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Stem Cells 2004;22:890-896 www.StemCells.com
© 2004 AlphaMed Press

RAPID COMMUNICATION

Differential Effects of Culture Conditions on the Migration Pattern of Stromal Cell–Derived Factor–Stimulated Hematopoietic Stem Cells

Corinna Weidta, Bernd Niggemanna, Wolfgang Hatzmannb, Kurt S. Zänkera, Thomas Dittmara

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{at}uni-wh.de


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
Evidence is mounting that hematopoietic stem cells (HSCs) play a critical role in bone marrow regeneration and tissue renewal, for which migration is an obvious prerequisite. Computer-aided analysis and a three-dimensional collagen matrix assay enabled us to analyze single-cell migratory characteristics of stromal cell–derived factor-1{alpha} (SDF-1{alpha})–stimulated cord blood–derived HSCs. We defined and resolved specific migratory parameters in spontaneous and SDF-1{alpha}–induced migration of these cells. The addition of interleukin 6 to the culture medium led to differential SDF-1{alpha}–stimulated migratory response, which comprised a recruitment of nonmoving cells and an increase in speed and frequency of pauses but a decrease in pause duration. We were thus able to decipher the exact parameters that result in an increase in the migration of HSCs and demonstrate that extensive analysis of single-cell behavior is elementary in the study of stem cell migration.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
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 [1], tissue renewal, and disease [2–6]. 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 [7,8]. 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 [9] 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{alpha} (SDF-1{alpha}). This chemokine is constitutively expressed by numerous tissues [10] and serves as a chemoattractant for tumor cells [11], lymphocytes [12], monocytes, neutrophil granulocytes, endothelial precursors, and HSCs and has been suggested to play a role as a homeostatic regulator in tissue renewal [13–16]. SDF-1{alpha} 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 [12, 17–19]. The CD34+ population of HSCs is comprised of CXCR4+ and CXCR4– subpopulations. CXCR4 expression and subsequent migration with SDF-1{alpha} 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 [20–22].

IL-6 and Flt3-ligand (FL) are common supplements used for HSC expansion [23,24]. 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 [25], 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 [26] compared with FL/IL-6-incubated HSCs in response to SDF-1{alpha} show a differential effect on the recruitment and migration pattern [27] 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
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
Isolation of CD133+ Hematopoietic Stem Cells from Cord Blood
Cord blood was collected following normal pregnancies and delivery by cesarean section after written parental consent. Mononuclear cells were isolated from heparinized cord blood by density gradient centrifugation over Ficoll-Hypaque (ICN, Meckenheim, Germany; http://www.icnpharm.com). CD133+ cells were isolated via magnetic-activated cell sorting, AC133 Cell Isolation Kit (Miltenyi Biotech, Bergisch-Gladbach, Germany, http://www.miltenyibiotec.com), according to manufacturer’s recommendations.

Cell Culture
Isolated cells were held in culture for 5 days in RPMI-1640 medium (PAA, Linz, Austria, http://www.paa.at), 1% human serum (HS) at 37°C humidified atmosphere with 5% CO2. We used two different culture conditions, comprised of either 100ng/ml FL and 1% HS (PAA) or 100ng/ml FL, 100ng/ml IL-6, and 1% HS (cytokines were purchased from R&D Systems GmbH, Wiesbaden, Germany, http://www.rndsystems.com).

Flow Cytometry
The purity of separated CD133 cells was determined using primary-conjugated monoclonal antibodies. Cells were stained with anti-CD133-PE (clone AC141; Miltenyi Biotech), anti-CD34-APC (clone 8G12; Becton, Dickinson Pharmingen, Heidelberg, Germany, http://www.pharmingen.com), anti-CD45-FITC (clone ALB11; Beckman Coulter GmbH, Krefeld, Germany, http://www.beckmancoulter.com), and anti-CXCR4-PE (clone 12G5; Becton, Dickinson). Isotype-matched mouse immunoglobulins served as controls (IgG1-PE, IgG1-FITC [Dianova, Hamburg, Germany, http://www.dianova.de]; IgG1-APC, IgG2-PE [Beckman Coulter]). Upon isolation, an average of 95 ± 2.3% of the cells were CD133/CD34+ and CD45–, the remainder being CD34+ and CD45–. The population was predominantly positive for CXCR4 expression (upon isolation, > 83.0 ± 10.9% [n = 6]). A total of 104 cells were stained in 100 µ1 of RPMI 1640 medium and incubated at 37°C for 20 minutes. Three-color flow cytometry analyses were performed on a FAC-Scalibur flow cytometer (Becton, Dickinson).

Migration Assay
Collagen lattices were generated by mixing 6 x 104 cells with 100 µl of buffered collagen solution (pH 7.4) containing 1.67 mg/ml collagen type I in minimal essential Eagle’s medium (Flow Laboratories, McLean, VA). Where applicable, the chemokine SDF-1{alpha} (Biotrend, Cologne, Germany, http://www.biotrend.com) was added to the mixture for a final concentration of 1 µg/ml. The suspension was filled into self-constructed glass chambers (Fig. 1Go) and allowed to polymerize for 30 minutes at 37°C and 5% CO2-humidified atmosphere. The migration behavior in the 3D collagen lattice was then recorded at an 80-fold time-lapse mode for 90 minutes at 37°C. After recording, 30 cells were selected randomly; their paths were digitized at 1-minute intervals by computer-assisted cell tracking. Average migration rates were defined as the average number of cells moving at each 1-minute interval. The average population of actually moving cells is the fraction of cells that moved per second during the observation period [25]. Statistical analysis was based on the paired t-test.



