Autoimmune diseases are a group of complex conditions in which the immune system mistakenly attacks the body’s own tissues. Examples include Crohn’s disease, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, and psoriasis. These diseases are chronic and often progressive, affecting multiple organs and causing long-term damage. Patients with autoimmune diseases experience inflammation and tissue injury that can lead to permanent organ dysfunction. Current treatments, including anti-inflammatory drugs, immunosuppressants, and biologic therapies, aim to control symptoms and prevent disease progression. However, these treatments often fall short, sometimes failing to maintain remission or causing significant side effects over time.
The limitations of existing therapies have prompted researchers to explore alternative strategies, and stem cell therapy has emerged as a promising option.
This study analyzes trends and challenges in clinical trials of stem cell therapy for autoimmune diseases.
Understanding Autoimmune Diseases
Autoimmune diseases vary widely in their clinical presentation and the parts of the body they affect. For example, rheumatoid arthritis primarily targets joints, leading to chronic pain and swelling, while scleroderma involves fibrosis and vascular problems that affect the skin and internal organs. Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis, result from impaired intestinal barrier function and abnormal immune responses in the gut. Systemic lupus erythematosus involves the production of autoantibodies that deposit in multiple organs, causing inflammation and tissue damage. Psoriasis affects the skin through immune cell interactions that drive excessive inflammation. Globally, autoimmune diseases impact over one billion people, with rising rates in developing countries due to environmental changes, lifestyle factors, and better diagnostic capabilities.
Treating autoimmune diseases typically requires balancing immediate symptom relief with long-term disease management. Anti-inflammatory drugs and glucocorticoids help control acute symptoms, while immunosuppressants and biologics maintain disease remission. Newer therapies, including small-molecule inhibitors targeting specific immune pathways like JAK-STAT, have been developed for patients who do not respond to conventional treatments. Despite these advances, significant challenges remain. Long-term use of medications can cause side effects such as metabolic syndrome, increased infection risk, or cardiovascular complications. Existing therapies often suppress immune responses but cannot reverse tissue damage or fibrosis, leaving patients at risk of permanent organ impairment even after symptoms improve.
The Role of Stem Cells in Autoimmune Disease Treatment
Stem cell therapy offers an innovative approach to address the limitations of traditional treatments. Different types of stem cells are being studied for their ability to modulate the immune system and repair damaged tissues. Mesenchymal stem cells, or MSCs, are among the most researched due to their immunomodulatory and regenerative properties. MSCs secrete molecules like TGF-β, prostaglandin E2, and IDO, along with exosomes containing regulatory microRNAs, which help suppress overactive immune responses while promoting regulatory immune cells that maintain balance. MSCs can also migrate to inflamed tissues and differentiate into functional cells, directly contributing to tissue repair.
Hematopoietic stem cell transplantation, or HSCT, works differently. It involves high-dose immunosuppression to remove the faulty immune system, followed by the reintroduction of stem cells to rebuild immune tolerance. HSCT has shown long-term remission potential in diseases such as scleroderma and multiple sclerosis. Induced pluripotent stem cells, or iPSCs, can be engineered to produce specific immune-regulating cells or to regenerate damaged tissues, offering precise treatment options for autoimmune conditions.
Despite these promising approaches, stem cell therapy faces challenges in clinical translation. Personalized treatments, including autologous iPSC preparation or selection of allogeneic MSCs, are complex and costly. Standardizing procedures for cell culture, differentiation, and quality control increases costs. Additionally, long-term safety data are limited, particularly regarding immune reactions to allogeneic cells. Thorough research and standardized protocols are needed to ensure that stem cell therapy can be widely adopted safely and effectively.
Trends in Stem Cell Clinical Trials for Autoimmune Diseases
Recent analyses of global clinical trial data from 2006 to 2025 provide insights into the current landscape of stem cell therapy for autoimmune diseases. Out of more than 1,500 trials, 244 met strict inclusion criteria for detailed analysis. Most trials are in early stages, with 83.6% in Phase I or Phase II. Crohn’s disease, systemic lupus erythematosus, and scleroderma are the most frequently studied conditions, highlighting high clinical interest in these diseases. The United States and China lead in the number of trials, reflecting strong governmental and institutional support for stem cell research. Academic institutions fund nearly half of the studies, though collaboration with industry remains limited, which may slow the translation of research findings into clinical practice.
The trials focus on key therapeutic strategies, including immune modulation, tissue repair, and suppression of overactive cell proliferation. Disease-specific differences in cell sources and delivery methods are evident. MSCs are the predominant stem cell type used, largely due to their strong immunoregulatory properties, safety, and allogeneic use. HSCT is applied in severe or refractory cases, while pluripotent stem cells like iPSCs are less common due to ethical concerns, tumor risk, and the need for directed differentiation.
