. Reciprocal interactions between beta1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology. Proc Natl Acad Sci U S A 1998;95:14821–14826.
Pablos JL, Amara A, Bouloc A et al. Stromal-cell derived factor is expressed by dendritic cells and endothelium in human skin. Am J Pathol 1999;155:1577–1586.
Muller A, Homey B, Soto H et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001;410:50–56.
Phillips R, Ager A. Activation of pertussis toxin-sensitive CXCL12 (SDF-1) receptors mediates transendothelial migration of T lymphocytes across lymph node high endothelial cells. Eur J Immunol 2002;32:837–847.
Terada R, Yamamoto K, Hakoda T et al. Stromal cell-derived factor-1 from biliary epithelial cells recruits CXCR4-positive cells: implications for inflammatory liver diseases. Lab Invest 2003;83:665–672.
Fedyk ER, Jones D, Critchley HO et al. Expression of stromal-derived factor-1 is decreased by IL-1 and TNF and in dermal wound healing. J Immunol 2001;166:5749–5754.
Henschler R, Piiper A, Bistrian R et al. SDF-1alpha-induced intracellular calcium transient involves Rho GTPase signalling and is required for migration of hematopoietic progenitor cells. Biochem Biophys Res Commun 2003;311:1067–1071.
Hattori K, Heissig B, Tashiro K et al. Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood 2001;97:3354–3360.
Wang JF, Park IW, Groopman JE. Stromal cell-derived factor-1alpha stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C. Blood 2000;95:2505–2513.
Voermans C,Anthony EC, Mul E et al. SDF-1-induced actin polymerization and migration in human hematopoietic progenitor cells. Exp Hematol 2001;29:1456–1464.
Dutt P, Wang JF, Groopman JE. Stromal cell-derived factor-1 alpha and stem cell factor/kit ligand share signaling pathways in hemopoietic progenitors: a potential mechanism for cooperative induction of chemotaxis. J Immunol 1998;161:3652–3658.
Peled A, Petit I, Kollet O et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 1999;283:845–848.
Rosu-Myles M, Gallacher L, Murdoch B et al. The human hematopoietic stem cell compartment is heterogeneous for CXCR4 expression. Proc Natl Acad Sci U S A 2000;97:14626–14631.
Kollet O, Petit I, Kahn J et al. Human CD34(+)CXCR4(–) sorted cells harbor intracellular CXCR4, which can be functionally expressed and provide NOD/SCID repopulation. Blood 2002;100:2778–2786.
Piacibello W, Sanavio F, Garetto L et al. Differential growth factor requirement of primitive cord blood hematopoietic stem cell for self-renewal and amplification vs proliferation and differentiation. Leukemia 1998;12:718–727.
Kuci S, Wessels JT, Buhring HJ et al. Identification of a novel class of human adherent CD34– stem cells that give rise to SCID-repopulating cells. Blood 2003;101:869–876.
Entschladen F, Gunzer M, Scheuffele CM et al. T lymphocytes and neutrophil granulocytes differ in regulatory signaling and migratory dynamics with regard to spontaneous locomotion and chemotaxis. Cell Immunol 2000;199:104–114.
Mueller YM, Cramer DE, Huang Y et al. Hematopoietic stem cells from the marrow of mice treated with Flt3 ligand are significantly expanded but exhibit reduced engraftment potential. Transplantation 2002;73:1177–1185.
Niggemann B, Drell IV TL, Joseph J et al. Tumor cell locomotion: different dynamics of spontaneous and induced migration in a 3D collagen matrix. Exp Cell Res 2004;298:178–187.
Kollet O, Spiegel A, Peled A et al. Rapid and efficient homing of human CD34(+)CD38(–/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.
Hirano T, Ishihara K, Hibi M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 2000;19:2548–2556.
Kira M, Sano S, Takagi S et al. STAT3 deficiency in keratinocytes leads to compromised cell migration through hyperphosphorylation of p130(cas). J Biol Chem 2002;277:12931–12936.
Wang Z, Newman WH. Smooth muscle cell migration stimulated by interleukin 6 is associated with cytoskeletal reorganization. J Surg Res 2003;111:261–266.
Badache A, Hynes NE. Interleukin 6 inhibits proliferation and, in cooperation wit an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. Cancer Res 2001;61:383–391.
Veiby OP, Jacobsen FW, Cui L et al. The flt3 ligand promotes the survival of primitive hemopoietic progenitor cells with myeloid as well as B lymphoid potential: suppression of apoptosis and counteraction by TNF-alpha and TGF-beta. J Immunol 1996;157:2953–2960.
