CN107630063B - Ultralow field magnetic detection method for measuring cell adhesion and cell migration rate - Google Patents
Ultralow field magnetic detection method for measuring cell adhesion and cell migration rate Download PDFInfo
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Abstract
The invention discloses an ultralow field magnetic detection method for measuring cell adhesion and cell migration rate. It comprises the following steps: inoculating the magnetically-labeled cells on the modified chip, incubating and magnetizing magnetic probes in the magnetically-labeled cells, and then determining cell adhesion and cell migration rate: 1) cells obtained by external force interference magnetization are dissociated from the chip, a modified spectrogram of the reduction of the residual magnetic signals on the chip is obtained by FIRMS recording, and the corresponding force when the residual magnetic signals are reduced by half is defined as adhesion calculation according to the spectrogram, so that the adhesion of the cells is obtained; 2) recording a spectrogram of decreased residual magnetic signals of the modified chip caused by cell migration obtained by magnetization by using FIRMS, and calculating the rate of decreased residual magnetic signals by linear fitting according to the spectrogram to obtain the migration rate of the cells. The invention adopts FIRMS to sensitively respond to the change of residual magnetic signals caused by external force or cell self-migration movement without being influenced by distance.
Description
Technical Field
The invention relates to an ultralow field magnetic detection method for measuring cell adhesion and cell migration rate, belonging to the field of biomedicine.
Background
Migration of tumor cells is the most fundamental phenomenon in the process of tumor metastasis. The migratory capacity of the cells may reflect potential tumor metastasis. The complex process of cell migration is driven primarily by genes within the tumor cells as well as by chemofactors outside the tumor cells. These factors include mainly growth factors, cytokines and chemokines. Scientists have discovered over the last two decades that in addition to changes in genes and chemical factors within cells or tissues, physical interactions and mechanical forces between cells and cells, cells and their microenvironment play a very important role in cell migration. The migration of cells is currently described as a cyclic process coordinated in time and space by cytoskeletal proteins (myokines and myosin) and extracellular adhesion. Firstly, cell actin polymerization enables cell polarization to form protrusions in the migration direction; the protrusions form adhesion sites by adhering to the extracellular matrix; and the actin which is polarized to generate traction extends from the cell edge to the vicinity of the cell nucleus to form a network structure together with myosin, so that the cell is contracted; the cell contraction produces traction on the strong adhesion points in front of the cells so that the weak adhesion points behind the cells are dissociated from the substrate to move the cells forward. Since adhesion is mainly controlled by the mechanical properties of the cell itself, which in turn feedback regulates cell migration. Therefore, the migration ability of the cells is judged and analyzed, and the judgment can be made based on the adhesion ability of the cells in addition to the examination of the migration rate of the cells.
At present, scientists often evaluate and measure the cell migration rate by the scarification method, the tracer method, the micro-filtration membrane culture chamber and the double-chamber combined culture system (Transwell test). Meanwhile, scientists have developed more and more new technical platforms and methods for measuring cell adhesion, such as microcolumns, Atomic Force Microscopy (AFM) and optical methods, and the combined use of AFM and optical methods, etc. Each method has its own advantages and limitations. For example, the micro-column method is difficult to realize the interaction force between single molecules between cells and a substrate. AFM can measure the interaction force between the cell surface and the substrate molecule, and the AFM has higher resolution and can measure the single molecule interaction force. The obvious disadvantage of AFM techniques, however, is the inability to achieve high throughput and simultaneously measure adhesion of large numbers of cells. Moreover, the existing method is difficult to adopt a certain platform to measure the migration rate of the cells and the adhesion force of the cells.
The force-induced residual magnetic spectroscopy (FIRMS) technique uses an ultra-low field optical atomic magnetometer (atomic magnetometer) to record the residual magnetic spectrum of a magnetically labeled sample, which is a spectrum formed by dissociating the magnetically labeled sample from a substrate in the process of gradually increasing an externally applied mechanical force so as to gradually reduce the residual magnetic signal of the sample. Wherein the decrease of the residual magnetic signal is mainly the change of the magnetic dipole of the magnetic probe (NPs) caused by the movement of the dissociated magnetically labeled sample.
Disclosure of Invention
The invention aims to provide an ultralow field magnetic detection method for measuring cell adhesion and cell migration rate.
