Definitions & Identification
Mesenchymal stem cells (MSCs) are multipotent stromal cells capable of differentiating into various cell types, including osteoblasts (bone), chondrocytes (cartilage), myocytes (muscle), and adipocytes (fat).
The term mesenchymal stem cell was introduced in 1991 by Arnold Caplan.
“Mesenchymal stem cells (MSCs) are adult stem cells with the ability to differentiate into various types of mesoderm-derived cells, showing promising results in preclinical studies for various medical conditions.”
ISCT Minimal Criteria (2006):
- Must be plastic-adherent under standard culture conditions.
- Express CD105, CD73, and CD90, while lacking CD45, CD34, CD14/CD11b, CD79α/CD19, and HLA-DR.
- Must demonstrate in vitro differentiation into osteoblasts, adipocytes, and chondroblasts.
MSCs often represent a heterogeneous population; only a subset shows true multipotency.
Criterion
Description
Plastic adherence
Retention in standard culture
Surface markers (+)
CD105, CD73, CD90 ≥95%+
Surface markers (−)
CD45, CD34, CD14/CD11b, CD79α/CD19, HLA-DR <2%+
Differentiation
Bone, cartilage, and fat differentiation in vitro
Historical, Clinical, and Regulatory Milestones
Publication Volume
- Over 80,000 peer-reviewed articles on MSCs as of 2025.
Clinical Research
- More than 1,760 studies with MSCs targeting over 920 conditions (May 2024).
- First clinical trials by Osiris Therapeutics (1995), involving 15 patients.
- Regulatory approvals include Canada and New Zealand (2012, GvHD) and Japan (Crohn’s disease fistula).
- Exceeding 1,500 completed clinical trials on diverse conditions.
Cancer Trials
- At least 14 registered trials as of 2020 examined MSCs in cancer therapy, with CELYVIR (MSC with oncolytic virus) reaching complete remission in one pediatric case at 3 years post-treatment.
“Among MSC-based therapies, the use of MSCs as Trojan horses to deliver therapeutic factors represents an important step forward to a more efficient cancer treatment.”
Sources and Isolation of MSCs
Tissue Origins
Bone marrow (most established source), adipose (fat) tissue, umbilical cord (Wharton's jelly), cord blood, placenta, menstrual blood, dental pulp, synovial fluid, muscle, hair follicles, and teeth.
Yield
Adipose-derived MSCs are safer and produce larger yields than bone marrow.
Wharton's Jelly MSCs offer primitive cells in large numbers, often from normally discarded tissue after childbirth.
In amniotic fluid, up to 1 in 100 cells from amniocentesis are MSCs.
Functional Properties & Differentiation
- Self-renewal: MSCs can proliferate extensively in culture.
- Differentiation: Standard confirmation by generating osteoblasts, adipocytes, chondrocytes; reports also show plasticity towards myocytes, neurocytes, hepatocytes, pancreatic, endothelial, and epithelial cells.
- Citations: The pivotal Pittenger et al. (1999, Science) study has accumulated over 30,000 citations by 2025.
Immunomodulatory and Therapeutic Roles
Immunomodulation
MSCs secrete factors (TGFβ, IDO, IL-10, TNFα, IFNγ, PGE2, nitric oxide) that suppress tumor growth, reduce inflammation, and regulate immune responses. This enables their use in autoimmune diseases, GvHD, Crohn’s, MS, lupus, systemic sclerosis, and RA.
Homimg Ability
MSCs use CXCL12/CXCR4 and multiple chemokine receptors (CCR1–10, CXCR1–6) for site-specific migration.
Clinical Results
The EBMT MSC Expansion Consortium (2006) treated severe GvHD in 40 patients with a median MSC dose of 1.0×10^6 cells/kg, achieving 19 complete remissions with no adverse events.
“As of January 2025, [the Pittenger et al. 1999 Science] paper has been cited over 30,000 times.”
Clinical and Research Outcomes
Pediatric Bone Disorders
Horwitz et al. (2002): Engraftment post-BMT led to growth acceleration in 5/6 children with osteogenesis imperfecta.
Neurological Disorders
Koc et al. (2002): Four of six children with metachromatic leukodystrophy showed improved nerve conduction after MSC infusion.
Cancer & Regenerative Medicine
MSCs can act as 'Trojan horses' to deliver engineered agents (e.g., IFNβ, interleukins, chemotherapeutics) directly to tumors, increasing effectiveness and reducing systemic toxicity.
Scaffold and hydrogel technologies bolster MSC retention and anti-tumor effects.
Safety
To date, infusion into over a hundred patients—including children—has resulted in no serious adverse events, supporting a strong safety profile.
Double-Edged Sword in Cancer
Anti-Tumor Effects: MSCs induce tumor cell apoptosis via TRAIL, downregulate PI3K/AKT, inhibit ERK1/2, and block Wnt and angiogenic signaling.
