CN105087468A - Method for effectively inducing stem cells to differentiate into pancreas islet beta cells - Google Patents
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Abstract
The invention discloses a method for effectively inducing stem cells to differentiate into pancreas islet beta cells. The method comprises the following steps: under the condition of inducing cell agglomeration, firstly treating the cell cluster through adopting an MET agonist, so as to achieve the method for effectively inducing stem cells to differentiate into pancreas islet beta cells. According to the method, the efficiency and vigour of stem cells differentiation into insulin secretory cells are improved, and hyperglycemia caused by the situations that beta cells are damaged and the absolute amount of insulin secretion decreases is treated.
Description
Technical field
The present invention relates to biomedical sector, be specifically related to after one lures that stem cell is reunited into, use this cell mass of MET agonist process, reach the method for efficient induced dry-cell to islet beta-like cytodifferentiation.
Background technology
Type i diabetes is that the hypoinsulinism caused causes because the β cell of excreting insulin is because receiving damage in the situations such as poisoning or autoimmune attack.Diabetics subjects obesity, hyperglycemia, limb movement disorder, the misery of injury of the kidney and eyes pathology.For many years, for radical cure of diabetes mellitus is sick, people find the regeneration replacement therapy method based on tissue and cell always.Wherein, stem-cell therapy gets most of the attention in recent years.It is believed that, stem cell induction is become insulin secreting cell, and to carry out transplanting be the reliable approach of stem cells in treatment of diabetes.There is a lot of method induced dry-cell to islet beta-like cytodifferentiation at present.But it is low that most method is all encountered by differentiation efficiency, the problem of cytoactive difference after differentiation.These problems hinder the application of stem cells in treatment of diabetes.
It is that vitro can not provide the whole prerequisites required for stem cell normal growth as internal milieu that stem cell cultivates the subject matter that differentiation faces in vitro.Stem cell differentiation in vivo is also by after interacting with the signaling molecule of its position, can be correct carry out differentiation program.The internal milieu of stem cell by various cytokine, the various kinds of cell such as glycoprotein, lipoprotein epimatrix composition, and the Molecular regulator such as various hormones is formed.Obvious vitro is difficult to stem cell living environment in complete analogue body.Which results in stem cell ahead of time decline, the phenomenons such as after the low and differentiation of differentiation efficiency cell viability is not good.Stem cell aggregate structure is that stem cell is concentrated and the 3-D solid structure formed, and it provides a relatively naturally support environment to stem cell, and causes the environment of regional hypoxia.Research proves, under this configuration, stem cell have expressed higher stem cell labeling thing such as Met, has larger differentiation potential.Research shows, Met can regulate and control the growth of stem cell, self and differentiation.Met is necessary in hepatocyte differentiation process.The β cell of Met gene knockout is very responsive to the stimulation of dexamethasone, hinders the response that β cell stimulates glucose simultaneously.Our research proves, activates MET path, is conducive to impelling mesenchyma stem cell to pancreatic islet cytodifferentiation.But provide more natural differentiation environment after aggregation undoubtedly, for use MET agonist, effective stimulus stem cell group, to islet beta-like cytodifferentiation, there is no report at present.
Based on above principle, the present invention is by luring that stem cell is reunited into, and this cell mass of application MET agonist process, reaches efficient induced dry-cell to islet beta-like cytodifferentiation.
Summary of the invention
Goal of the invention: method from a kind of efficient induced dry-cell of the present invention to islet beta-like cytodifferentiation by lure into stem cell reunite after, use MET agonist agonizes MET/HGF signal path, efficiently to islet beta-like cell, and can improve its vigor by induced dry-cell.
Technical scheme: in order to solve the problems of the technologies described above, the invention provides the method for a kind of efficient induced dry-cell to islet beta-like cytodifferentiation, the method comprises the following steps: step a: reunited by entice cell;
Step b: application MET agonist agonizes process cell mass, efficient induced dry-cell is to islet beta-like cytodifferentiation.
Wherein, above-mentioned stem cell is embryonic stem cell, fills stem cell between fat, one or more in mesenchymal stem cells in umbilical cord blood or umbilical cord mesenchymal stem cells.
Wherein, above-mentioned steps a entice cell is reunited the method taked, and refers to carry out suspension culture on the culture plate of gelatin bag quilt, thus makes aggregation.
Wherein, above-mentioned MET agonist refers to the various molecule that can activate MET albumen, comprises HGF, bioactive peptide, one or more in chemical molecular or engineered protein molecule.