The invention provides an ultralow field magnetic detection method for measuring cell adhesion and cell migration rate, which comprises the following steps:
(1) modification and blocking of the chip: modifying the chip with anti-aging protein FN, and then sealing the chip with fetal calf serum to obtain a modified chip; sequentially undergoing amination, aldehyde group formation and
(2) magnetic labeling of cells: incubating the cells and the magnetic probe together to obtain magnetically labeled cells;
(3) magnetization of cells: inoculating the magnetically labeled cells on the modified chip to incubate and magnetize magnetic probes within the magnetically labeled cells;
(4) measurement of cell adhesion and cell migration rate:
1) dissociating the cells obtained by the processing of the external force interference step (3) from the chip, simultaneously recording by using FIRMS (finite intensity measurement) to obtain a spectrogram of the modified chip with reduced residual magnetic signals, and defining the corresponding force when the residual magnetic signals are reduced by half as the adhesion calculation according to the spectrogram to obtain the adhesion of the cells;
2) and (4) recording a spectrogram of the residual magnetic signal reduction of the modified chip caused by the cell migration obtained by the step (3) by using FIRMS, and calculating the residual magnetic signal reduction rate by linear fitting according to the spectrogram to obtain the migration rate of the cell.
In the invention, according to the spectrogram of the reduction of the residual magnetic signal on the modified chip, the method for calculating the adhesion force of the cell by defining the corresponding force when the residual magnetic signal is reduced by half as the adhesion force is common knowledge in the field and can be carried out according to a common method in the field;
the method for calculating the migration rate of the cells by calculating the decline rate of the remanent magnetization signal through linear fitting according to the reduced spectrogram of the remanent magnetization signal of the modified chip is also common knowledge in the field, and can be performed according to the common method in the field.
In the method, step (2) is followed by a step of performing final screening for viability of cells processed in step (2);
the FIRMS feasibility verification comprises the following steps: adding trypsin into the cells obtained by the treatment of the step (2), and then detecting the map of the remanence change of the cells in the process of moving and dissociating the cells on the modified chip and comparing the map with the map of the remanence change of the cells without adding the trypsin.
In the FIRMS feasibility verification, in the extended cells which are in good adherent growth state and are already magnetically marked, trypsin is added after magnetization, and the spectrum of remanence change in the process of dissociating the cells from the substrate due to the fact that the trypsin acts as an external force to interfere the cells to cause cell contraction movement is monitored.
In the above method, the chip is made of polydimethylsilane or glass;
the surface of chip sets up one and caves in, specifically can be a length, width and height and be 1.4cm, 0.6cm, 0.2 cm's Polydimethylsilane (PDMS) cuboid respectively, is the circular sunken of diameter for 0.4cm in the middle of its cuboid, and sunken degree of depth is: 0.1 cm;
the chip is activated by adopting a plasma method;
the reagent for chip amination is absolute ethyl alcohol and/or 3-aminopropyltriethoxysilane, specifically, an absolute ethyl alcohol solution of 3-aminopropyltriethoxysilane, preferably an absolute ethyl alcohol solution of 2% volume fraction 3-aminopropyltriethoxysilane;
the reagent for aldehyde group reaction of the chip is water and/or glutaraldehyde, and specifically, a glutaraldehyde aqueous solution, preferably a glutaraldehyde aqueous solution with the volume fraction of 1%, can be adopted;
the modified concentration of the anti-aging protein FN on the chip can be 20-30 mu g/m L, and specifically can be 20ug/m L.
The method also comprises the steps of activating the chip modified anti-senescence protein FN, and then sequentially carrying out amino and aldehyde alkylation.
In the above method, the chip is activated by a plasma method;
the reagent for chip amination is absolute ethyl alcohol or 3-aminopropyl triethoxysilane;
the reagent for aldehyde group reaction of the chip is water or glutaraldehyde.
In the above method, the magnetic probe is Fe3O4Cubic crystals with a size of 20nm and a polydispersity index of 0.16;
in the step (2), the incubation time may be 120-240 min, specifically 240 min.
In the invention, the preparation of the magnetic probe comprises the following steps: the magnetic nano probe with surface oleic acid and oily ammonium as ligands is prepared by a method of pyrolyzing ferric acetylacetonate, and then the nano probe in an oil phase is converted into a magnetic probe with surface modified water-soluble ligand (DHCA) and good biocompatibility by a ligand exchange mode.
In the above method, when the cells obtained by the step (3) are used for measuring cell adhesion, the incubation time may be 20-30 min, specifically 30 min;
when the cells obtained by the treatment in the step (3) are used for measuring the cell migration rate, the incubation time can be 10-40 h, specifically 36h, 10-36 h, 36-40 h or 20-40 h;
magnetizing by adopting a magnet; the strength of the magnet can be 0.5-1T, specifically can be 1T, and the distance between the magnet and the magnetic bead can be 1.5-2 cm, specifically can be 2 cm.
