Yonsei Med J.  2017 Sep;58(5):1031-1039. 10.3349/ymj.2017.58.5.1031.

Immune Tolerance of Human Dental Pulp-Derived Mesenchymal Stem Cells Mediated by CD4⁺CD25⁺FoxP3⁺ Regulatory T-Cells and Induced by TGF-β1 and IL-10

Affiliations
  • 1Department of Plastic & Reconstructive Surgery, College of Medicine, Yonsei University, Seoul, Korea. hsaturn@hanmail.net
  • 2Institute for Human Tissue Restoration, College of Medicine, Yonsei University, Seoul, Korea.
  • 3Department of Orthodontics, College of Dentistry, Yonsei University, Seoul, Korea.
  • 4Yujin Plastic Surgery, Seoul, Korea.

Abstract

PURPOSE
Most studies on immune tolerance of mesenchymal stem cells (MSCs) have been performed using MSCs derived from bone marrow, cord blood, or adipose tissue. MSCs also exist in the craniofacial area, specifically in teeth. The purpose of this study was to evaluate the mechanisms of immune tolerance of dental pulp-derived MSC (DP-MSC) in vitro and in vivo.
MATERIALS AND METHODS
We isolated DP-MSCs from human dental pulp and co-cultured them with CD4⁺ T-cells. To evaluate the role of cytokines, we blocked TGF-β and IL-10, separately and together, in co-cultured DP-MSCs and CD4⁺ T-cells. We analyzed CD25 and FoxP3 to identify regulatory T-cells (Tregs) by fluorescence-activated cell sorting (FACS) and real-time PCR. We performed alloskin grafts with and without DP-MSC injection in mice. We performed mixed lymphocyte reactions (MLRs) to check immune tolerance.
RESULTS
Co-culture of CD4⁺ T-cells with DP-MSCs increased the number of CD4⁺CD25⁺FoxP3⁺ Tregs (p<0.01). TGF-β or/and IL-10 blocking suppressed Treg induction in co-cultured cells (p<0.05). TGF-β1 mRNA levels were higher in co-cultured DP-MSCs and in co-cultured CD4⁺ T-cells than in the respective monocultured cells. However, IL-10 mRNA levels were not different. There was no difference in alloskin graft survival rate and area between the DP-MSC injection group and the non-injection group. Nonetheless, MLR was reduced in the DP-MSC injected group (p<0.05).
CONCLUSION
DP-MSCs can modulate immune tolerance by increasing CD4⁺CD25⁺FoxP3⁺ Tregs. TGF-β1 and IL-10 are factors in the immune-tolerance mechanism. Pure DP-MSC therapy may not be an effective treatment for rejection, although it may module immune tolerance in vivo.

Keyword

Dental pulp; mesenchymal stem cell; immune tolerance

MeSH Terms

Allografts/immunology
Animals
Biomarkers/metabolism
CD4 Antigens/*metabolism
Cell Proliferation/drug effects
Coculture Techniques
Dental Pulp/*cytology
Forkhead Transcription Factors/metabolism
Graft Survival/immunology
Humans
*Immune Tolerance/drug effects
Interleukin-10/*pharmacology
Interleukin-2 Receptor alpha Subunit/*metabolism
Lymphocyte Culture Test, Mixed
Mesenchymal Stem Cell Transplantation
Mesenchymal Stromal Cells/cytology/*immunology
Mice, Inbred BALB C
Real-Time Polymerase Chain Reaction
Skin Transplantation
T-Lymphocytes, Regulatory/drug effects/*immunology
Transforming Growth Factor beta1/*pharmacology
Biomarkers
CD4 Antigens
Forkhead Transcription Factors
Interleukin-2 Receptor alpha Subunit
Transforming Growth Factor beta1
Interleukin-10
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