Efficient induced dry-cell is to a method for islet beta-like cytodifferentiation, and concrete steps are as follows:
1) mesenchymal stem cells in umbilical cord blood is incubated at the culture plate of 2% gelatin bag quilt, in the DMEM suspension culture containing 20% foetal calf serum after 7 days, starts induction when cell ball mean diameter reaches 100 microns;
2) cell PBS cleaning twice, uses substratum I to cultivate 24 hours;
3) after 24 hours, PBS cleans cell, and is replaced by medium ii, continues cultivation 48 hours;
4) after 48 hours, PBS cleans cell, and is replaced by medium ii I, continues cultivation 48 hours;
5) after 48 hours, PBS cleans cell, and is replaced by substratum IV, continues cultivation 24 hours;
6) through ELISA immunological quantitative determining;
7) generation diabetes are induced to mouse peritoneal injection in 7 week age 160mg/kg U-9889;
8) when blood sugar concentration reaches 16.7mmol/L, every mouse peritoneal injection into liver 2.5 × 10
6within after islet beta-like cell every two weeks, detect blood sugar concentration.
The composition of described substratum I is: DMEM/F12,1mM Sodium propanecarboxylate and 50ng/mL activin A.
The composition of described medium ii is: DMEM/F12,0.1-0.2% foetal calf serum and 50ng/mLActivinA.
The composition of described medium ii I is: DMEM/F12,50ng/mLKGF/FGF, 10ng/mLRA, 10ng/mLHGF and 1% foetal calf serum.
The composition of described substratum IV is: DMEM/F12,10ng/mLHGF, 1%B27 and 2% foetal calf serum.
Beneficial effect: relative to prior art, the present invention has the following advantages: the present invention, by after luring that stem cell is reunited into, uses MET agonist process stem cell group, can efficiently induced dry-cell to islet beta-like cell, and its vigor can be improved, achieve the present invention.
Accompanying drawing explanation
Fig. 1 is through ELISA quantitative assay, and the content breaking up (A, B) and extracellular (C, D) outer Regular Insulin and C-peptide (C-peptide) in cell successfully significantly increases;
Fig. 2 applies the successful islet beta-like cell of differentiation can make the hyperglycemia of hyperglycemia mouse model be eased.
Embodiment
embodiment 1
Efficient induced dry-cell is to a method for islet beta-like cytodifferentiation, and the method comprises the following steps:
1, mesenchymal stem cells in umbilical cord blood is incubated at the culture plate of 2% gelatin bag quilt, containing 20% foetal calf serum (Ultrapureagarose, Invitrogen, Carlsbad, CA) DMEM(LifeTechnologies, Gaithersburg, MD, USA) suspension culture is after 7 days, starts induction when cell ball mean diameter reaches 100 microns.
2, cell PBS cleaning twice, use substratum I to cultivate 24 hours, the composition of substratum I is: DMEM/F12 (LifeTechnologies), 1mM Sodium propanecarboxylate (Sigma, St.Louis, MO, USA), 50ng/mLActivinA (Sigma).
3, after 24 hours, PBS cleans cell, and is replaced by medium ii, and continue cultivation 48 hours, the composition of medium ii is: DMEM/F12,0.1-0.2% foetal calf serum, 50ng/mLActivinA.
4, after 48 hours, PBS cleans cell, and be replaced by medium ii I, continue cultivation 48 hours, the composition of medium ii I is: DMEM/F12,50ng/mLKGF/FGF (LifeTechnologies), 10ng/mLRA (LifeTechnologies), 10ng/mLHGF, 1% foetal calf serum.
5, after 48 hours, PBS cleans cell, and is replaced by substratum IV, continue cultivation 24 hours, the composition of substratum IV is: DMEM/F12,10ng/mLHGF (LifeTechnologies), 1%B27 (LifeTechnologies), 2% foetal calf serum.
6, through ELISA immunological quantitative determining (UltrasensitiveELISAkits; Merocodia, Uppsala, Sweden)), break up successfully and significantly increase (Fig. 1) with the content of extracellular outer Regular Insulin and C-peptide in cell.
7, to inducing generation diabetes mouse peritoneal injection 160mg/kg U-9889 in 7 week age (STZ, Sigma, St-Louis, MO, USA).
8, when blood sugar concentration reaches 16.7mmol/L, every mouse peritoneal injection into liver 2.5 × 10
6within after islet beta-like cell every two weeks, detect blood sugar concentration.
9, the successful islet beta-like cell of application differentiation can make the hyperglycemia of hyperglycemia mouse model be eased (Fig. 2).