In the method, the mass percentage concentration of the trypsin is 0.25%, and the detection time in the FIRMS feasibility verification can be 3-10 min.
In the invention, the trypsin is special trypsin for digesting cells by hyclone company.
In the above method, in the step (4) -1), the external force is a centrifugal force having a strength of 10pN, 12pN, 22pN, 28pN, 36pN, 46pN, 60pN, 72pN, and 90 pN.
In the present invention, the cell adhesion is a mechanical force corresponding to a half-reduction in the remanence signal, and is about 50 pN. Wherein the adhesion determined is validated as being based on the interaction force between cell surface integrin (integrin) and extracellular matrix FN: the method that the substrate is not modified by the anti-aging protein FN or the small molecular peptide with RGD at the end occupies a cell surface ligand is adopted for verification, and the acting force of the two cases is obviously reduced to 25 pN. And the remanence signal of the intracellular magnetic probe can be stably maintained for at least 2h when no external force acts on the cell.
In the present invention, the migration rate mainly refers to the decrease of remanent magnetic signal caused by the self-migration movement of the magnetically labeled living cells. The stability of the magnetic probe in the cell was judged by long-term recording of the residual magnetic spectrum of the fixed cells in 3.8% formaldehyde solution.
The invention has the following advantages:
1. the signal source adopted by the invention is a magnetic signal, and compared with the traditional fluorescent signal, the signal source is not interfered by ambient light and solution color, so that the detection is more sensitive and the application range is wider.
2. The invention adopts FIRMS to sensitively respond to the change of remanent magnetic signal caused by external force or cell self-migration movement without being influenced by distance.
3. The invention realizes high-flux measurement of the single-molecule adhesion of the cells.
4. The cell surface adhesion molecules (integrins) are not modified or disturbed at all during the experiments of the present invention.
5. The invention can not only determine the adhesion of the tumor cells, but also determine and compare the migration rate of the tumor cells by a cell culture mode.
Drawings
FIG. 1 is a schematic diagram of the change of remanence signal caused by the interference of FIRMS response to external force on cell movement or dissociation from the substrate, i.e. when magnetically labeled tumor cells are spread and grown on the substrate, the magnetic dipole direction of the magnetic probe is consistent in all cells after magnetization. When the pancreatic enzyme is used for simulating external force to digest interfering cells, the cells shrink into a spherical shape and even dissociate from the substrate, so that the magnetic probe magnetic dipoles are randomly arranged to reduce the residual magnetic signal, and the atomic magnetometer can sensitively detect the change of the residual magnetic signal.
FIG. 2 is a time-dependent residual spectrum of the FIRMS test with or without the addition of pancreatin interfering cells. The control group is the remanence spectrum of well-grown tumor cells without magnetic labeling or pancreatin addition (the remanence signal of the magnetic probe NPs in living cells can be maintained for at least two hours).
FIG. 3 is a schematic diagram of the measurement of cell adhesion by FIRMS.
FIG. 4 shows force-dependent residual magnetic signal spectra of tumor cells A549 and R-A549, and quantified cell adhesion, wherein FIG. 4(a) shows the residual magnetic signal spectra, and FIG. 4(b) shows the quantified cell adhesion.
FIG. 5 shows the relative remanence spectrum of tumor cell A549 on a substrate which is not modified by anti-aging protein FN and the remanence spectrum of a cell surface adhesion molecule after being blocked by a small molecule polypeptide terminated with RGD measured by FIRMS.
FIG. 6 is a schematic diagram of the measurement of cell migration by FIRMS.
Fig. 7 is a plot of time-dependent residual magnetic signal spectra and quantified cell migration rates of tumor cells a549 and R-a549 determined by FIRMS, where fig. 7(a) is the residual magnetic signal spectrum and fig. 7(b) is the quantified cell migration rate.
