CN111529551A - Application of MSC (mesenchymal stem cell) in adjusting number of plasma cells - Google Patents
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Abstract
The invention specifically discloses an application of MSC (mesenchymal stem cell) in adjusting the number of plasma cells, in particular to an application of MSC in adjusting the number of plasma cells of a virus infected patient, relating to the technical field of biomedical engineering. The prepared MSC preparation is added into the MSC treatment group to carry out combined treatment on the patients with viral infection, so that the plasma cell number of the patients after the healing of the MSC treatment group is effectively increased, the plasma cell number of the patients after the healing of the MSC treatment group is increased more than that of the patients without the MSC treatment group, and the plasma cells can participate in the inflammatory reaction of the patients after the healing in the recovery stage, so that the patients after the healing of the MSC treatment group have stronger anti-inflammatory capability.
Description
Technical Field
The invention relates to the technical field of biomedical engineering, in particular to application of MSC (mesenchymal stem cell) in adjusting the number of plasma cells.
Background
Plasma cells (plasma cells), also known as effector B cells. Plasma cells are found mostly in the connective tissue of the digestive tract and the lamina propria of the respiratory tract. The cells are small, circular or oval, the nucleus is circular but deviated from one side of the cell, the chromatin is thick, and the cells are radially arranged into a wheel shape along the nuclear membrane. The cytoplasm is basophilic and blue-stained. There is a lighter and transparent area near the nucleus. Under an electron microscope, the cytoplasm contains a large number of dense rough endoplasmic reticulum, and the light-dyed area is the part where the Golgi complex is located. Plasma cells are derived from B cells. Plasma Cell (PC) is a plasma cell which is a mature B cell and becomes an activated B cell under the assistance of an antigen presenting cell and a Th cell after receiving antigen stimulation, then is differentiated into a plasma cell, synthesizes and secretes various immunoglobulins, and simultaneously expresses plasma cell specific markers such as plasma cell antigen-1 (PC-1), and the markers such as mIg, MHC class II molecules, CD19, CD20, CD21 and the like disappear. Plasma cells (Plasma cells), also known as effector B cells (effector Bcell), are cells in the immune system that release large amounts of antibodies. The diameter is 10-20 μm, the cell nucleus is small, occupies less than half of the cell, is more inclined to one side, and occasionally has double cores. The chromatin of the plasma cells is thick and dense, is gathered and stacked, is often like the color of lilac and is not uniform, and a half-moon-shaped light staining area is often extended out of one side of the near nucleus; cavitation or foaming was occasionally observed in the slurry. The plasma cells have the function of synthesizing and storing antibodies, namely immunoglobulin (immunoglobulin), and participate in humoral immune response. Immunoglobulins are formed primarily in the rough endoplasmic reticulum pool, and it has been demonstrated by immunofluorescence techniques that after injection of an antigen into the body, the corresponding antibody is first present in the cytoplasm of plasma cells.
Viral infection refers to infectious diseases caused by viruses that can parasitize and propagate in the human body and cause diseases. Mainly shows general toxic symptoms such as fever, headache, general malaise and the like and local symptoms caused by inflammatory injury caused by virus hosts and invading tissues and organs. Viral infections of the human body are classified into recessive infections, dominant infections, and lentivirus infections. In most cases, the infection is recessive (after the infection of the human body with the virus, no symptoms appear, but specific antibodies can be produced). A few are dominant infections (meaning that symptoms appear after the human body is infected with viruses). The majority of the dominant infections are acute infections, the onset of diseases is acute, the course of diseases is short, and the minority of the dominant infections are latent infections (such as herpes virus infections) and chronic infections (such as hepatitis B virus infections). At present, the virus infection diseases lack specific treatment, mainly support and symptomatic treatment, and antiviral drugs and hormone treatment cannot play an effective treatment role. And viral infections (such as influenza, SARS, MERS and ebola) spread rapidly in humans, posing a significant threat to human health. Especially, the novel coronavirus which is outbreaked worldwide in 2020 causes serious loss to human health and economy.