The above is only the preferred embodiment of the present invention; be noted that for those skilled in the art; under the premise without departing from the principles of the invention, can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (9)
1. efficient induced dry-cell is to a method for islet beta-like cytodifferentiation, it is characterized in that, the method comprises the following steps: step a: reunited by entice cell;
Step b: application MET agonist agonizes process cell mass, efficient induced dry-cell is to islet beta-like cytodifferentiation.
2. a kind of efficient induced dry-cell according to claim 1 is to the method for islet beta-like cytodifferentiation, it is characterized in that, described stem cell is embryonic stem cell, fills stem cell between fat, one or more in mesenchymal stem cells in umbilical cord blood or umbilical cord mesenchymal stem cells.
3. a kind of efficient induced dry-cell according to claim 1 is to the method for islet beta-like cytodifferentiation, it is characterized in that, described step a entice cell is reunited the method taked, and refers to carry out suspension culture on the culture plate of gelatin bag quilt, thus makes aggregation.
4. a kind of efficient induced dry-cell according to claim 1 is to the method for islet beta-like cytodifferentiation, it is characterized in that, described MET agonist refers to the various molecule that can activate MET albumen, comprises HGF, bioactive peptide, one or more in chemical molecular or engineered protein molecule.
5. a kind of efficient induced dry-cell according to claim 1 is to the method for islet beta-like cytodifferentiation, and it is characterized in that, concrete steps are as follows:
1) mesenchymal stem cells in umbilical cord blood is incubated at the culture plate of 2% gelatin bag quilt, in the DMEM suspension culture containing 20% foetal calf serum after 7 days, starts induction when cell ball mean diameter reaches 100 microns;
2) cell PBS cleaning twice, uses substratum I to cultivate 24 hours;
3) after 24 hours, PBS cleans cell, and is replaced by medium ii, continues cultivation 48 hours;
4) after 48 hours, PBS cleans cell, and is replaced by medium ii I, continues cultivation 48 hours;
5) after 48 hours, PBS cleans cell, and is replaced by substratum IV, continues cultivation 24 hours;
6) through ELISA immunological quantitative determining;
7) generation diabetes are induced to mouse peritoneal injection in 7 week age 160mg/kg U-9889;
8) when blood sugar concentration reaches 16.7mmol/L, every mouse peritoneal injection into liver 2.5 × 10
6within after islet beta-like cell every two weeks, detect blood sugar concentration.
6. a kind of efficient induced dry-cell according to claim 5 is to the method for islet beta-like cytodifferentiation, it is characterized in that, the composition of described substratum I is: DMEM/F12,1mM Sodium propanecarboxylate and 50ng/mL activin A.
7. a kind of efficient induced dry-cell according to claim 5 is to the method for islet beta-like cytodifferentiation, it is characterized in that, the composition of described medium ii is: DMEM/F12,0.1-0.2% foetal calf serum and 50ng/mLActivinA.
8. a kind of efficient induced dry-cell according to claim 5 is to the method for islet beta-like cytodifferentiation, it is characterized in that, the composition of described medium ii I is: DMEM/F12,50ng/mLKGF/FGF, 10ng/mLRA, 10ng/mLHGF and 1% foetal calf serum.
9. a kind of efficient induced dry-cell according to claim 5 is to the method for islet beta-like cytodifferentiation, it is characterized in that, the composition of described substratum IV is: DMEM/F12,10ng/mLHGF, 1%B27 and 2% foetal calf serum.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20210024639A1 (en) * | 2018-01-03 | 2021-01-28 | Agomab Therapeutics | Methods for promoting pancreatic islet cell growth |
| CN109053866A (en) * | 2018-09-03 | 2018-12-21 | 洛阳轩智生物科技有限公司 | The improved method that epidermal stem cells break up to pancreatic cell |
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| CN111875675A (en) * | 2018-09-03 | 2020-11-03 | 洛阳轩智生物科技有限公司 | Improved method for differentiation of epidermal stem cells into pancreatic cells |
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| CN111848744B (en) * | 2018-09-03 | 2021-07-23 | 宁波希诺赛生物科技有限公司 | Improved method for differentiation of epidermal stem cells into pancreatic cells |
| CN111875674B (en) * | 2018-09-03 | 2021-12-10 | 内蒙古创润生物科技有限公司 | Improved method for differentiation of epidermal stem cells into pancreatic cells |
| CN111848745B (en) * | 2018-09-03 | 2022-01-18 | 山东卓东生物科技有限公司 | Improved method for differentiation of epidermal stem cells into pancreatic cells |
| CN113544259A (en) * | 2020-01-31 | 2021-10-22 | 瑞帝安有限公司 | Method for differentiating human adipose-derived mesenchymal stem cells into hair papilla cells |
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