FIG. 8 shows the stability of residual magnetic signals of intracellular magnetic probes measured by FIRMS of magnetically labeled tumor A549 cells under fixed conditions.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1 modification of extracellular matrix protein FN of FIRMS chip
Preparing a Polydimethylsilane (PDMS) cuboid with the length, width and height of 1.4cm, 0.6cm and 0.2cm respectively, wherein the middle of the cuboid is a circular recess with the diameter of 0.4cm, the recess part is a FIRMS detection part, placing the recess surface of a FIRMS chip in a culture dish upwards, cleaning the chip by using plasma for 40s, quickly dropping 3-aminopropyl triethoxysilane (APTES) absolute ethanol solution with the volume fraction of 2% after the surface of the chip is activated, reacting for 4h, discarding the solution, cleaning the chip by using absolute ethanol for 5 times, cleaning the chip by using deionized water for 5 times, drying the chip by using the deionized water for 5 times, then adding glutaraldehyde aqueous solution (1%, v/v) into the aminated chip for standby, cleaning the chip by using the deionized water for 5 times after reacting for 3h, cleaning the chip by using the ethanol for 5 times, drying the chip by using FN solution (20ug/m L), placing the chip at a reaction solution with the temperature of 4 ℃ and then sucking off the protein solution, cleaning the chip by using the deionized water for 5 times, cleaning the chip by using the deionized water for 5min, cleaning the chip for 5 times, soaking the chip by using the BSA solution for 10 hours, completely soaking the BSA solution after incubating, and drying the chip for at least after incubating for 10h, adding the bovine serum containing the BSA after the serum is added to the bovine serum after the serum is dried by using the bovine serum after the serum is dried by using the serum for 5 hours, and the bovine.
Example 2 magnetic labeling of cells
1 × 106The human lung cancer cell (A549) cell is inoculated in a 6-hole cell culture plate, after 17h of culture, the cell culture medium is discarded, the cell is cleaned by adopting serum-free culture for 3 times, the serum-free culture medium dispersed with a magnetic probe (20ug/m L) is added for continuous culture for 4h, the culture medium containing the magnetic probe is sucked, the cell is cleaned by adopting phosphate buffer solution for 5 times, then the cell which is endocytosed with the magnetic probe is digested by adopting trypsin (0.25 percent) for 3min, the digested cell is centrifugally separated to contain the trypsin solution, and the cell is completely blown to be dispersed in the complete culture medium for standby.
Example 3 FIRMS feasibility verification
As shown in FIG. 1, in order to verify that FIRMS can sensitively respond to the change of residual magnetic signals caused by external force interference or cell self-migration movement, cells are firstly cultured on a FIRMS chip, after 17h of culture, the complete culture medium is discarded, the cells are washed twice by using a serum-free culture medium, and a magnetic probe is added for culture for 4 h. After washing away the magnetic probe that was not endocytosed or adsorbed on the cell surface, the intracellular probe was magnetized for 2min (intensity of magnet 1T). After the addition of 0.25% trypsin, the decrease in residual magnetic signal caused by the cell contraction process under trypsinization, from the spreading state to the spherical shape until finally the cell detachment from the substrate was recorded rapidly using FIRMS. The residual magnetic signal was compared to that of cells without pancreatin or without magnetic labeling, as shown in FIG. 2.
Example 4 measurement of cell adhesion
According to the principle of FIRMS measurement of cell adhesion, first magnetically labeled 5 × 10 was used as shown in FIG. 34The adhesion measured in the present invention was confirmed by a blank test without FN modification and blocking integration based on the interaction between surface receptor integrin of cells and ligand FN on the substrate, using a FN-modified FIRMS chip, culturing the magnetically labeled cells on the FN-modified FIRMS chip after 30min, measuring the adhesion by the same method after washing the cells after magnetic labeling, washing off the probes in the cells, adding small cell-bound molecules (PBS with modified cell ends) to the chip, and measuring the adhesion of the cells after digestion with trypsin-containing medium (RGD 5. RGD. medium) by the same method as described in FIG. 5. RGD. medium, RGD. cells, and RGD. cells, wherein the amount of cells were measured in a cell surface of cells were cultured in a small cell surface of FIRMS molecule, and RGD. A.5. A. cells, and RGD.5. cells, and RGD.5cell-ρmedium)Vcellω2And r. In the formula, F is the relative centrifugal force, rhocellIs the cell density (. about.1.07 kg/m)3)，ρmediumThe density of the culture medium (about 1.00 kg/m)3)，VcellIs the volume of the cell (525 um)3) Omega is a centrifugal spinThe rotational speed, r, is the distance of the sample from the center of rotation (4.5 cm).