The etiology of COVID-19 has been shown to be a novel coronavirus, now known as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At present, no specific medicine or vaccine aiming at the virus is successfully developed, and the appearance of SARS-CoV-2 brings a difficult treatment dilemma to clinicians. Most infected patients exhibit non-specific symptoms such as fever, dry cough, and fatigue. The prognosis of most patients is good, and some patients with severe disease can rapidly develop acute respiratory distress syndrome, septic shock, metabolic acidosis, blood coagulation dysfunction and even die. The deterioration of the patient's condition may be due to a cytokine storm in the body, and since SARS-CoV-2 is a novel strain that causes a global pandemic, there is an urgent need for effective targeted therapies, including antiviral and immunotherapy. Currently, although many clinical trials have begun, there is currently no effective antiviral or immunomodulatory therapy for treating COVID-19.
Clinical studies have found that MSC is an effective tool for treating diseases associated with Human Immunodeficiency Virus (HIV) immune abnormality, Hepatitis B Virus (HBV) chronic hepatitis, influenza virus Acute Lung Injury (ALI), and the like. Mesenchymal Stem Cells (MSCs) refer to a group of pluripotent stem cells with diverse differentiation potential that have differentiated into osteoblasts, chondroblasts and adipoblasts. They are derived from immature embryonic connective tissues of mesoderm and ectoderm in early embryonic development stage, and can differentiate into various tissue cells such as fat, bone, cartilage, muscle, tendon, ligament, nerve, liver, cardiac muscle, endothelium and even blood under specific induction conditions in vitro and in vivo. Clinical studies have found that MSC is an effective tool for treating diseases associated with Human Immunodeficiency Virus (HIV) immune abnormality, Hepatitis B Virus (HBV) chronic hepatitis, influenza virus Acute Lung Injury (ALI), and the like. MSCs have low immunogenicity as well as significant and extensive immune-regulatory functions. MSCs do not express co-stimulatory molecules such as CD40, CD80, and CD86, as well as MHC-class II molecules. The T cell inhibitory effect of MSCs is not restricted by MHC, i.e. the effect on autologous and allogeneic T cells is similar. The antiviral response is critical to eradicate the virus and prevent the development of virus-related diseases. If antiviral specific T cells are allowed to function in the presence of MSCs, they have the ability to maintain the integrity of the host's defense against infection. EB virus-specific cytotoxic T Cells (CTL) or cytomegalovirus CTL cultured together with MSC have been found to maintain the ability to proliferate and produce interferon-in vitro and have a killing effect on virus-infected cells. MSC-derived interferon-is thought to counteract the immunosuppressive effects of MSCs by mediating a partial cytotoxic response during viral infection. Therefore, when using MSCs as regenerative medicine, it is very important to recognize the dual role of MSCs in fighting viral infections of the immune system.
In view of the above, the present invention provides an application of MSC for regulating plasma cell number, and more particularly, an application of MSC for regulating plasma cell number of a patient with viral infection.
Disclosure of Invention
The invention aims to provide application of MSC (mesenchymal stem cells) for regulating the number of plasma cells, in particular application of MSC for regulating the number of plasma cells of a patient infected by virus. The quantity of plasma cells of the healed patients is increased by the combined treatment of the MSC treatment group, so that a large amount of antibodies are released by the increased plasma cells and participate in humoral immunity, and therefore, the healed patients of the MSC treatment group have stronger immunocompetence.
The application of the MSC for regulating the plasma cell number of a virus infection patient comprises the following specific steps:
s1, preparing an MSC preparation;
s2, screening patients with viral infection and bringing the screened patients with viral infection into an MSC treatment group for combination treatment;
and S3, sampling and analyzing the peripheral blood mononuclear cell sample of the patient after the recovery, thereby obtaining the plasma cell number of the patient after the recovery.
Preferably, the preparation method of the MSC preparation comprises:
s11, collecting an umbilical cord, placing the umbilical cord in a culture dish, and then cleaning an umbilical cord tissue through physiological saline;
s12, cutting the cleaned umbilical cord tissue into small tissue blocks and planting the small tissue blocks in a culture dish for culture;
s13, removing the culture solution in the culture dish, cleaning the culture dish by using normal saline, adding pancreatin for digestion, adding a stop solution to stop digestion until the cells in the culture dish are digested, transferring the cell suspension into a centrifuge tube for centrifugation, discarding supernatant, resuspending the cells by using a proper amount of culture solution, counting, and finally planting the cell suspension into a new culture dish for culture according to a counting result;
s14, removing the culture solution in the new culture dish in the step S13, then washing with normal saline, adding pancreatin and digesting until the cells in the culture dish are digested, adding a stop solution to stop the digestion, filtering with a cell sieve, transferring the filtered cell suspension into a centrifuge tube, counting and centrifuging to discard the supernatant, preparing cell preparation suspension, adding cell preparation suspension to resuspend the cells, transferring the cell suspension into a transfer bag, and putting the transfer bag into a low-temperature environment for taking, thereby completing the preparation of the MSC preparation;
s15, carrying out qualification detection on the MSC preparation prepared in the step S14.
