MSCs Showing Both Aspects of Stromal Cell and Stem Cell
In the previous articles, we examined how MSCs suppress inflammatory responses and secrete various factors necessary for tissue repair, thereby creating an environment conducive to healing. To summarize again, MSCs coordinate to suppress the activation of T cells, B cells, NK cells, and dendritic cells, forming an environment favorable for tissue recovery; they secrete HGF and IGF-1 to inhibit apoptosis and reduce fibrosis in order to preserve tissue function; they secrete factors such as VEGF, Angiopoietin-1, and FGF-2 to promote rapid formation of new blood vessels at the site of injury to supply oxygen and nutrients; and they secrete SDF-1 (CXCL12), SCF, and Wnt signaling molecules to awaken resident stem cells in the damaged organ and induce differentiation and regeneration.
All of these roles are not about directly creating new tissue through regeneration and differentiation for reconstruction and recovery, but rather about functioning as stromal cells that support surrounding cells. Of course, MSCs that receive these signals will themselves differentiate and regenerate according to those signals, so MSCs can be considered to exhibit both functions — those of stromal cells and those of stem cells. They contribute to tissue repair in both respects.
Whether by cell replication to regenerate tissue, or by encouraging and supporting neighboring cells so that repair proceeds well, one thing is clear: MSCs make a very large contribution to tissue recovery, and therefore efforts to utilize these MSCs therapeutically are a natural outcome.
MSCs Contributing to Immune Regulation and Tissue Regeneration
Since the early experiments in which MSCs were observed to self-replicate and form colonies, they have been expected to be used in various therapies as stem cells. However, despite considerable efforts in the field of regenerative medicine, unlike in animal studies where MSCs have been shown to differentiate into bone, there have been very few successful cases in clinical trials on humans in which MSCs were induced to differentiate into specific tissues. Nevertheless, the supportive roles of MSCs in modulating immunity and promoting regeneration have been observed to be extremely important, and numerous clinical trials are currently being actively conducted to utilize the strong immunoregulatory capacity of MSCs for the treatment of various degenerative and inflammatory diseases, as well as autoimmune and transplantation-related disorders.
When one searches for MSC-related clinical trials registered on the global clinical trial database (https://clinicaltrials.gov/) operated and managed by the U.S. National Library of Medicine (under the National Institutes of Health, NIH), it is clear that interest in MSCs has increased significantly in recent years. In fact, I initially intended to visit the site myself and look up the exact number of current trials, but as it turned out to be somewhat complicated, I instead referred to a recent paper that contained the most up-to-date figures. As of 2021, there were approximately 1,000 MSC-based clinical trials [1], and according to another study, as of the end of October 2023, a total of 1,654 studies had been registered [2]. The graph below clearly shows that the number of clinical trials has surged sharply in recent years. Of course, most of these trials remain in the early Phase I or Phase II stages, with only about 7% (120 out of 1,654) progressing to Phase III or IV, reflecting the current limitations and the fact that there is still a long way to go. It also suggests that continued and expanded research will be necessary in the future.
In clinical studies based on MSCs, the regenerative medicine (tissue replacement) field, which focuses on MSC differentiation and regenerative capacity, has relatively low success rates, whereas clinical trials in immunoregulation-related fields such as autoimmune diseases and graft-versus-host disease (GvHD) have shown more consistent results and are much more active. GvHD is an immunological disease in which immune cells of the graft recognize host cells as non-self and attack normal host tissues — a serious post-transplant complication that threatens patient survival and claims many lives. It is reported that chronic GvHD develops in about 35% of patients who received hematopoietic stem cell transplantation. [3] In the 2021 MSC clinical trial dataset mentioned above, of 1,000 total trials, 491 (47.1%) targeted immune or inflammation-mediated diseases; among these, 91 were for transplant rejection, 129 for autoimmune diseases, and 269 for non-immune diseases with inflammatory components — more detailed counts by disease are shown in the table below.
In the most recent data, a paper that surveyed stem cell clinical trials worldwide from 2006 to 2025, covering both ClinicalTrials.gov (U.S.) and the EU clinical trial registry, summarized stem cell-based clinical trials for autoimmune diseases at 244 trials in total. Clinical trials targeting autoimmune diseases have been increasing recently; among them, Crohn’s disease accounted for 85 trials (34.8%), the most studied, followed by systemic lupus erythematosus (36 trials, 14.8%), systemic sclerosis (32 trials, 13.1%), and psoriasis (12 trials, 4.9%). By clinical phase, most remain in early phases 1–2 (204 trials, 83.6%), and only 40 trials (16.4%) are in phases 3–4. [4]
Autoimmune Diseases
Autoimmune diseases affect more than about one billion people worldwide and are steadily increasing with environmental and lifestyle changes. Autoimmune diseases are often closely linked to environmental changes. Since industrialization, pollution has increased, daily-use chemical products have become more numerous (increasing chances of toxic exposure), dietary habits have shifted toward processed foods altering the gut microbiome and worsening imbalance, and physical activity has declined amid convenience — these environmental factors contribute to disruption of immune balance and are considered causes of the recent steady rise in autoimmune diseases. Autoimmune diseases share the characteristic of persistent inflammation in the body, though they present various symptoms depending on the disease. Let us briefly examine the mechanisms of representative autoimmune diseases.
