CN-121987667-A - Application of mesenchymal stem cells from in-vivo stem cell generator

Abstract

The invention discloses application of mesenchymal stem cells from an in-vivo stem cell generator in preparing a medicament for treating inflammatory diseases, in particular inflammatory enteritis. According to the invention, an artificially controllable inflammatory microenvironment is constructed in vivo through a stem cell generator, so that the immunoregulation function of the mesenchymal stem cells is activated, the activated MSC can effectively promote the M1 type macrophage to M2 type phenotype conversion, induce the T cells to differentiate into regulatory T cells, and inhibit the proliferation of the activated T cells. In the treatment of inflammatory bowel disease of mice, MSC obtained by the method of the invention obviously improves the survival rate of mice, reduces weight loss, maintains a complete crypt structure of colon parts, inhibits infiltration of inflammatory cells into the colon, and remodels the inflammatory microenvironment of the colon. The invention provides a brand-new method for activating the immunoregulation function of mesenchymal stem cells, which opens up a new path for treating inflammatory and immune diseases.

Inventors

• LIU CHANGSHENG
• ZHU FUWEI
• WANG JING

Assignees

• 华东理工大学

Dates

Publication Date

20260508

Application Date

20241104

Claims (10)

1. 1. Use of mesenchymal stem cells isolated from a stem cell generator for the preparation of a medicament for the treatment of an inflammatory disease.
2. 2. The use according to claim 1, wherein the mesenchymal stem cells are activated by the inflammatory microenvironment of the stem cell generator.
3. 3. The use according to claim 1, wherein the stem cell generator is formed by the development of organoids following implantation of active substances and/or cellular-loaded biomaterials, or biomaterials having osteoinductive capacity themselves, into animals or humans.
4. 4. The method of claim 3, wherein the biological material is selected from collagen, gelatin, methacrylic acid modified gelatin (GelMA), chitosan, alginic acid, methacrylic acid modified hyaluronic acid (HAMA), methacrylic acid modified silk fibroin (SilMA), hyaluronic acid, bacterial cellulose, polylactic acid, polyglycolide, polylactide, polyhydroxyalkanoate, polycarbonate, polycaprolactone, polyethylene glycol, polyfumaric acid, hydroxyapatite, calcium sulfate, tricalcium phosphate, tetracalcium phosphate, octacalcium phosphate, calcium metaphosphate, magnesium phosphate, pyrophosphates, calcium silicate, bioglass, decalcified bone matrix, and the like.
5. 5. The use according to claim 3, wherein the animal or human is a muscle pouch, muscle gap, intramuscular, subcutaneous, or intraperitoneal of the animal or human.
6. 6. Use according to claim 3, wherein the active substance is bone morphogenic protein-2, bone morphogenic protein-7 or other growth factors/polypeptides or growth factor/polypeptide combinations having the ability to induce bone regeneration, angiogenesis.
7. 7. Use according to claim 3, characterized in that the time of development in animals or humans is 3-25 days, preferably 5-20 days, more preferably 7-15 days.
8. 8. The use according to claim 1, wherein the stem cell generator comprises inflammatory cells, stem cells and inflammatory factors, wherein, The inflammatory cells are selected from the group consisting of neutrophils, macrophages (M1-type macrophages and M2-type macrophages); the stem cells are selected from the group consisting of mesenchymal stem cells, hematopoietic stem cells and endothelial progenitor cells; the inflammatory factor is selected from the group consisting of IL-1 beta, TNF-alpha and IFN-gamma.
9. 9. The use according to claim 1, wherein the preparation comprises grinding, crushing, and sieving the stem cell generator in a buffer to obtain a single cell suspension.
10. 10. The use according to claim 1, wherein the inflammatory disease is inflammatory bowel disease or chronic inflammatory disease due to immune dysfunction, in another preferred example, the inflammatory bowel disease is crohn's disease or ulcerative colitis, and the chronic inflammatory disease is rheumatoid arthritis, systemic lupus erythematosus, psoriasis and psoriatic arthritis or systemic sclerosis.