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  		Figure 1. Migration analysis experimental set up. (A): Chamber in which the mixture of collagen gel and cells is filled and left to polymerize, after which the chamber is sealed with wax. (B): Path of an individual cell in the collagen matrix. The arrowhead in the left panel points to a cell at the start of the migration path taken at t = 0. The middle panel illustrates the path taken between t = 0 and t = 42 minutes. The third panel shows the path taken in 87 minutes and the final position of the cell. Bar = 30 µm.

 

   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
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{alpha} (Fig. 2AGo). The average population of moving cells in the control was 63.9%, and the average population of SDF-1{alpha}–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{alpha} (Fig. 2BGo). Actually motile cells comprised 72.2% in the control population and 81.1% in SDF-1{alpha}–induced cells, whereby recruitment could only explain a minute part of the elevated average migration rate (data not shown).



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  		Figure 2. Average migration of FL- and FL/IL-6–cultivated CD133 cells response to SDF-1{alpha}. (A): The average migration rate of FL-cultivated CD133 cells in response to SDF-1{alpha} (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{alpha} (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{alpha}, stromal cell–derived factor-1{alpha}.

 
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{alpha}–stimulated cells were active 42.6% of the time (Fig. 3AGo; 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. 3BGo; p < .05) for SDF-1{alpha}–stimulated cells. Average speed of the cells was 0.75 µm/minute for unstimulated cells and 1.26 µm/minute (Fig. 3CGo; 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. 3DGo; 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{alpha}–activated cells (Fig. 3EGo; 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. 3FGo; p < .001) for stimulated cells.



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  		Figure 3. Migration pattern of FL/IL-6–cultivated CD133 cells in response to SDF-1{alpha}. 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{alpha} 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{alpha}, stromal cell–derived factor-1{alpha}.

 
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{alpha} 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 1Go.


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  		Table 1. Culture conditions used and migration analysis results
 

   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
Using 3D-based, single-cell analysis, we have been able to show for the first time that the addition of the inflammatory cytokine IL-6 to the culture medium of CD133+ cells not only stimulated the recruitment of nonmoving cells but moreover gave rise to an altered migratory phenotype in response to SDF-1{alpha}.

It may be presumed that the addition of IL-6 to our cell-culture medium increases the expression of CXCR4, as has been shown for CD34+ cells in combination with SCF and IL-6, and thus contributes to the migratory differences [20, 21, 28]. Cells incubated in a combination of FL and IL-6 show only a marginal increase in the number of moving cells (81.1%) compared with FL-incubated cells (78.4%) when stimulated with SDF-1{alpha}, which indicates that differential CXCR4 expression was not the source of the observed distinct effects on migration. This is supported by the observation that the most predominant origin of disparity is the altered migration pattern of most of the cells, thus pointing to the genuine effect of IL-6 beyond mere CXCR4 expression dependency.

Kollet et al. [28] found that a population of CD34–CD38– lineage-negative cells, despite expressing CXCR4, had decreased migration potential toward SDF-1. This suggests that cell-surface level expression of the SDF-1 receptor alone does not necessarily correlate with elevated migration nor successful engraftment but is obviously influenced by other factors. The inflammatory factor IL-6 itself involves the heterodimerization with gp130 and results in the activation of gp130-associated Janus kinases and subsequently the transcription factor STAT3. In keratinocytes, STAT3 has been shown to modulate tyrosine phosphorylation of p130cas and thus has been suggested to regulate cell adhesiveness and migration [29,30]. Furthermore, IL-6 augments the migration of vascular smooth muscle cells and the breast cancer cell line T47D [31,32].

FL has been shown to promote the survival of lineage-negative, Sca-1+ bone marrow progenitors [33] as well as CD34+, cord blood–derived progenitors [34]. To further differentiate the effect seen with FL and IL-6, it would be of great interest to cultivate cells in IL-6 alone. This would allow for the discernment of migration caused by IL-6 alone and a possible synergism between IL-6 and FL but is unfortunately not possible because CD133+ cells are not viable in IL-6 alone.

Basic characteristics of migration, such as recruitment, speed, and pauses made, can vary among cell types. In the breast cancer cell line MDA-MB-468, migrational stimulation with norepinephrine does not cause an increase in the level of recruitment but is solely based on a change in the migration pattern [27], which constitutes an increase in speed, velocity, and number of pauses made in conjunction with a decrease in the pause length. In contrast, HSC-increased migration rate was the result of a coalescence of both recruitment and migration patterns. We here clearly demonstrate that the parameters such as velocity, speed, time active, and distance migrated, i.e., the migrational phenotype, are affected by IL-6. This gives a clear lead to an altered functional and signal state of CD133/HSC population.


   CONCLUSIONS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
These data are of particular relevance in light of obligatory HSC expansion before therapy, whereby SDF-1{alpha} 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{alpha}–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
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
The authors would like to thank Silvia Keil for excellent technical assistance. We would also like to express our most sincere gratitude to Theodore Drell for invaluable input. This work was supported by the Fritz-Bender-Foundation, Munich, Germany.


   REFERENCES
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

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Received May 13, 2004; accepted for publication July 13, 2004.



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