Rheumatoid arthritis (RA)
RA is a disease in which self-reactive immune cells are activated due to an imbalance between Th17 and Treg cells and attack collagen-rich joint tissues. Th17 cells promote inflammatory responses by secreting the pro-inflammatory cytokine IL-17, while Treg cells act as the “brakes” of the immune response, helping to suppress excessive immune activation. Both of these cell types begin to differentiate under the influence of the same signal, TGF-β. In other words, when an inflammatory environment predominates (with IL-6 present), differentiation is directed toward Th17 cells, whereas under stable conditions, differentiation of Treg cells is promoted. When the balance between these two cell types is properly maintained, immune homeostasis is preserved; however, when this balance is disrupted and Th17 activity becomes excessive, autoreactive immune cells become overactivated, leading to the destruction of cartilage and bone, inflammation of the synovial membrane, and consequent tissue damage. MSCs can reduce the production of pro-inflammatory cytokines while increasing the secretion of anti-inflammatory cytokines (IL-4, IL-10), which are critical for tissue regeneration. This suppresses Th17 cells and increases Treg cells, thereby restoring balance and improving rheumatoid arthritis (RA).
Type 1 Diabetes (T1DM)
Type 1 diabetes is caused by an autoimmune reaction in which T cells attack and destroy pancreatic β-cells that secrete insulin, resulting in the inability to produce insulin.
Multiple Sclerosis (MS)
The axon is the long, wire-like part of a neuron that transmits electrical signals (action potentials) to other nerve cells, with lengths varying from a few millimeters to over a meter. The myelin sheath that wraps around the axon is a fatty insulating layer, much like the rubber coating around an electrical wire. Myelin not only prevents signal loss and ensures proper transmission, but also serves as an efficient signal booster—electrical impulses “jump” between the small gaps where myelin is absent (the nodes of Ranvier).
However, when T cells become abnormally activated and begin to attack and destroy myelin in the central nervous system (the brain, spinal cord, and optic nerves), this causes disruption of signal transmission. As a result, commands from the brain fail to reach the body properly, leading to paralysis and muscle stiffness, along with symptoms such as numbness, pain, difficulty walking, urinary or fecal dysfunction, memory impairment, and visual disturbances.
Related article: Generation of Action Potentials in Neurons
Systemic Lupus Erythematosus (SLE)
In systemic lupus erythematosus, antibodies produced by B cells mistakenly recognize DNA, RNA, and proteins within the nucleus as antigens and bind to them, forming antinuclear antibodies (ANA). These antigen–antibody complexes deposit on the skin, kidneys, joints, and blood vessel walls, where white blood cells accumulate and trigger inflammatory reactions.
The disease causes a characteristic butterfly-shaped rash on the face (the name lupus originates from the rash resembling a wolf bite), along with fatigue, joint pain, renal failure, and respiratory difficulties, leading to a significant reduction in quality of life.
Inflammatory Bowel Disease (IBD): Example – Crohn’s Disease
Crohn’s disease is a chronic inflammatory bowel disease that can occur anywhere along the digestive tract—from the small intestine and colon to the anus—due to genetic predisposition and various other factors. Repeated damage to the intestinal barrier can lead to ulcers, fistulas, and strictures. As described in a previous article on oligosaccharides, beneficial gut bacteria use oligosaccharides as nutrients to produce short-chain fatty acids (SCFAs), which acidify the intestinal environment and favor the growth of beneficial microbes. These beneficial bacteria in turn promote the differentiation of T cells into anti-inflammatory Treg cells. Conversely, when the microbial balance is disturbed and harmful bacteria predominate, excessive stimulation of the intestinal mucosa can lead to chronic inflammation. Thus, the relationship between intestinal microbes and inflammation is very close.
When intestinal epithelial cells are damaged and bacteria or antigens penetrate the barrier, immune responses are triggered, leading to the persistent overproduction of inflammatory cytokines such as TNF-α, IL-17, and IL-23. MSCs can promote the repair of intestinal epithelial cells by secreting growth factors such as HGF, EGF, and VEGF, and molecules like TSG-6, PGE2, and IDO secreted by MSCs can suppress the excessive recruitment of immune cells. An MSC-based therapeutic product (Alofisel), using locally injected adipose tissue–derived MSCs to treat perianal fistulas in Crohn’s disease, was approved for clinical use in 2018. However, due to insufficient efficacy data, it was withdrawn from the EU market in late 2024. [5]
Thyroid Diseases (Hashimoto’s Thyroiditis and Graves’ Disease)
Among autoimmune thyroid disorders, Hashimoto’s thyroiditis is caused by autoantibodies (anti-TPO and anti-thyroglobulin antibodies) attacking thyroid cells, leading to hypothyroidism. Graves’ disease, in contrast, involves autoantibodies (TSH receptor antibodies, TRAb) that continuously stimulate the thyroid-stimulating hormone (TSH) receptor, causing excessive thyroid hormone production and resulting in hyperthyroidism. Both are representative autoimmune thyroid diseases.