Takahira H, Lyman SD, Broxmeyer HE. Flt3 ligand prolongs survival of CD34++ + human umbilical cord blood myeloid progenitors in serum-depleted culture medium. Ann Hematol 1996;72:131–135.(Corinna Weidta, Bernd Nig)
b Department of Gynecology, Marienhospital, University of Witten/Herdecke, Witten, Germany
Key Words. SDF-1 ? Ex vivo expansion ? Cell migration ? Cytokines ? Hematopoietic stem cells
Correspondence: Corinna Weidt, Institute of Immunology, University of Witten/Herdecke, Stockumer Str. 10, 58448 Witten, Germany. Telephone: 49-2302-669-152; Fax:49-2302-669-158; e-mail: cweidt@uni-wh.de
ABSTRACT
The aptitude of hematopoietic stem cells (HSCs) to migrate is increasingly becoming of interest to researchers and oncologists, not only for the benefit of augmenting the success rate of hematopoietic system regeneration after transplantation of HSCs but also in examining microchimerism , tissue renewal, and disease . In light of technical and ethical issues concerning the usage of embryonic stem cells as a quiescent panacean source, it is all the more important to scrutinize the apparent migrational capacity of facilely available HSCs. Migration is a sine qua non characteristic that enables the homing of HSCs to bone marrow and damaged tissue . The importance of investigating cells in a three-dimensional (3D) surrounding becomes apparent when comparative 2D and 3D experiments are performed. Experiments to this effect have unambiguously shown that a 3D environment brings forth differential results and must therefore be considered.
To investigate the locomotory behavior of HSCs in 3D, we used the highly efficacious migratory stimulant stromal cell–derived factor-1 (SDF-1). This chemokine is constitutively expressed by numerous tissues and serves as a chemoattractant for tumor cells , lymphocytes , monocytes, neutrophil granulocytes, endothelial precursors, and HSCs and has been suggested to play a role as a homeostatic regulator in tissue renewal . SDF-1 belongs to the CXC subgroup of chemokines and binds to the CXCR4 receptor. CXCR4 is a member of the seven-helix receptor family, and signaling induces the migration of HSCs via calcium release and reorganization of actin cytoskeleton structure . The CD34+ population of HSCs is comprised of CXCR4+ and CXCR4– subpopulations. CXCR4 expression and subsequent migration with SDF-1 was seen to be stimulated and enhanced by the addition of stem cell factor (SCF) or SCF and interleukin 6 (IL-6) to the medium .
IL-6 and Flt3-ligand (FL) are common supplements used for HSC expansion . We thus chose to examine cell migration characteristics of HSCs cultivated under these conditions. The study of single-cell migration in a 3D collagen matrix, using video microscopy and computer-aided analysis , enabled us to examine the migration pattern of a population of cord blood–derived cells isolated via the CD133 antigen. A change in the average migration rate can be the result of a permutation of several factors, including the recruitment of immobile cells and a change in the migratory pattern, which is comprised of time active, pauses, and speed. Results of our analysis using FL-incubated HSCs compared with FL/IL-6-incubated HSCs in response to SDF-1 show a differential effect on the recruitment and migration pattern of these cells induced by IL-6. This demonstrates that the inflammatory cytokine IL-6, when present in the culture media, leads to an altered migratory phenotype of these cells.
MATERIALS AND METHODS
Cord blood–derived cells were placed in a collagen-based migration system after cultivation in either FL or a combination of FL and IL-6. Cultivation in IL-6 alone does not allow for such an experiment, because cells are no longer viable after 5 days (data not shown).
Cells previously cultivated in FL alone showed an increase in the average migration rate of 7.4% when stimulated with SDF-1 (Fig. 2A). The average population of moving cells in the control was 63.9%, and the average population of SDF-1–stimulated cells was 78.4%. Additional analysis showed that recruitment of cells alone explained the increase in the average migration rate, because single-cell analysis disclosed no change in the migratory behavior of individual cells (data not shown). In contrast, cells cultivated in FL/IL-6 showed an increase in the average migration rate of 21.7% when stimulated with SDF-1 (Fig. 2B). Actually motile cells comprised 72.2% in the control population and 81.1% in SDF-1–induced cells, whereby recruitment could only explain a minute part of the elevated average migration rate (data not shown).
Figure 2. Average migration of FL- and FL/IL-6–cultivated CD133 cells response to SDF-1. (A): The average migration rate of FL-cultivated CD133 cells in response to SDF-1 (1 μg/ml) showed an average increase of 7.4% due to a recruitment of nonmoving cells. (B): CD133 cells cultivated in FL/IL-6 responded to SDF-1 (1 μg/ml) stimulation, with an average increased migration rate of 21.3%. Each diagram represents the results of cells isolated from three independent cord blood donors. Abbreviations: FL, Flt3-ligand; IL-6, interleukin 6; SDF-1, stromal cell–derived factor-1.