Preferably, the combination therapy in the MSC treatment group is: the MSC preparation prepared in step S1 is incorporated into an MSC treatment group to be used in combination for patients with viral infection.
Preferably, the combination in the combination therapy refers to: MSC preparation is added in the original treatment scheme as a unique interference factor, and the condition of the combined medicine is tracked and recorded in the process of combined treatment.
Preferably, the patients after healing include patients with viral infection cured by the MSC-treated group and patients with viral infection not cured by the MSC-treated group.
Preferably, the step S3 is to analyze the peripheral blood mononuclear cell sample by single cell transcriptome sequencing, so as to obtain the plasma cell number of the patient after healing.
Compared with the prior art, the invention effectively increases the number of plasma cells of the patient after the recovery of the MSC treatment group by preparing the MSC preparation and applying the prepared MSC preparation to the MSC treatment group for combined treatment of the patient with viral infection, and compared with the patient after the recovery of the MSC treatment group without the MSC treatment group, the number of the plasma cells of the patient after the MSC treatment group is more increased.
Drawings
FIG. 1 is a flow chart of an application of MSC for regulating plasma cell number of a patient with viral infection in the present invention,
figure 2 is a flow chart of a method of preparing the MSC formulation of the present invention,
FIG. 3 is a graph showing the ratio of the plasma cell count of each group among all the immune cells in the healthy group population, the patients after MSC-treated group recovery and the patients without MSC-treated group recovery according to the present invention,
FIG. 4 is a graph showing the fold change of the ratio of plasma cell number in each group with respect to the healthy group in the present invention, wherein the ratio of plasma cell number in the healthy group is set to 1.
Detailed Description
In order to make the technical solutions of the present invention better understood, the present invention is further described in detail below with reference to the accompanying drawings.
It should be noted that the original treatment plan in the present invention refers to a treatment plan adopted in a novel coronavirus pneumonia diagnosis and treatment plan issued by the office of the national Health and care committee and the office of the national traditional Chinese medicine administration, MSC + represents an MSC treatment group, MSC-represents a non-MSC treatment group, and Health represents a healthy group.
As shown in FIG. 1, in order to study the application of MSC for regulating the number of plasma cells, the invention provides an application of MSC for regulating the number of plasma cells of a patient with viral infection, which comprises the following specific steps:
s1, preparing an MSC preparation;
s2, screening patients with viral infection and bringing the screened patients with viral infection into an MSC treatment group for combination treatment;
and S3, sampling and analyzing the peripheral blood mononuclear cell sample of the patient after the recovery, thereby obtaining the plasma cell number of the patient after the recovery.
As shown in fig. 2, wherein the preparation method of the MSC preparation comprises:
s11, collecting an umbilical cord, placing the umbilical cord in a culture dish, and then cleaning an umbilical cord tissue through physiological saline;
s12, cutting the cleaned umbilical cord tissue into small tissue blocks and planting the small tissue blocks in a culture dish for culture;
s13, removing the culture solution in the culture dish, cleaning the culture dish by using normal saline, adding pancreatin for digestion, adding a stop solution to stop digestion until the cells in the culture dish are digested, transferring the cell suspension into a centrifuge tube for centrifugation, discarding supernatant, resuspending the cells by using a proper amount of culture solution, counting, and finally planting the cell suspension into a new culture dish for culture according to a counting result;
s14, removing the culture solution in the new culture dish in the step S13, then washing with normal saline, adding pancreatin for digestion, adding a stop solution to stop digestion after cell digestion in the culture dish is finished, filtering with a cell sieve, transferring the filtered cell suspension into a centrifuge tube, counting, centrifuging, discarding supernatant, preparing cell preparation suspension, adding cell preparation suspension for cell suspension resuspension, transferring the cell suspension into a transfer bag, and putting the transfer bag into a low-temperature environment for taking, thereby completing preparation of the MSC preparation;
s15, carrying out qualification detection on the MSC preparation prepared in the step S14.
