CN111849860B - Method for regulating and controlling intestinal stem cell differentiation by using iron element and application - Google Patents
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Abstract
The invention discloses a method for regulating and controlling intestinal stem cell differentiation by using iron element and application thereof. The iron with proper concentration is injected into the abdominal cavity or added into the culture medium of the cells to realize the regulation and control of the differentiation of the intestinal stem cells of the mice in vivo or in vitro. The method has the following purposes: reducing the differentiation of intestinal stem cells to absorption-type mature cells (intestinal epithelial absorption cells) and promoting the differentiation of the intestinal stem cells to secretion-type mature cells (intestinal secretory cells, Pan cells and goblet cells); enhance the function of goblet cells, promote the goblet cells to secrete immune factors and improve the intestinal immunity of mice.
Description
Technical Field
The invention belongs to the technical field of biomedicine, and particularly relates to a method for regulating and controlling intestinal stem cell differentiation and application thereof.
Background
The mammalian intestinal tract is called the "largest" immune organ of the mammal, not only because there are many immune cells in the intestinal tract, but also because the epithelial cells in the intestinal tract secrete many immune factors, mucins, antimicrobial peptides, etc., to protect against the invasion of pathogenic microorganisms in the intestinal tract.
Lgr5+Intestinal stem cells were discovered in 2007, and these intestinal stem cells are the "origin" of the intestinal epithelium, and they have the ability to self-renew and proliferate and differentiate, and are of great significance in maintaining the integrity of the intestinal epithelium and the proportion of various mature intestinal epithelial cells. And Lgr5+The intestinal stem cells can be mainly differentiated into four kinds of mature cells, namely secretory mature cells (goblet cells, Pan cells and enteroendocrine cells) and absorptive mature cells (intestinal epithelial absorptive cells), which have different functions. Goblet cells, which take mucin 2 (Muc 2) as a marker, specially synthesize and secrete mucin and various cytokines and immune factors to form an intestinal mucosal barrier, participate in the immune system and play a great role in intestinal immunity. The Pan cell uses lysozyme 1 (Lyz) as a marker, can secrete growth factors, provides ecological niches for intestinal stem cells, and secretes antibacterial peptide and hydrolase to enhance the host defense mechanism against pathogenic microorganisms. Enteroendocrine cells, marked by chromogranin A (ChrA), constitute about 1% of the enterocyte and produce a variety of hormones to regulate gastrointestinal motility, secretion of enzymes, appetite, and intestinal cell metabolism. Intestinal epithelial absorptive cells are characterized by villin 1 (Vil 1), the most abundant cell in the intestinal epithelium, and they function primarily to absorb nutrients. Therefore, if the differentiation of intestinal stem cells can be inducedThe differentiation of secretory mature cells (goblet cells, Pan cells and enteroendocrine cells) can effectively improve the concentration of secretory factors and immune-related proteins of the intestinal tract, thereby improving the immune function of the intestinal barrier and protecting the body from intestinal infection.
There have been some reports on methods for regulating differentiation of intestinal stem cells: only feeding 60% of daily ration to the mice for 18 weeks, regularly supplementing vitamins and minerals every two weeks can promote intestinal stem cells of the mice to differentiate to Pangolian cells, but the method needs additional supplementation of the vitamins and minerals, and is long in time and tedious; short-term fasting for 24 h can also promote the intestinal stem cells of the mice to differentiate into Pan cells; feeding 15% alcohol for 8 weeks to mice can increase the number of enteroendocrine cells, indicating that intestinal stem cells are differentiated into enteroendocrine cells, but alcohol not only causes obesity and increases the risk of cardiovascular system diseases, but also causes the loss of DNA; lack of methionine can lead the intestinal stem cells of mice to differentiate into Pan cells and intestinal secretory cells, but lack essential amino acids of the body and cannot be executed for a long time. The above methods cannot simultaneously promote the differentiation of the above three secretory mature cells (goblet cell, intestinal secretory cell, panne cell), and are especially ineffective for goblet cell, so a method capable of stably, efficiently, comprehensively and conveniently regulating the differentiation of mouse intestinal stem cells into goblet cells is urgently needed in the current intestinal health field.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a method for regulating and controlling intestinal stem cell differentiation by using iron element and application thereof.