Based on the observation that cells do not move constantly, we calculated the percent time in which cells were active. Control cells were active on average 21.1% of the time, and SDF-1–stimulated cells were active 42.6% of the time (Fig. 3A; p < .0001). For more detailed analysis, we decided to differentiate distance over time. Velocity denotes distance over time of each individual cell omitting pauses. Conjointly, speed denotes distance over time including pauses made. Control cells showed an average velocity of 3.16 and 2.68 μm/minute (Fig. 3B; p < .05) for SDF-1–stimulated cells. Average speed of the cells was 0.75 μm/minute for unstimulated cells and 1.26 μm/minute (Fig. 3C; p < .001) for stimulated cells. Pause characteristics, such as pause frequency, showed that, on average, control cells put in 8.8 pauses and stimulated cells put in 13.8 pauses (Fig. 3D; p < .0001). This observation is at first contradictory to the increased time active but could be explained by a marked reduction in the length of each individual pause. Pause length was on average 16.7 minutes for unstimulated cells and 8.3 minutes for the SDF-1–activated cells (Fig. 3E; p < .001). The combined effect of the aforementioned precipitates into an increase in the average distance migrated, which was 86.2 μm for control cells and 134.6 μm (Fig. 3F; p < .001) for stimulated cells.
Figure 3. Migration pattern of FL/IL-6–cultivated CD133 cells in response to SDF-1. Time-lapse video microscopy combined with computer-assisted cell tracking allows for detailed analysis of the migration pattern on a single-cell level. The following parameters were analyzed in this study: time active (%) (A), velocity (excluding pauses; μm/min) (B), speed (including pauses; μm/min) (C), pause frequency (D), pause length (min) (E), and distance migrated (μm) (F). Stimulation of FL/IL-6–cultivated CD133 cells with SDF-1 resulted in a decrease in velocity. In contrast, there was a significant increase in the time active, speed, pause frequency, and distance migrated. Abbreviations: FL, Flt3-ligand; IL-6, interleukin 6; SDF-1, stromal cell–derived factor-1.
To investigate whether the migration effect seen was caused by the differential conditions, FL and FL/IL-6 per se, we analyzed the migration pattern of these cells without SDF-1 stimulation. Upon comparing the migration pattern of FL- and FL/IL-6-incubated cells, we found no significant difference. For a summary of the results, see Table 1.
Table 1. Culture conditions used and migration analysis results
DISCUSSION
These data are of particular relevance in light of obligatory HSC expansion before therapy, whereby SDF-1 plays a significant role in maintaining and reinstating the hematopoi-etic system and also conceivably in tissue regeneration. Parameters such as recruitment, speed, and pauses made are elementary in characterizing migration and demonstrably play a significant role in the migration of IL-6–incubated, SDF-1–stimulated HSCs. This level of qualitative and quantitative analysis bares potential to help interpret repopulation data with HSCs and gives reason to carefully consider the supplements of expansion media, which may enhance or even compromise the efficacy of therapy involving HSC migration.
ACKNOWLEDGMENTS
Tutschek B, Reinhard J, Kogler G et al. Clonal culture of fetal cells from maternal blood. Lancet 2000;356:1736–1737.
Kale S, Karihaloo A, Clark PR et al. Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. J Clin Invest 2003;112:42–49.
Kayali AG, Van Gunst K, Campbell IL et al. The stromal cell-derived factor-1/CXCR4 ligand-receptor axis is critical for progenitor survival and migration in the pancreas. J Cell Biol 2003;163:859–869.
Krause DS, Theise ND, Collector MI et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001;105:369–377.
Camargo FD, Green R, Capetenaki Y et al. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med 2003;9:1520–1527.
Cao B, Zheng B, Jankowski RJ et al. Muscle stem cells differentiate into haematopoietic lineages but retain myogenic potential. Nat Cell Biol 2003;5:640–646.
Askari AT, Unzek S, Popovic ZB et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 2003;362:697–703.
Tran SD, Pillemer SR, Dutra A et al. Differentiation of human bone marrow-derived cells into buccal epithelial cells in vivo: a molecular analytical study. Lancet 2003;361:1084–1088.
Wang F, Weaver VM, Petersen OW et al. Reciprocal interactions between beta1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology. Proc Natl Acad Sci U S A 1998;95:14821–14826.
Pablos JL, Amara A, Bouloc A et al. Stromal-cell derived factor is expressed by dendritic cells and endothelium in human skin. Am J Pathol 1999;155:1577–1586.