In this embodiment, the MSC preparation is prepared from Human umbilical cord mesenchymal stem cells (hiuc-MSC), the preparation process is performed in a sterilized clean bench, instruments and consumables and the like required in the preparation process are sterilized with 75% alcohol, and the collection or cells in the culture dish and the specific operation process need to be labeled in detail in the preparation process; meanwhile, the stem cells can be frozen between the step S13 and the step S14, and if the frozen stem cells need to be revived before the step S14 is performed on the stem cell preparation, the stem cell freezing and reviving operations both belong to the prior art, and are not described in detail herein.
In this embodiment, the MSC preparation is performed in a sterilized clean bench, and in the preparation process, multi-thread instruments, consumables, etc. are sterilized with 75% alcohol, and in the preparation process, the collected materials or cells in the culture dish and the specific operation process need to be labeled in detail; meanwhile, the stem cells can be frozen between the step S13 and the step S14, and if the frozen stem cells need to be revived before the step S14 is performed on the stem cell preparation, the stem cell freezing and reviving operations both belong to the prior art, and are not described in detail herein.
In this embodiment, the qualification testing of the MSC preparation further includes quality testing of the collected material, warehousing testing of the primary cell bank of the umbilical cord mesenchymal stem cells, and warehousing testing of the main cell bank of the umbilical cord mesenchymal stem cells, and the step and standard of the qualification testing are consistent with those of the conventional passing testing, which is not repeated here.
Wherein the combination therapy in the MSC treatment group is: the MSC preparation prepared in step S1 is included in the MSC treatment group and used as the only interfering factor in the original treatment regimen to perform the combination for the patients with viral infection, and the combination is followed and recorded in the combination treatment regimen. In this example, the mesenchymal stem cells of umbilical cord were concentrated in the MSC preparationDegree of 0.1 × 105-5×108Cell number/ml, MSC preparation was administered by peripheral intravenous infusion throughout the MSC treatment group and was used several times. Wherein the number of times of use can be controlled between 1 and 10 times according to actual conditions.
In this example, the general type of patients with new coronary positive disease (SARS-CoV-2 viral infection) was divided into two groups, and used as MSC treatment group samples and non-MSC treatment group samples (i.e. original treatment protocol), after viral infection patients in the two groups of samples were cured, the peripheral blood mononuclear cells of the cured patients were sampled, to better illustrate the working principle and technical effect of the invention, we choose to sample the peripheral blood mononuclear cells of a corresponding number of healthy group persons at the same time, then, the collected peripheral blood mononuclear cell samples are subjected to grouping analysis through single cell sequencing, and the analysis results are processed to obtain plasma cell quantity comparison relations of patients after MSC treatment groups are cured, patients without MSC treatment groups are cured and healthy group personnel in the two groups of samples (see table 1). In other embodiments, other virally infected patients may be selected as samples for the MSC-treated group and the non-MSC-treated group.
TABLE 1 plasma cell number between healthy group members, patients after MSC-treated group recovery and patients without MSC-treated group recovery
Table of relationship of quantities
Meanwhile, drawing a relationship graph of the number of plasma cells between the healed patients and healthy group personnel in two groups of samples according to the processing result data after single cell sequencing analysis (as shown in fig. 3 and fig. 4, wherein, the first represents Health, the second represents MSC +, and the third represents MSC-), the abscissa in fig. 3 represents the plasma cells, the ordinate represents the proportion of the number of the plasma cells in each group in all the corresponding immune cells, the abscissa in fig. 4 represents the plasma cells, and the ordinate represents the change multiple of the ratio of the plasma cells in each group relative to the healthy group.