A method for regulating and controlling intestinal stem cell differentiation by using iron element comprises intraperitoneal injecting 120 mg/kg body weight of iron dextran into 8-week-old mice fed under standard conditions, and intraperitoneal injecting once every two weeks for 7 times. After intraperitoneal injection, the differentiation of intestinal stem cells into secretory mature cells (goblet cells, panne cells, enteroendocrine cells) is up-regulated, and the differentiation into absorptive mature cells (intestinal epithelial absorptive cells) is down-regulated. The standard conditions are that the temperature is 24-28 ℃, the relative humidity is 50% -70%, and the illumination is 12 hours and the darkness is 12 hours every day.
A method for regulating intestinal stem cell differentiation in vitro by using iron comprises dissolving ferric ammonium citrate with final concentration of 10 mmol/L in mouse IntestiCult (TM) organoid growth medium (Stemcell technology, Toronto, Canada), treating mouse intestinal organoid (a three-dimensional cell structure containing intestinal stem cells and various differentiated cells), and regulating intestinal stem cell differentiation to goblet cell and absorption mature cell (intestinal epithelial absorptive cell) differentiation.
A culture medium for efficiently regulating and controlling intestinal stem cell differentiation is prepared by adding 10 mmol/L ferric ammonium citrate into mouse IntestiCult ™ organoid growth culture medium (Stemcell technology, Toronto, Canada).
A preparation for improving intestinal immunity of mice contains high-concentration iron element, and is injected into body of mice via abdominal cavity for improving the ability of goblet cells to secrete immune factors, thereby improving intestinal immunity of mice.
The invention has the beneficial effects that:
1. the number of secretory mature cells (goblet cells, Pan cells and enteroendocrine cells) in the intestinal tract of the mouse is increased, the secretory capacity of the intestinal tract of the mouse is enhanced, and the lubrication of the intestinal tract is promoted;
2. the ability of goblet cells to secrete immune factors is enhanced, so that the intestinal immunity of mice is improved, and the intestinal disease resistance of the mice is enhanced.
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FIG. 1 is a graph showing the control results of the differentiation and transcription level of iron on mouse duodenal stem cells, which are the average values of 4 independent repeated experiments.
FIG. 2 is a graph showing the results of controlling the level of differentiated protein of mouse duodenal stem cells by iron, which is the average of 3 independent experiments.
FIG. 3 is a graph showing the results of in vitro control of the differentiation and transcription levels of mouse intestinal stem cells by iron with different concentrations, which is the average value of 3 independent repeated experiments.
FIG. 4 is a graph showing the control results of iron on the transcription level of mouse duodenal goblet cell secretion factor, which is the average of 4 independent experiments.
FIG. 5 is a graph showing the results of controlling mouse goblet cell secretion factor in vitro by different concentrations of iron, which is the average of 3 independent replicates.
Detailed Description
The invention is further elucidated with reference to the figures and embodiments.
Example 1 iron control of mouse duodenal Stem cell differentiation transcript levels
Using iron dextran (trade name: iron dragon) purchased from Pharmacosmos A/S, Denmark, intraperitoneal injection was performed at a dose of 120 mg/kg mouse body weight to 8-week-old mice bred under standard conditions, i.e., 7 times per two weeks, and the duodenum of the mice was examined for gene expression (transcription level) of various markers of mature cells (intestinal secretion cell marker ChrA, Pan cell marker Lyz, goblet cell marker Muc2, intestinal epithelial absorption cell marker Vil 1). Compared with the control group, the gene expression levels of the markers of the enteroendocrine cell (ChrA), the Pan cell (Lyz) and the goblet cell (Muc 2) in the duodenum of the mouse are respectively and obviously increased by 1.67 times, 1.81 times and 6.86 times, while the gene expression level of the intestinal epithelial absorptive cell (Vil 1) is reduced to 32.28 percent of the original level (see figure 1).
