Safety of Mesenchymal Stem Cell Therapy

Although many animal experiments have proved the safety of infusing mesenchymal stem cells (MSCs), clinical research observation and evaluation are more meaningful.

1. Fever: immune response and inflammatory response?

After MSC infusion therapy, fever is the most common adverse reaction, and the highest incidence rate in the literature is about 39% [1-4]. Generally, no special treatment is required, and the patient will recover naturally. Some studies have speculated that the cause of fever may be related to the acute inflammatory response caused by the transfusion of allogeneic MSCs [5]. However, MSC has low immunogenicity and has the characteristics of "immune immunity", so it is difficult to cause immune rejection [6]. More direct evidence is that MSC can effectively treat various immune diseases, especially the treatment of GVHD [7].

Animal experiments have proved that MSC can effectively treat and eliminate inflammation [8]. A study evaluated 137 patients with rheumatoid arthritis who did not experience immunotoxicity after MSC treatment [9]. Therefore, fever induced by MSC treatment has nothing to do with immune response or inflammatory response.

2. Adverse reactions: fetal bovine serum

Studies have found that the use of fetal bovine serum (FBS) to culture MSCs may increase the immunogenicity of MSCs [10, 11]. However, a large number of clinical data found that there is no correlation between the residual fetal bovine serum in MSC cell suspension and adverse reactions. Even so, considering that there are a large number of foreign proteins in fetal bovine serum, we should also reduce the residual amount of fetal bovine serum in MSC cell suspension as much as possible (the national regulation should not exceed 50ng/ml).

3. Adverse reactions: DMSO

What is more noteworthy is that the MSC cell suspension containing dimethyl sulfoxide (DMSO, a necessary reagent for cryopreservation of cells) can significantly increase toxic side effects and cause hypersensitivity reactions [1, 12, 13]. Therefore, reducing the amount of DMSO contained in the MSC cell suspension can reduce the adverse reactions caused by MSC treatment.

4. Adverse reactions: endotoxin

We have found in clinical application that if the endotoxin content in MSC suspension exceeds the standard (the national regulation cannot exceed 2EU/ml), it is easy to cause fever, regardless of whether it is heterogeneous or not. The residual amount of fetal bovine serum, dimethyl sulfoxide and endotoxin are all closely related to the production process, and have nothing to do with the mesenchymal stem cells themselves.

5. Adverse reactions: nervous system adverse events

After infusion of MSCs in healthy volunteers, no infusion-induced toxicity (heart rate, respiration, blood oxygen saturation, blood pressure) occurred, and no abnormalities were found in the functions of various organs [14].

Most of the studies found that there was no or slight infusion toxicity in patients after infusion of MSCs [2, 4, 7, 9, 15-30]. Only three clinical trials reported MSC-induced cardiotoxicity, manifested as transient arrhythmias, with an incidence of 7% (2 of 30 patients) [23, 31, 32]. Only one randomized controlled trial found that 16 patients treated with MSC had neurologic symptoms in 3 patients, while 5 of 36 patients in the control group had the same symptoms [16].

6. Adverse reactions: risk of infection and risk of tumor formation

Although in a non-randomized controlled trial, 3 patients out of 100 patients in the MSC treatment group and 3 patients out of 100 patients in the control group died due to infection after treatment [33]. However, more randomized controlled clinical trials, through statistical analysis, found that there was no difference in the infection rate between the MSC treatment group and the control group, clearly stating that MSC treatment did not increase the risk of infection [15, 16, 18], and the MSC treatment group There was no difference in dyscrasia and tumorigenesis compared with the control group [15-18]. Long-term observation did not find the phenomenon of increased microbial infection and tumorigenicity of mesenchymal stem cells in patients [7, 34]. Some scholars even gave 41 patients with cartilage damage infusion of MSCs for treatment. After 11 years of observation, no tumors were found [35].

Large-scale clinical studies have demonstrated the safety of MSC therapy [7, 9, 36-38]. Some scholars have also analyzed a large number of current clinical trial literature (Meta-Analysis), and found that MSC infusion therapy is only related to fever to a certain extent, and has no necessary connection with adverse reactions reported in other literature. safe [39].

In fact, MSCs exist widely in the human body, and it has never been found that MSCs in the human body can become cancerous, or that tumors originate from MSCs. MSC cells themselves are safe, and the adverse reactions of MSC treatment are closely related to some impurities in the MSC suspension, such as endotoxin content, residual fetal bovine serum, etc.

Overall, mesenchymal stem cell therapy has a good safety record, and has no obvious side effects on patients. A small number of patients experience local discomfort after injection, short-term low-grade fever, etc., and symptomatic treatment is enough.