It can be seen from the combination of table 1 and fig. 3 that, compared with the population of the healthy group, the plasma cell numbers of the patients after the healing of the MSC-treated group and the patients without the healing of the MSC-treated group are both significantly increased, the plasma cell number of the patients after the healing of the MSC-treated group accounts for 1.327% of all the immune cells, the plasma cell number of the patients without the healing of the MSC-treated group accounts for 0.869% of all the immune cells, while the plasma cell number of the healthy group is 0.366% of all immune cells, the plasma cell number of the patients after the MSC treatment group is 1.527 times of the patients without the MSC treatment group, while the number of plasma cells in the patients after the healing of the MSC treatment group was 3.630 times that of the healthy group, since plasma cells can not only participate in inflammatory reactions in the latter stages of the patient's healing, but also release large amounts of antibodies and participate in humoral immunity, therefore, the patients after the treatment by the MSC treatment group have stronger immunity and stronger anti-inflammatory ability.
Plasma cells can participate in the process of killing target cells, so that the number of plasma cells of a virus infected patient cured by the MSC treatment group is increased to be more, which means that the patient cured by the MSC treatment group has stronger virus infection immunity and stronger virus killing capability.
The use of an MSC for regulating plasma cell number according to the present invention is described in detail above. The principles and embodiments of the present invention are explained herein using specific examples, which are presented only to assist in understanding the core concepts of the present invention. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (8)
1. Use of MSCs for modulating plasma cell numbers.
2. The use of the MSCs of claim 1 for modulating the number of plasma cells, wherein said MSCs are used for modulating the number of plasma cells in a virally infected patient.
3. The use of MSCs as claimed in claim 2 for modulating the number of plasma cells, wherein the use of MSCs for modulating the number of plasma cells in a virally infected patient comprises the steps of:
s1, preparing an MSC preparation;
s2, screening patients with viral infection and bringing the screened patients with viral infection into an MSC treatment group for combination treatment;
and S3, sampling and analyzing the peripheral blood mononuclear cell sample of the patient after the recovery, thereby obtaining the plasma cell number of the patient after the recovery.
4. The use of the MSCs of claim 3 for modulating plasma cell numbers, wherein the preparation of the MSC comprises:
s11, collecting an umbilical cord, placing the umbilical cord in a culture dish, and then cleaning an umbilical cord tissue through physiological saline;
s12, cutting the cleaned umbilical cord tissue into small tissue blocks and planting the small tissue blocks in a culture dish for culture;
s13, removing the culture solution in the culture dish, cleaning the culture dish by using normal saline, adding pancreatin for digestion, adding a stop solution to stop digestion until the cells in the culture dish are digested, transferring the cell suspension into a centrifuge tube for centrifugation, discarding supernatant, resuspending the cells by using a proper amount of culture solution, counting, and finally planting the cell suspension into a new culture dish for culture according to a counting result;
s14, removing the culture solution in the new culture dish in the step S13, then washing with normal saline, adding pancreatin for digestion, adding a stop solution to stop digestion after cell digestion in the culture dish is finished, filtering with a cell sieve, transferring the filtered cell suspension into a centrifuge tube, counting, centrifuging, discarding supernatant, preparing cell preparation suspension, adding cell preparation suspension for cell suspension resuspension, transferring the cell suspension into a transfer bag, and putting the transfer bag into a low-temperature environment for taking, thereby completing preparation of the MSC preparation;
s15, carrying out qualification detection on the MSC preparation prepared in the step S14.
5. The use of the MSC of claim 4 for modulating the number of plasma cells, wherein the combination therapy in the MSC treatment group is: the MSC preparation prepared in step S1 is incorporated into an MSC treatment group to be used in combination for patients with viral infection.
6. The use of the MSC of claim 5 for modulating the number of plasma cells, wherein the combination in a combination therapy is: MSC preparation is added in the original treatment scheme as a unique interference factor, and the condition of the combined medicine is tracked and recorded in the process of combined treatment.
7. The use of the MSCs for modulating the number of plasma cells according to claim 6, wherein the patients after healing comprise patients with viral infection cured in the MSC-treated group and patients with viral infection cured in the MSC-untreated group.
8. The use of the MSCs of claim 7 for modulating plasma cell count, wherein step S3 comprises analyzing a sample of peripheral blood mononuclear cells by single cell sequencing to obtain plasma cell count of the healed patient.
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| CN110540959A (en) * | 2019-10-08 | 2019-12-06 | 孟明耀 | Umbilical cord mesenchymal stem cell isolation culture amplification method |
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