Challenges in Clinical Translation
A major barrier to stem cell therapy is the variability in cell preparation. Differences in cell source, harvesting techniques, expansion protocols, and quality control can impact treatment outcomes. For example, MSCs derived from bone marrow, adipose tissue, or umbilical cord each have distinct properties and applications. Standardizing cell preparation and testing, including assessing cell viability, potency, and safety, is critical to improving consistency across studies.
Financial and logistical challenges also limit the widespread use of stem cell therapies. Autologous treatments are expensive and labor-intensive, while allogeneic therapies require careful immunological matching to prevent rejection. Regulatory hurdles add further complexity, as safety and efficacy must be thoroughly demonstrated before treatments can become mainstream. Long-term follow-up studies are particularly important for evaluating the durability of treatment effects and for monitoring potential adverse events.
Advances in Targeted Therapies and Delivery Methods
Clinical trials have explored novel targets and delivery strategies to enhance the effectiveness of stem cell therapy. Immune targets like CD19 and CD52 are used in therapies that aim to selectively deplete pathogenic immune cells, while growth factors secreted by stem cells support tissue repair. The routes of administration vary based on disease and cell type. MSCs are often delivered intravenously for systemic immune modulation, whereas localized injections are used for tissue repair. HSCT is uniformly administered intravenously, and epithelial stem cells are transplanted directly to target tissues. Emerging technologies, such as MSCs combined with drug-loaded nanoparticles or injectable hydrogels, are being developed to extend therapeutic effects and reduce the frequency of treatments.
Clinical Outcomes and Effectiveness
Stem cell therapies have demonstrated promising results in several autoimmune diseases. In systemic lupus erythematosus, allogeneic MSCs have induced complete or partial remission in roughly half of patients with refractory disease. HSCT in SLE and scleroderma shows long-term disease modification, with improvements in organ function and symptom relief. In Crohn’s disease, local MSC injections have achieved high rates of fistula healing, whereas HSCT offers limited benefits due to its associated risks. Rheumatoid arthritis studies have shown short-term improvements in patients who have failed conventional therapies, indicating the potential of MSC therapy as an alternative treatment for refractory cases.
The source of stem cells can influence treatment outcomes. Umbilical cord-derived MSCs are particularly useful in systemic lupus erythematosus due to their immunomodulatory potential and ability to differentiate into multiple cell types. Bone marrow- and adipose-derived MSCs are commonly used for localized tissue repair, such as in Crohn’s disease. Ongoing research aims to refine stem cell selection, identify subpopulations with optimal therapeutic effects, and develop precision therapies tailored to individual patients.
Future Directions in Stem Cell Therapy
The future of stem cell therapy in autoimmune diseases lies in technological innovation, international collaboration, and precision medicine. Advances in gene editing, such as CRISPR-Cas9, allow for enhanced stem cell function and tracking, while multi-omics analyses can help identify the most effective cell subpopulations. Establishing stem cell banks, similar to Japan’s iPSC Bank, can address limitations of autologous stem cells and facilitate wider access. Precision medicine approaches, including biomarker-based patient stratification, real-time monitoring of treatment response, and integration of genetic and microbiome data, can help tailor therapies to individual needs. Large-scale, multicenter clinical studies and real-world data collection will be crucial for assessing the safety and effectiveness of stem cell therapies.
Combining stem cell therapy with other treatments, improving delivery methods, and targeting multiple pathways simultaneously may further enhance outcomes. For example, MSCs combined with drug-loaded nanoparticles or hydrogels can provide sustained anti-inflammatory effects, while engineered stem cells can selectively regulate immune responses and repair damaged tissues. By integrating these strategies, future therapies may offer safer, more effective, and cost-efficient options for patients with autoimmune diseases.
Implications for Clinical Practice and Future Research
Stem cell therapy represents a promising frontier in the treatment of autoimmune diseases. Clinical trials indicate significant potential for conditions such as Crohn’s disease, systemic lupus erythematosus, and scleroderma, though most studies are still in early stages. Current therapies focus on immune regulation, tissue repair, and the suppression of overactive cells, but challenges such as high costs, limited long-term safety data, and variability in cell preparation persist. Technological innovation, global collaboration, and precision medicine will be essential to overcome these challenges. With continued research and clinical development, stem cell therapy has the potential to provide patients with safer, more effective, and individualized treatment options that go beyond symptom management to address the underlying mechanisms of autoimmune disease.
Source: Chen Y, Li X, Zhang J, Peng J, Huang F, Bao J, Fan Y and Huang S (2025) Global clinical trials on stem cell therapy for autoimmune diseases: trends and future directions. Front. Immunol. 16:1616231. doi: 10.3389/fimmu.2025.1616231
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