Skin Diseases: Systemic Sclerosis, Psoriasis, and Atopic Dermatitis
Systemic sclerosis, psoriasis, and atopic dermatitis are all autoimmune diseases characterized by an overactivation of the Th2-type immune response (T cells associated with allergic reactions). Normally, Th2 cells promote antibody production and inflammation to defend against parasites or allergens, but when this balance is disrupted, the immune system mistakenly attacks the body’s own tissues.
Systemic sclerosis arises from overactivation of T and B cells, causing fibroblasts to produce excessive collagen. Collagen normally helps repair tissue damage, but in this disease, uncontrolled collagen deposition (fibrosis) thickens the skin and affects internal organs such as the lungs, heart, kidneys, and gastrointestinal tract. This leads to symptoms such as finger contractures, pulmonary hypertension, renal failure, and respiratory difficulty due to stiffened lung tissue. Pulmonary fibrosis is reported to be the leading cause of death in systemic sclerosis. [6]
Psoriasis results from T cells sending abnormal signals to the skin. Normally, keratinocytes gradually mature and shed after a fixed cycle, but in psoriasis, immune activation causes keratinocytes to proliferate 5–10 times faster than normal. Immature skin cells accumulate in layers, forming thick white scales, redness, itching, and pain.
Atopic dermatitis, the most common chronic inflammatory skin disease and a form of eczema, is closely related to genetic and environmental factors. It often involves genetic mutations or deficiencies in ceramide—the key lipid that maintains the barrier function of the stratum corneum—leading to impaired skin barriers. This allows bacteria, fungi, and allergens to penetrate the skin, triggering inflammation. The Th2-centered immune response activates B cells to increase IgE antibody production, resulting in allergic reactions. Scratching the dry, itchy skin further damages keratinocytes, allowing bacterial infection and intensifying inflammation in a vicious cycle.
Conventional Autoimmune Treatments (Steroids, Immunosuppressants, Biologics) vs. MSC-Based Therapies
Common treatments for autoimmune diseases—conditions that can make daily life unbearable—include steroids, immunosuppressants, and biologics targeting specific cytokines. Steroids provide strong and rapid anti-inflammatory effects but can cause side effects with long-term use, while immunosuppressants increase susceptibility to infections. Steroid drugs are synthetic corticosteroids modeled after cortisol, a stress hormone secreted by the adrenal glands in life-threatening “fight-or-flight” situations. Cortisol mobilizes energy by raising blood glucose while suppressing less urgent processes like immunity, digestion, and growth. In other words, conventional therapies primarily aim to suppress inflammation, but long-term use often leads to drug resistance and frequent relapse upon discontinuation.
Compared with these, MSC-based therapies have been reported to be remarkably safe. They suppress inflammation without completely shutting down immune defense, thereby restoring immune balance rather than inducing global immunosuppression. MSCs also secrete various growth factors that protect and regenerate damaged tissues. Unlike biologics that target a single cytokine, MSCs interact with multiple immune cells to produce complex effects, offering the potential to treat a wide range of diseases. Consequently, MSC-based approaches are being actively studied as complementary or even long-term alternative therapies for autoimmune diseases. Furthermore, MSCs can be easily obtained from umbilical cords, Wharton’s jelly (a gelatinous substance within the umbilical cord), adipose tissue, bone marrow, teeth, and even menstrual blood—providing excellent accessibility.
[References]
[1] Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell‐free products and human pluripotent stem cell‐derived mesenchymal stem cells
doi: 10.1002/sctm.21-0021
[2] Enhancing Immunomodulatory Function of Mesenchymal Stromal Cells by Hydrogel Encapsulation
https://doi.org/10.3390/cells13030210
[3] Current status of clinical trials assessing mesenchymal stem cell therapy for graft versus host disease: a systematic review
doi: 10.1186/s13287-022-02751-0
[4] Global clinical trials on stem cell therapy for autoimmune diseases: trends and future directions
https://doi.org/10.3389/fimmu.2025.1616231
[5] https://www.ema.europa.eu/en/news/alofisel-withdrawn-eu-market
[6] Systemic Sclerosis (Scleroderma)
https://www.ncbi.nlm.nih.gov/books/NBK430875/
Psoriasis
https://www.ncbi.nlm.nih.gov/books/NBK448194/
Atopic Dermatitis
https://www.ncbi.nlm.nih.gov/books/NBK448071/
Focus of each stage: Phase