Pro-Tumor Risks: MSCs may also promote tumor growth through secretion of CCL5, VEGF, TGFβ, IL-6, and potential differentiation into cancer-associated fibroblasts, which support the tumor microenvironment.
Clinical Context: The effect depends strongly on MSC source, patient characteristics, cancer type, dosing, and delivery route.
“Bone marrow has a limited mesenchymal stem cell pool that depletes with age and after disease. … This is one major reason bones fail to regenerate in osteoporotic conditions.”
Challenges and Future Directions
- Heterogeneity: Wide inter-donor variability complicates standardization and reproducibility.
- Diminished Yield: Aging and disease reduce bone marrow MSC numbers, limiting regenerative capacity.
- Translational Barriers: Disparities in isolation/expansion protocols and marker panels impede wider adoption.
- Therapeutic Uncertainties: Optimal dosing, cell retention, and long-term efficacy await further elucidation.
- Safety & Efficacy: New technologies—standardized carriers, exosome-based, or cell-free approaches—are being developed; regulatory safety and monitoring remain paramount.
Table: Key Quantitative and Qualitative Data
Category
Data/Findings
ISCT Definition (2006)
CD105+, CD73+, CD90+, and CD45−, CD34−, CD14/CD11b−, CD79α/CD19−, HLA-DR−
Peer-reviewed MSC papers (2025)
>80,000
Clinical trials listed (May 2024)
>1,760 studies for over 920 conditions
MSCs Clinical Research (Cancer)
≥14 cancer therapy trials (2020); CELYVIR: 1 pediatric full remission (3 years)
MSC Dosing (GvHD trial, 2006)
Median: 1.0×10^6 cells/kg (range: 0.4–9×10^6)
Adipose MSC yield
Higher & easier extraction than bone marrow
Amniotic MSCs
1 in 100 cells in amniotic fluid may be MSCs
Pittenger et al. (1999) Citations (2025)
>30,000
References
Wikipedia contributors. (2025, July 18). Mesenchymal stem cell. Wikipedia. https://en.wikipedia.org/wiki/Mesenchymal_stem_cell
Narzisi, A., Halladay, A., Masi, G., Novarino, G., & Lord, C. (2023). Tempering expectations: considerations on the current state of stem cells therapy for autism treatment. Frontiers in psychiatry, 14, 1287879. https://doi.org/10.1038/s41536-019-0083-6
Ding, D. C., Shyu, W. C., & Lin, S. Z. (2011). Mesenchymal stem cells. Cell transplantation, 20(1), 5–14. https://doi.org/10.3727/096368910X
Keating A. (2006). Mesenchymal stromal cells. Current opinion in hematology, 13(6), 419–425. https://doi.org/10.1097/01.moh.0000245697.54887.6f
Li, C., Wang, S., Jiang, J., Fu, W., & Zeng, J. (2025). The promise of cell-based therapies in diabetes: A review of mesenchymal stem cell applications and trials. Biochimie, 237, 54–65. https://doi.org/10.1016/j.biochi.2025.07.011
Liu, J., Gao, J., Liang, Z. et al. Mesenchymal stem cells and their microenvironment. Stem Cell Res Ther 13, 429 (2022). https://doi.org/10.1186/s13287-022-02985-y
Zhuang, WZ., Lin, YH., Su, LJ. et al. Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications. J Biomed Sci 28, 28 (2021). https://doi.org/10.1186/s12929-021-00725-7
Hmadcha, A., Martin-Montalvo, A., Gauthier, B. R., Soria, B., & Capilla-Gonzalez, V. (2020). Therapeutic potential of mesenchymal stem cells for cancer therapy. Frontiers in Bioengineering and Biotechnology, 8, Article 43. https://doi.org/10.3389/fbioe.2020.00043
Han, Y., Li, X., Zhang, Y., Han, Y., Chang, F., & Ding, J. (2019). Mesenchymal Stem Cells for Regenerative Medicine. Cells, 8(8), 886. https://doi.org/10.3390/cells8080886
Arnold I. Caplan, Mesenchymal Stem Cells: Time to Change the Name!, Stem Cells Translational Medicine, Volume 6, Issue 6, June 2017, Pages 1445–1451, https://doi.org/10.1002/sctm.17-0051
Williams, A. R., Hare, J. M., Dimmeler, S., & Losordo, D. (2011). Mesenchymal stem cells. Circulation Research, 109(8), 923–940. https://doi.org/10.1161/CIRCRESAHA.111.243147
Fitzsimmons, R. E. B., Mazurek, M. S., Soos, A., & Simmons, C. A. (2018). Mesenchymal Stromal/Stem cells in regenerative medicine and tissue engineering. Stem Cells International, 2018, 1–16. https://doi.org/10.1155/2018/8031718
Wang, L.-T., Ting, C.-H., Yen, M.-L., Liu, K.-J., Sytwu, H.-K., Wu, K. K., & Yen, B. (2016). Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: Review of current clinical trials. Journal of Biomedical Science, 23, Article 76. https://doi.org/10.1186/s12929-016-0289-5
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