Adverse Effects of Stem Cell Therapy: Is There a Risk of the Treatment, and How to Avoid?

Stem cell therapy is a promising field of medicine for the treatment of various diseases and injuries, but like any medical approach, it also may cause potential adverse reactions. In this article, we will look at the possible risks and side effects of stem cell treatment, and how to avoid them.

Overall risks and concerns about stem cell treatment:

One of the most significant risks associated with stem cell therapy is the development of tumors. Stem cells are suspected to become cancerous if they divide uncontrollably or differentiate into abnormal cells. However, it’s only true for embryonic or fetal stem cells, or reprogrammed stem cells as well, because the risk is based on their pluripotency. In stem cell treatment clinics, mesenchymal stem cells (MSCs) are mostly used for therapy due to their safety and because they are well tolerated.
Another potential complication of stem cell therapy is immune rejection. The body may recognize foreign stem cells as a threat and attack them, which leads to inflammation and damage. However, this is more likely in hematopoietic stem cells (HSCs), a type of stem cell that are blood cell precursors.
In some cases, stem cell therapy can cause infection or other complications associated with invasive medical procedures. Stem cell therapy can also lead to damage if the injection site is not properly located or if the needle is not inserted correctly. This is why the procedure must be performed by qualified nurses under the supervision of a specialist in regenerative medicine.
In addition, stem cell therapy may unpredictably interact with other medications a patient takes, which may result in adverse drug interactions.
Ethical considerations are also a factor when discussing the risks of stem cell therapy. Some people have ethical concerns about the use of stem cells from embryonic sources.
There is also the risk of unethical practitioners who offer unproven or untested stem cell therapies that may not be safe or effective.
Patients should also be aware that stem cell therapy is not a guaranteed cure, and in some cases, it may not be effective at all. There is a chance that stem cell therapy may not provide long-lasting results, and the patient may require additional treatment.
The cost of stem cell therapy can also be a concern, as it may not be covered by insurance, and the patient could be left with significant out-of-pocket expenses.

Hematopoietic stem cell transplantation (HSCT) vs. Therapy based on mesenchymal stem cells

The most adverse effects are linked to the oldest and most well-known method of stem cell treatment — hematopoietic stem cell transplantation (HSCT).

Hematopoietic stem cells have a high expression human leukocytes antigens (HLA) system on their surface. This can cause the immune system of the recipient to recognize the transplanted cells as foreign antigens and triggers an immune response against them. High levels of HLA expression on HSCs require the donor’s matching and immune suppression during the allogenic (donor’s) HSCT procedure (bone marrow transplant) and cause numerous adverse effects.

Most of the adverse effects of HSCT are related to graft-versus-host disease reactions (an autoimmune response of the transplanted cells to the foreign HLAs of the body), which occur in about 22% of all patients. Another frequent complication is infections due to the massive immune suppression used in treatment protocols. Other serious adverse effects are:

graft rejection;
graft failure (failure of the transplanted cells to fulfil their functions in the recipient’s body);
relapse of the disease.

Due to this, HSCT is only used when the benefits outweigh the risks, for diseases such as leukemias and other blood system malignancies, and congenital blood cell abnormalities, like sickle-cell anemia and spherocytosis. Most recently, HSC treatment protocols have been introduced in severe cases of multiple sclerosis (MS) and advanced stages of some autoimmune diseases.

The mesenchymal stem cells used in our clinics are characterized by low expression of HLAs on the surface with further auto-downregulation of HLA expression on their surface. This makes the MSCs potentially safe for different regenerative medical protocols without donor-recipient matching. Because of their high regenerative potential, MSCs are widely used for the treatment of different diseases. However, the safety of this type of treatment always attracts the attention of investigators and regulatory bodies.

The main concerns about the potential risks of MSCs treatment were mentioned in the FDA statement, i.e. site reactions, the ability of stem cells to move from the placement sites and change into inappropriate cell types or multiply, failure to work as expected and the growth of tumors. However, the results of existing clinical trials in patients with different pathological conditions, confirm the safety of MSCs’ use in cases where the invasive procedures are performed safely, according to the existing standards, and by qualified specialists.

Adverse Effects of Stem Cell Therapy: Is There a Risk of the Treatment, and How to Avoid?

Stem cell therapy: Is it safe?

The publications about the safety of treatment based on mesenchymal stem cells include a wide meta-analysis (reviewing the results of the published trials) and reports of the results of concrete trials. In most trials, the frequency of adverse effects in MSC-treated patients is compared with placebo (false treatment) and non-treated groups.

The largest meta-analyses were performed by Manoj M. Lalu (2012) and Yang Wang (2021) and between the period 2004 to 2021:

the 2012 study included 36 clinical trials with 1 005 patients in 14 different countries;
2021 had 62 studies; 3 546 patients and more than 20 pathological conditions.