Example 2 iron modulation of mouse duodenal Stem cell differentiation protein levels
Using iron dextran (trade name: iron dragon) purchased from Pharmacosmos A/S, Denmark, intraperitoneal injection was performed at a dose of 120 mg/kg body weight to 8-week-old mice bred under standard conditions, 7 times per two weeks, and the duodenum of the mice was examined for protein expression of various markers of mature cells (intestinal secretion cell marker ChrA, Pan cell marker Lyz, goblet cell marker Muc2, intestinal epithelial absorption cell marker Vil 1). Compared with the control group, the protein expression levels of the markers of the enteroendocrine cell (ChrA), the Pan cell (Lyz) and the goblet cell (Muc 2) in the duodenum of the mouse are respectively and remarkably improved by 3.91 times, 1.91 times and 4.17 times, while the protein expression level of the intestinal epithelial absorptive cell (Vil 1) is reduced to 43.71 percent of the original level (see figure 2).
Example 3 in vitro control of differential transcript levels of mouse intestinal Stem cells by iron concentrations
After treating mouse intestinal organoids (a three-dimensional cell structure comprising intestinal stem cells and various differentiated cells) with ferric citrate amine citrate (reagent grade) purchased from sigma aldrich trade ltd in normal mouse IntestiCult organoid growth medium (stemo, canada) at final concentrations of 3 mmol/L and 10 mmol/L, respectively, for 12h, the gene expression level of the goblet cell marker Muc2 in mouse organoids was significantly increased by 1.82-fold and 3.46-fold, respectively, and the gene expression level of the intestinal epithelial absorptive cell marker Vil1 was decreased to 20.36% and 3.87%, respectively, compared to the control group (0 mmol/L), under the induction of ferric citrate amine at 3 mmol/L and 10 mmol/L, respectively (see fig. 3).
Example 4 iron Regulation of mouse duodenal goblet cell secretion factor transcript levels
Using iron dextran (trade name: iron dragon) purchased from Pharmacosmos A/S, Denmark, 8-week-old mice bred under standard conditions were intraperitoneally injected at a dose of 120 mg/kg of mouse body weight once every two weeks for 7 times, and the duodenum of the mice was taken to examine the gene expression of the goblet cell secreted factor. Compared with the control group, the gene expression levels of the goblet cell immune factors CCL9, IL-13 and the trefoil factor TFF3 in the duodenum of the mouse are respectively and obviously improved by 3.58 times, 4.90 times and 1.98 times, while the gene expression levels of the antibacterial peptides Relm-beta and ZG16 are respectively improved by 1.86 and 1.44 times, but the difference is not obvious (see figure 4).
Example 5 in vitro modulation of mouse goblet cell secreted factor by iron at various concentrations
After treating mouse intestinal organoids (a three-dimensional cell structure comprising intestinal stem cells and various differentiated cells) in normal mouse IntestiCult organoid growth medium (Stemcell technology, toronto, canada) at final concentrations of 3 mmol/L and 10 mmol/L, respectively, using ferric citrate amine (reagent grade) purchased from sigma aldrich (shanghai) trade ltd, the gene expression level of goblet cell trefoil factor TFF3 in mouse organoids was significantly increased by 2.25-fold under the induction of 3 mmol/L ferric citrate amine compared to control (0 mmol/L) after 12 h. Compared with a control group (0 mmol/L), under the induction of 10 mmol/L ferric ammonium citrate, the gene expression levels of the goblet cell immune factors CCL9, IL-13 and the trefoil factor TFF3 in mouse organoids are respectively and obviously improved by 8.44 times, 2.86 times and 8.23 times, while the gene expression levels of the antibacterial peptides Relm-beta and ZG16 are respectively reduced to 99.41 percent and 89.07 percent of the original levels, but the difference is not obvious (see figure 5).
Finally, it is also noted that the above-mentioned lists merely illustrate a few specific embodiments of the invention. It is clear that the invention is not limited to the embodiments described above, but that many variations and equivalents are possible. All modifications and equivalents that may be directly derived or suggested to one of ordinary skill in the art from the disclosure are to be included within the scope of this invention.
Claims (2)
1. A method for regulating and controlling intestinal stem cell differentiation by using iron in vitro is characterized in that ferric ammonium citrate is dissolved in a mouse organoid growth culture medium at a final concentration of 10 mmol/L, and after the mouse intestinal organoid is treated, the differentiation of the intestinal stem cells to goblet cells is up-regulated, and the differentiation to intestinal epithelial absorptive cells is down-regulated.
2. A culture medium for efficiently regulating and controlling intestinal stem cell differentiation is characterized in that 10 mmol/L ferric ammonium citrate is added into a mouse organoid growth culture medium.
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