Fibroblast Cells vs. Stem Cells: A Superior Option for Chronic Disease Therapy

Fibroblasts—as much or even more than stem cells—look like the key to new and transformational treatments of chronic diseases, including multiple sclerosis and rheumatoid arthritis.  This reality represents a paradigm shift that will impact medicine in dramatically and positive ways.

Publications have indicated that mesenchymal stem cells (MSCs) and fibroblasts share many surface markers in common, are phenotypically indistinguishable (1), can differentiate into various cell types, including adipocytes, chondrocytes, osteoblasts, hepatocytes, and cardiomyocytes, and can regulate the immune system (2). However, transcriptomics and epigenetics studies have indicated a clear difference between the two cell types(3).

Fibroblast cells offer distinct advantages over stem cells in therapeutic applications and the treatment of chronic diseases. The therapeutic potential of the immune regulatory capability of MSCs in treating degenerative diseases has been demonstrated in multiple sclerosis (MS), sepsis, diabetes, rheumatoid arthritis, and various other autoimmune disorders (4-7). Their prevalence, robust proliferation, stability, immune modulation, and regenerative functions set them apart as a potential superior cell type. These attributes position fibroblasts not only at the forefront of biomedical research but also as practical tools for developing advanced therapies for persistent health challenges.

Proliferation and Robustness

A distinguishing feature of fibroblast cells is their significantly faster proliferation rate compared to stem cells, with a doubling time of approximately 24 hours, as opposed to 48 hours or more for stem cells (8). Furthermore, fibroblasts can be passaged to a higher number as compared to stem cells without a significant increase in the percentage of senescent cells. Their stability in culture, even after numerous passages, renders fibroblasts a reliable resource for clinical settings that require consistent cell purity and viability at scale. In contrast, stem cells have been demonstrated to be more sensitive to environmental conditions, with a highly variable spontaneous differentiation rate that complicates their manufacturing at scale for clinical use (9-11).

Practical Harvesting and Expansion

Fibroblasts are far more prevalent and easier to source in large quantities from various human biological sources as compared to stem cells. Publications indicate a ratio of 1:5000 to 1:15000 compared to stem cells, which renders them easier and more ethical to source (12-15). This accessibility means fewer ethical concerns and a less resource-intensive process compared to the extraction of bone marrow stem cells. The ease of expansion in vitro translates into lower operational costs and swifter production timelines for cell-based therapies.

Potential Therapeutic Superiority for Chronic Diseases

Chronic diseases such as multiple sclerosis (MS), rheumatoid arthritis, and fibrotic disorders represent significant challenges for global health systems. Fibroblast cell therapy has demonstrated strong potential in these areas by exerting long-lasting immune modulation and anti-inflammatory effects. Fibroblasts’ inherent ability to regulate immune responses rivals, and often surpasses, that of stem cells(16-18). For example, preclinical studies have shown that fibroblasts can suppress inflammatory lymphocyte proliferation and influence macrophage activity, thereby providing benefits for chronic inflammatory and autoimmune conditions.

Regenerative Medicine and Wound Healing

Fibroblasts play a central role in wound healing and tissue regeneration. While mesenchymal stem cells (MSCs) are somewhat limited in their regenerative capabilities due to source and availability, fibroblasts consistently deposit extracellular matrix and produce collagen and fibronectin—essential components for tissue repair (19-23). Fibroblast-based products are already revolutionizing clinical applications such as skin grafts for diabetic foot ulcers and surgical wounds, where they support rapid closure and long-term stability.

Immune Modulation and Anti-Inflammatory Properties

Fibroblasts share many characteristics with MSCs, including surface markers and the ability to differentiate into multiple cell types (adipocytes, chondrocytes, osteoblasts). They are exceptionally effective at suppressing inflammatory responses, orchestrating the resolution of inflammation, and acting as mediators for tissue-specific immune responses(17, 18). This robust immune modulation allows fibroblasts to be leveraged for treatments that require both regeneration and control of destructive inflammation in diseases such as MS, sepsis, and type 1 diabetes.

Heterogeneity and Disease-Specific Targeting

Unlike stem cells, which may require directed differentiation and pose a risk of tumorigenicity, fibroblasts possess a remarkable diversity of phenotypes that can be harnessed for personalized medicine. Advances in single-cell sequencing and imaging now enable the precise targeting of pathological fibroblast states, allowing for tailored therapies that address the unique microenvironments of chronic diseases (24).

Safety, Efficacy, and Future Perspectives

The therapeutic manipulation of fibroblasts—either by topical, subcutaneous, or intravenous administration potentially offers a safe, reproducible, and efficacious approach to disease modification. Fibroblast therapies circumvent many of the pitfalls associated with stem cell treatments, including potential immune rejection and the risk of uncontrolled differentiation. The growing evidence base supports the transition from classical stem cell therapies to fibroblast-based solutions, leading to improved patient outcomes.

