What factors determine the treatment effect of MSC (Part Four)

Posted by beauty33 on December 31st, 2019

4. Timing of treatment

The timing of MSC is also important: should MSC be used for prevention or treatment?

In the treatment of difficult and severe diseases, MSC has high hopes; but these difficult disease models are difficult to simulate the actual clinical situation. In animal experiments, MSCs are often given immediately after injection of a drug that induces a disease model. For example, in a pig experiment in which MSC was used to treat acute liver failure, MSCs were administered via liver portal vein within 2 hours of injecting a drug that induces the disease, and the effect was very significant; in a mouse experiment, carbon tetrachloride was used to induce acute liver failure in 24 hours. MSCs were given intrasplenic injections immediately.

In clinical studies, there are also cases where MSC is given before the disease has appeared. Co-transplantation of MSC and hematopoietic stem cells is the most common. MSC can reduce the rejection reaction (GVHD) and increase the survival rate of hematopoietic stem cell transplantation after hematopoietic stem cell transplantation. It is very suitable for allogeneic hematopoietic stem cell transplantation (bone marrow transplantation) with less than 6 matching types. At this time, MSC plays the role of adjuvant therapy, escorting the treatment of hematopoietic stem cell transplantation.

MSC promotes the healing of diabetic foot, and the healing of the ulcer surface is not accompanied by the proliferation of scar tissue, which suggests that MSC can inhibit the proliferation of scar tissue. It is not only suitable for the treatment of skin trauma (including plastic surgery), but also for the prevention of pioneering surgery. Postoperative scar hyperplasia, such as the most common postoperative abdominal adhesions. It should be noted that the timing of MSC application is because MSC does not eliminate scar tissue, but only prevents the appearance of scar tissue.

Cell drugs are very different from traditional chemical drugs in that cells are alive and chemical drugs are dead. MSCs, as living cells, enter the body and must interact with the microenvironment in the body. Does the microenvironment help the MSC to better exert its therapeutic effect, or does it limit the therapeutic function of the MSC?

In short, that is, under pathological conditions, the ischemia and hypoxia microenvironment is conducive to MSC secreting more growth factors, and inflammatory factors (TNF-α and IL-1β) can promote MSC secretion of cytokines (IL -1A, RANTES, G-CSF), but overall, the impact of the inflammatory environment on MSCs is more harmful than beneficial. Because inflammatory factors can also cause MSC death, the inflammatory environment can also increase the expression of HLA-DR (MHC class II antigen) antigens of MSCs, enhance the immunogenicity of MSCs, be recognized by immune cells, and accelerate the clearance of MSCs.

For example, in a multi-center clinical study, in the clinical trial of bone marrow MSCs in the treatment of GvHD in children with steroid ineffectiveness, the use of MSC treatment in the early stage of the disease (5-12 days after starting steroid therapy) is more advanced (13-85 days after starting steroid therapy) in better efficacy (fully effective 78% vs. 52%).

MSC has also been used in clinical studies of kidney organ transplantation, and it has been found that MSC therapy before transplantation is beneficial to reduce the rejection reaction after organ transplantation, promote the survival rate of organ transplantation and restore organ function. Of course, MSCs can also play an immunosuppressive role when immune rejection occurs after liver transplantation.

The results of these clinical studies give us an obvious hint that the timing of MSC treatment is very important and even affects the treatment effect, although there are few clinical studies to study the effect of treatment timing on the effect.

As the disease progresses from onset to acute phase to chronic phase, there may be a time window in the clinical process, which is suitable for MSC to play the best therapeutic function.

More importantly, MSC alone should not be expected to have a good therapeutic effect. Comprehensive treatment is needed for difficult and serious diseases. So, should MSC be the main therapeutic or adjuvant treatment is likely to depend on the specific disease. For example, hematopoietic stem cells are used to treat hematological tumors. Hematopoietic stem cells are the main protagonist and MSC is an adjuvant therapy. For organ transplantation, MSC is also an adjuvant therapy. In the treatment of immune rejection (including GVHD and rejection of organ transplantation), MSC is the protagonist and plays the main therapeutic role.

5. Summary

MSC has multiple functions, such as immunosuppressive function, promoting the repair function of tissues and organs in the body, promoting angiogenesis / regeneration, and supporting the proliferation and differentiation of hematopoietic stem cells. Its clinical indications are relatively wide.

Rat experiments even have found that MSC can enhance the body's resistance to bacterial infection and promote the elimination of bacteria. A clinical study of MSC in the treatment of refractory AIDS shows that MSC can enhance the effect of anti-HIV drugs. Therefore, MSC is also an interesting research area in the treatment of refractory bacterial and viral infections.