Description

Application of mesenchymal stem cells from in-vivo stem cell generator Technical Field The invention relates to the technical field of stem cell biology, in particular to an application of Mesenchymal Stem Cells (MSC) activated based on an in vivo stem cell generator inflammatory microenvironment in the treatment of Inflammatory Bowel Disease (IBD). Background Mesenchymal Stem Cells (MSCs) have attracted considerable attention in the clinical field due to their multipotent differentiation potential, immunomodulatory properties, anti-inflammatory effects and low immunogenicity. MSCs have demonstrated their ability to inhibit inflammation, alleviate disease progression in clinical studies and treatments of inflammatory diseases such as crohn's disease, graft versus host disease, systemic lupus erythematosus, and organ fibrosis. MSCs also show great potential in the treatment of Inflammatory Bowel Disease (IBD). IBD, including crohn's disease and ulcerative colitis, is commonly manifested as chronic inflammation of the gut, and current treatments rely mainly on immunosuppressants and biologicals, but these treatments often have problems with side effects, limited efficacy, and resistance. MSC can regulate immune system cells such as macrophages, T cells and neutrophils by secreting a series of factors such as Nitric Oxide (NO), prostaglandin E2 (PGE 2), tumor necrosis factor stimulating gene 6 (TSG-6) and the like through the immunoregulatory function of the MSC, inhibit excessive inflammatory reaction, and further play an anti-inflammatory and immunoregulatory role in the treatment of IBD. However, studies have shown that the immunomodulatory function of MSCs cultured in vitro is dependent on stimulation by inflammatory factors. Although inflammatory factor pretreatment of MSCs may enhance their immunomodulatory function, this approach may result in MSCs losing immune immunity and being rapidly cleared by the host's immune system, thereby limiting their therapeutic efficacy and persistence. Furthermore, the effect of the pre-treated MSCs on functional enhancement is generally short, and their immunosuppressive ability gradually decreases with prolonged in vitro culture time, which also limits their long-term use in chronic inflammatory diseases such as IBD. Disclosure of Invention The present application aims to provide a novel method for constructing a controllable in vivo inflammatory microenvironment using a stem cell generator, thereby enhancing the immunoregulatory function of Mesenchymal Stem Cells (MSCs), and applying the activated MSCs in the treatment of inflammatory bowel disease. The invention provides application of mesenchymal stem cells separated from a stem cell generator, which is used for preparing a medicament for treating inflammatory diseases. In another preferred embodiment, the inflammatory bowel disease is Crohn's disease or ulcerative colitis. In another preferred embodiment, the mesenchymal stem cells are activated by the inflammatory microenvironment of the stem cell generator. The inflammatory microenvironment of the stem cell generator is formed in the early stages of ectopic bone development (fibroproliferative phase) induced by bone morphogenic protein-2 or other growth factors/polypeptides or growth factor/polypeptide combinations that have the ability to induce bone regeneration. The inflammatory microenvironment of the stem cell generator is characterized by elevated levels of inflammatory factors (e.g., IL-1 beta, TNF-alpha, and IFN-gamma), a higher proportion of neutrophils to macrophages, and a higher proportion of M1-type macrophages than normal femur The invention generates and activates mesenchymal stem cells based on the early inflammatory microenvironment of a stem cell generator, can obtain MSC with unique immunoregulatory function, and develops a stem cell therapy aiming at inflammatory bowel disease. Specifically, after the immunoregulation function of the mesenchymal stem cells is activated by the inflammatory microenvironment of the artificially constructed in-vivo stem cell generator, the mesenchymal stem cells have high-efficiency and durable immunoregulation capacity, can promote the transformation of macrophages from M1 type to M2 type, inhibit the proliferation of activated T cells, promote the differentiation of the T cells into regulatory T cells (Tregs), and induce the differentiation of the Treg cells. Meanwhile, the cell also maintains low immunogenicity and good stress tolerance, can resist the stress stimulation of H 2O2 and LPS in vitro, and remarkably improves the survival time and the treatment effect of the cell in enteropathy mice. The treatment effect comprises remarkably improving the survival rate of animal model of inflammatory bowel disease, reducing weight loss, keeping the hidden structure of colon intact, preventing infiltration of immune cells (such as neutrophils, macrophages and T cells) to colon, and increasing the proportion of M2 typ