Conclusion

In the rapidly evolving landscape of cell therapy, fibroblasts clearly outpace traditional stem cells in terms of practical scalability or clinical use, potential therapeutic effectiveness, and disease-modifying potential. Their demonstrated roles in wound healing, chronic disease management, and immune regulation position fibroblasts as a potentially more suitable tool for today’s regenerative medicine and tomorrow’s innovative treatments. The future belongs to those who recognize and harness the untapped power of fibroblast cells.

References

1. M. Soundararajan, S. Kannan, Fibroblasts and mesenchymal stem cells: Two sides of the same coin? J Cell Physiol 233, 9099-9109 (2018).
2. R. A. Denu et al., Fibroblasts and Mesenchymal Stromal/Stem Cells Are Phenotypically Indistinguishable. Acta Haematol136, 85-97 (2016).
3. C. Fan et al., Single-Cell Transcriptome Integration Analysis Reveals the Correlation Between Mesenchymal Stromal Cells and Fibroblasts. Front Genet 13, 798331 (2022).
4. J. A. Cohen et al., Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Mult Scler 24, 501-511 (2018).
5. F. Locatelli, M. Algeri, V. Trevisan, A. Bertaina, Remestemcel-L for the treatment of graft versus host disease. Expert Rev Clin Immunol 13, 43-56 (2017).
6. J. M. Álvaro-Gracia et al., Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial. Ann Rheum Dis 76, 196-202 (2017).
7. L. F. Newell, R. J. Deans, R. T. Maziarz, Adult adherent stromal cells in the management of graft-versus-host disease. Expert Opin Biol Ther 14, 231-246 (2014).
8. H. I. Huang et al., Multilineage differentiation potential of fibroblast-like stromal cells derived from human skin. Tissue Eng Part A 16, 1491-1501 (2010).
9. Y. H. Song et al., VEGF is critical for spontaneous differentiation of stem cells into cardiomyocytes. Biochem Biophys Res Commun 354, 999-1003 (2007).
10. M. Matsuo-Takasaki et al., Complete suspension culture of human induced pluripotent stem cells supplemented with suppressors of spontaneous differentiation. Elife 12, (2024).
11. T. Yamamoto, M. Arita, H. Kuroda, T. Suzuki, S. Kawamata, Improving the differentiation potential of pluripotent stem cells by optimizing culture conditions. Sci Rep 12, 14147 (2022).
12. M. F. Pittenger, B. J. Martin, Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 95, 9-20 (2004).
13. M. D. Lynch, F. M. Watt, Fibroblast heterogeneity: implications for human disease. J Clin Invest 128, 26-35 (2018).
14. L. Xu, G. Li, Circulating mesenchymal stem cells and their clinical implications. Journal of Orthopaedic Translation 2, 1-7 (2014).
15. R. Hass, C. Kasper, S. Böhm, R. Jacobs, Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal 9, 12 (2011).
16. Y. Liu et al., Fibroblasts: Immunomodulatory factors in refractory diabetic wound healing. Front Immunol 13, 918223 (2022).
17. K. J. Cavagnero, R. L. Gallo, Essential immune functions of fibroblasts in innate host defense. Front Immunol 13, 1058862 (2022).
18. X. Chen, F. Chen, S. Jia, Q. Lu, M. Zhao, Antigen-presenting fibroblasts: emerging players in immune modulation and therapeutic targets. Theranostics 15, 3332-3344 (2025).
19. M. Xue, R. Zhao, L. March, C. Jackson, Dermal Fibroblast Heterogeneity and Its Contribution to the Skin Repair and Regeneration. Adv Wound Care (New Rochelle) 11, 87-107 (2022).
20. S. Barrientos, O. Stojadinovic, M. S. Golinko, H. Brem, M. Tomic-Canic, Growth factors and cytokines in wound healing. Wound Repair Regen 16, 585-601 (2008).
21. L. E. Tracy, R. A. Minasian, E. J. Caterson, Extracellular Matrix and Dermal Fibroblast Function in the Healing Wound. Adv Wound Care (New Rochelle) 5, 119-136 (2016).
22. I. A. Darby, T. D. Hewitson, Fibroblast differentiation in wound healing and fibrosis. Int Rev Cytol 257, 143-179 (2007).
23. I. A. Darby, B. Laverdet, F. Bonté, A. Desmoulière, Fibroblasts and myofibroblasts in wound healing. Clin Cosmet Investig Dermatol 7, 301-311 (2014).
24. K. Wei, H. N. Nguyen, M. B. Brenner, Fibroblast pathology in inflammatory diseases. J Clin Invest 131, (2021).