Side effects of stem cell therapy

Some of the most frequent adverse effects are:

transient fever;
mild anemia;
administration site adverse events;
constipation;
fatigue and sleeplessness.

Adverse reactions of stem cell treatment procedure

The maximal frequency of reactions after infusions of MSC-based drugs reported in trials was 8%. These are some of the results:

The arrhythmias and other cardiac effects didn’t differ significantly between the MSCs and the non-treated group, and the maximal frequency of non-arrhythmic effects was 7%.
For gastrointestinal adverse events, no significant difference between MSCs and non-treated patients was found. Only in one study, bilirubin elevation was detected in 11% of patients.
In one patient, phlebitis was diagnosed.
The frequency of pulmonary adverse effects varied from absence to 3% – 13% and included mild pulmonary dysfunction, bronchiolitis obliterans, and significant improvement of pulmonary function.

The frequency of some rare serious adverse effects (metabolism and nutrition disorders, infection, death, arrhythmia, central nervous system and vascular disorders) were not impacted by the administration MSCs and didn’t differ significantly between the placebo and treated patients.

The safety of MSC treatment was also confirmed in disease-specific trials.

Safety of stem cell therapy in autoimmune diseases

9 clinical trials of systemic sclerosis with 133 participants reported side reactions in 16 cases, most of which were mild and related to the procedure (local pain, edema, hyperemia) and resolved or improved within 1 week. One case with a moderate skin infection at the orofacial injection was reported but improved with oral antibiotics.

10 clinical studies in patients with systemic lupus erythematosus with 231 patients reported a lower incidence of severe adverse effects in the MSC-treated group if compared to the controlled (placebo or non-treated) group during the same time period. Both groups presented with respiratory tract infections. In the MSC-treated groups, only one patient developed leucopenia, pneumonia and subcutaneous abscess, while in the non-MSC-treated group, one patient developed stroke and ascites.

13 clinical studies of 557 Covid-19 patients reported no severe MSC-related adverse effects in any of the studies. The non-severe effects were rare and included mild fever, which resolved spontaneously.

A study with a large number of patients with heart failure didn’t reveal a difference in the severe adverse effects of treatment and placebo groups. This is based on:

the review of 12 studies with 823 patients;
the review of 6 studies with 625 patients with heart failure;
and an earlier review of 23 randomized trials with 1 255 participants.

The death rate was significantly lower in patients who received MSCs. In one of the reviews, only 4 events from 1 255 patients were suspected to be related to the treatment (local hematoma, periprocedural transient bundle branch block, pericardial effusion and pulmonary edema during the procedure).

Safety of stem cell therapy in neurological conditions

The multi-disease review of clinical trials of spinal cord injury, MS and ischemic stroke included 1 044 patients within:

25 studies with spinal cord injury;
14 studies for MS;
9 studies for ischemic stroke.

The studies revealed one death of a spinal cord injury patient where the cells were implanted directly into the cord. In other cases, fever (8% of patients) and mild headache were reported. There was one case of epileptic seizures which required hospitalization and 2 cases of meningitis after intrathecal injections, but they resolved in a short period.

No serious adverse effects were reported in 7 trials of multiple sclerosis patients, published from 2016 to 2022. The review of studies (6 trials with 86 patients, and one long-term study with a follow-up observation of 10 years) didn’t reveal any serious adverse effects related to MSC treatment. In a 4 year-long MS study of 24 MS patients, mild and moderate symptoms included headache, low-grade fever, and backache, with no serious adverse effects reported during the period of observation.

An autism studies analysis with 325 patients included 16 non-severe adverse effects, and among them were:

low fever
headache
lumbar pain
fatigue
nausea and vomiting

Some concerns were related to the risk of tumor growth, which seems to be based on the high reproductive potential of MSCs and the secretion of numerous growth factors. These are also mentioned in the FDA statement. However, the increase in tumor growth was only present in experimental animal studies, in which some animals were either contaminated with cancer, or MSCs were injected simultaneously with cancer cells.

In recent years, the role of MSCs in cancer treatment is more and more widely discussed. However, based on the mechanism of MSCs in action, this method still seems to be a double-edged sword and should be used with caution and proper research. The tumor growth is more typical for embryonic stem cells (obtained from embryos or in vitro fertilization materials). The use of these cells in clinical practice is limited due to ethical concerns.

Conclusion

Most of the patients’ concerns about stem cell treatment are related to the possible adverse effects. However, these effects significantly depend on the type of the cells and the use of invasive treatment methods (higher risks carry intravitreal, intracoronary or intramyocardial injections). Currently, MSCs are the safest, most researched and most predictable within cell-based therapy.

While stem cell therapy holds great potential for the treatment of various diseases and injuries, there are potential adverse effects that patients must be aware of. They should carefully consider the risks and benefits of this treatment with their healthcare provider before making a decision.