Muller A, Homey B, Soto H et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001;410:50–56.
Phillips R, Ager A. Activation of pertussis toxin-sensitive CXCL12 (SDF-1) receptors mediates transendothelial migration of T lymphocytes across lymph node high endothelial cells. Eur J Immunol 2002;32:837–847.
Terada R, Yamamoto K, Hakoda T et al. Stromal cell-derived factor-1 from biliary epithelial cells recruits CXCR4-positive cells: implications for inflammatory liver diseases. Lab Invest 2003;83:665–672.
Fedyk ER, Jones D, Critchley HO et al. Expression of stromal-derived factor-1 is decreased by IL-1 and TNF and in dermal wound healing. J Immunol 2001;166:5749–5754.
Henschler R, Piiper A, Bistrian R et al. SDF-1alpha-induced intracellular calcium transient involves Rho GTPase signalling and is required for migration of hematopoietic progenitor cells. Biochem Biophys Res Commun 2003;311:1067–1071.
Hattori K, Heissig B, Tashiro K et al. Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood 2001;97:3354–3360.
Wang JF, Park IW, Groopman JE. Stromal cell-derived factor-1alpha stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C. Blood 2000;95:2505–2513.
Voermans C,Anthony EC, Mul E et al. SDF-1-induced actin polymerization and migration in human hematopoietic progenitor cells. Exp Hematol 2001;29:1456–1464.
Dutt P, Wang JF, Groopman JE. Stromal cell-derived factor-1 alpha and stem cell factor/kit ligand share signaling pathways in hemopoietic progenitors: a potential mechanism for cooperative induction of chemotaxis. J Immunol 1998;161:3652–3658.
Peled A, Petit I, Kollet O et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 1999;283:845–848.
Rosu-Myles M, Gallacher L, Murdoch B et al. The human hematopoietic stem cell compartment is heterogeneous for CXCR4 expression. Proc Natl Acad Sci U S A 2000;97:14626–14631.
Kollet O, Petit I, Kahn J et al. Human CD34(+)CXCR4(–) sorted cells harbor intracellular CXCR4, which can be functionally expressed and provide NOD/SCID repopulation. Blood 2002;100:2778–2786.
Piacibello W, Sanavio F, Garetto L et al. Differential growth factor requirement of primitive cord blood hematopoietic stem cell for self-renewal and amplification vs proliferation and differentiation. Leukemia 1998;12:718–727.
Kuci S, Wessels JT, Buhring HJ et al. Identification of a novel class of human adherent CD34– stem cells that give rise to SCID-repopulating cells. Blood 2003;101:869–876.
Entschladen F, Gunzer M, Scheuffele CM et al. T lymphocytes and neutrophil granulocytes differ in regulatory signaling and migratory dynamics with regard to spontaneous locomotion and chemotaxis. Cell Immunol 2000;199:104–114.
Mueller YM, Cramer DE, Huang Y et al. Hematopoietic stem cells from the marrow of mice treated with Flt3 ligand are significantly expanded but exhibit reduced engraftment potential. Transplantation 2002;73:1177–1185.
Niggemann B, Drell IV TL, Joseph J et al. Tumor cell locomotion: different dynamics of spontaneous and induced migration in a 3D collagen matrix. Exp Cell Res 2004;298:178–187.
Kollet O, Spiegel A, Peled A et al. Rapid and efficient homing of human CD34(+)CD38(–/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.
Hirano T, Ishihara K, Hibi M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 2000;19:2548–2556.
Kira M, Sano S, Takagi S et al. STAT3 deficiency in keratinocytes leads to compromised cell migration through hyperphosphorylation of p130(cas). J Biol Chem 2002;277:12931–12936.
Wang Z, Newman WH. Smooth muscle cell migration stimulated by interleukin 6 is associated with cytoskeletal reorganization. J Surg Res 2003;111:261–266.
Badache A, Hynes NE. Interleukin 6 inhibits proliferation and, in cooperation wit an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. Cancer Res 2001;61:383–391.
Veiby OP, Jacobsen FW, Cui L et al. The flt3 ligand promotes the survival of primitive hemopoietic progenitor cells with myeloid as well as B lymphoid potential: suppression of apoptosis and counteraction by TNF-alpha and TGF-beta. J Immunol 1996;157:2953–2960.
Takahira H, Lyman SD, Broxmeyer HE. Flt3 ligand prolongs survival of CD34++ + human umbilical cord blood myeloid progenitors in serum-depleted culture medium. Ann Hematol 1996;72:131–135.(Corinna Weidta, Bernd Nig)