Example 5 determination of relative migration Rate of cells
Magnetically labeled cells (. about.1 1 х 10) were assayed according to the principle of FIRMS measurement of cell migration rate as shown in FIG. 64) Inoculating on a FIRMS chip, standing in a carbon dioxide incubator for 1h, and magnetizing with a magnet (intensity of 1T) for 2 min. The residual magnetic signal at this time was measured as the residual magnetic signal of the initial magnetic probe. As the incubation time increased, the profile of the time-dependent change in residual magnetic signal of the magnetic probe caused by the cell migration movement was recorded using FIRMS. The relative migration rate of tumor cells was calculated as shown in fig. 7. The control test was: cells are magnetically marked and then inoculated and cultured on a FIRMS chip, and after the adherent growth state is good, 3.8 percent formaldehyde solution is adopted for fixing for 1 h. After this was then magnetized, changes in the residual magnetic signal of the immobilized intracellular magnetic probe at different time periods were recorded using FIRMS, as shown in FIG. 7. Comparing two groups of experimental results, the reduction of the obtained remanence signal can reflect the speed of cell migration, and the influence of the movement of the intracellular magnetic probe can be ignored.
Example 6 extension of the FIRMS technique to determine adhesion and migration rates of other tumor cells
Adhesion and migration rates of human lung cancer resistant cells (R-A549) with anti-paclitaxel were determined using FIRMS according to the methods of examples 4 and 5 of the present invention. The measured adhesion was higher than that of a549 cells due to its long-term resistance, which enhances its own mechanical properties, while its migration rate was also increased compared to a549 cells, as shown in fig. 4 and 7. Thus, the method of the present invention can be used to determine and compare the adhesion and migration rates of different cells, so that the possibility of tumor metastasis can be judged according to their migration ability.
Claims (2)
1. An ultra-low field magnetic detection method for measuring cell adhesion and cell migration rate, comprising the following steps:
(1) modification and blocking of the chip: modifying anti-aging protein FN with FIRMS chip, and sealing the chip with fetal calf serum to obtain modified chip;
the material of the FIRMS chip adopts polydimethylsilane or glass;
the method also comprises the steps of activating the FIRMS chip before modifying the anti-senescence protein FN, and then sequentially carrying out amino and aldehyde alkylation;
a recess is arranged on the surface of the chip;
the modified concentration of the anti-aging protein FN on the chip is 20-30 mug/m L;
the chip is activated by adopting a plasma method;
the reagent for chip amination is absolute ethyl alcohol or 3-aminopropyl triethoxysilane;
the reagent for aldehyde group reaction of the chip is glutaraldehyde;
(2) magnetic labeling of cells: incubating the cells and the magnetic probe together to obtain magnetically labeled cells;
the magnetic probe is Fe3O4Cubic crystals with a size of 20nm and a polydispersity index of 0.16;
the concentration of the magnetic probe is 20ug/m L;
after the step (2), the step of performing FIRMS feasibility verification on the cells obtained by the step (2) is further included;
the FIRMS feasibility verification comprises the following steps: adding trypsin into the cells obtained by the treatment in the step (2), and then detecting the map of the remanence change of the cells in the process of moving and dissociating the cells on the modified chip and comparing the map with the map of the remanence change of the cells without adding the trypsin;
the mass percentage concentration of the trypsin is 0.25%, and the detection time in the FIRMS feasibility verification is 3-10 min;
in the step (2), the incubation time is 120-240 min;
(3) magnetization of cells: inoculating the magnetically labeled cells on the modified chip to incubate and magnetize magnetic probes within the magnetically labeled cells;
when the cells obtained by the step (3) are used for measuring the cell adhesion force, the incubation time is 20-30 min;
when the cells obtained by the step (3) are used for measuring the cell migration rate, the incubation time is 10-40 h;
magnetizing by adopting a magnet;
the strength of the magnet is 0.5-1T, and the distance between the magnet and the magnetic beads is 1.5-2 cm;
(4) measurement of cell adhesion and cell migration rate:
1) dissociating the cells obtained by the processing of the external force interference step (3) from the chip, simultaneously recording by using FIRMS (finite intensity measurement) to obtain a spectrogram of the modified chip with reduced residual magnetic signals, and defining the corresponding force when the residual magnetic signals are reduced by half as the adhesion calculation according to the spectrogram to obtain the adhesion of the cells;
2) and (4) recording a spectrogram of the residual magnetic signal reduction of the modified chip caused by the cell migration obtained by the step (3) by using FIRMS, and calculating the residual magnetic signal reduction rate by linear fitting according to the spectrogram to obtain the migration rate of the cell.
2. The method of claim 1, wherein: in the step (4) -1), the external force is a centrifugal force, and the strength of the centrifugal force is 10pN, 12pN, 22pN, 28pN, 36pN, 46pN, 60pN, 72pN, and 90 pN.
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