Uncontrolled inflammation is a major impediment to tissue engineering, regeneration and reconstruction of both diseased and injured tissues resulting in further tissue injury, tissue scarring and fibrosis. Stem cell activity is disrupted by persistent signals promoting inflammation, whereas specific anti-inflammatory signals enhance stem cell activity. In successful regeneration, mesenchymal stem cells assume an anti-inflammatory phenotype. Specialized Proresolving lipid Mediators (SPMS), including Lipoxin A4 (LXA4), attenuate the dental stem cell inflammatory response. Resolution of inflammation is an active biochemical and metabolic process, not merely a passive termination of inflammation, mediated by SPMs. SPMs activate wound healing with tissue regeneration instead of fibrosis and scarring and directly improve bone healing and regeneration, including in periodontitis. Human periodontal ligament stem cells release SPMs, including lipoxin, to regulate immunomodulatory and pro-healing properties. Characterizing the biomimetic properties of SPMs in humans is hampered by a lack of suitable large animal models. There is a critical need for a validated large animal regeneration model to test therapeutic potential of SPMs for translation to humans. Our goal is to determine the pathways to regeneration that control local inflammation and enhance mesenchymal stem cell differentiation into connective tissues, including bone. The Central Hypothesis is that resolution of inflammation pathways and mediators can promote regeneration of the periodontal organ (bone, cementum and periodontal ligament) by directing stem cell phenotype, proliferation and differentiation. In this application, we will use a large animal model to dissect the SPM pathways leading to periodontal ligament stem cell control of regeneration. In this proposal, we will: 1: Provide direct evidence for SPM production by Yorkshire miniature pig periodontal ligament stem cells (mpPDLSC) by determining the lipid mediator profile of mpPDLSC; 2: Determine stem cell function in miniature pig by determining mpPDLSC proliferation and response to SPMs, and determination of synthetic enzyme expression, signaling pathways and SPM receptor expression, and 3: Demonstrate SPM enhanced stem cell mediated periodontal regeneration in Miniature Pigs using SPM local delivery to enhance periodontal regeneration alone or in combination with transplanted, ex vivo expanded miniature pig stem cells. Results from these studies will advance our practical clinical knowledge of dose and delivery of lipoxins in tissue regeneration, identify potential new molecular targets, and further develop and characterize a large animal model to test novel stem cell-based strategies for translation to human oral and craniofacial tissue regeneration. The research team comprises experts in periodontal regeneration, biochemistry, and large animal models.

Public Health Relevance

Uncontrolled inflammation is a major impediment to tissue engineering, regeneration and reconstruction of both diseased and injured tissues. Stem cells are hampered activity by inflammation, but certain anti- inflammatory signals enhance stem cell activity. Specialized Proresolving lipid Mediators (SPMS), including Lipoxin A4 (LXA4), attenuate the dental stem cell inflammatory response. Our goal is to determine the pathways to regeneration that control local inflammation and enhance mesenchymal stem cell differentiation into connective tissues, including bone. Results from these studies will advance our practical clinical knowledge of dose and delivery of lipoxins in tissue regeneration, identify potential new molecular targets, and further develop and characterize a large animal model to test novel stem cell-based strategies for translation to human oral and craniofacial tissue regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE025020-05
Application #
9817440
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lumelsky, Nadya L
Project Start
2015-05-01
Project End
2024-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Forsyth Institute
Department
Type
DUNS #
062190616
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Sima, Corneliu; Montero, Eduardo; Nguyen, Daniel et al. (2018) Author Correction: ERV1 Overexpression in Myeloid Cells Protects against High Fat Diet Induced Obesity and Glucose Intolerance. Sci Rep 8:4143
Mizraji, Gabriel; Heyman, Oded; Van Dyke, Thomas E et al. (2018) Resolvin D2 Restrains Th1 Immunity and Prevents Alveolar Bone Loss in Murine Periodontitis. Front Immunol 9:785
El Kholy, Karim; Freire, Marcelo; Chen, Tsute et al. (2018) Resolvin E1 Promotes Bone Preservation Under Inflammatory Conditions. Front Immunol 9:1300
Van Dyke, T E; Diaz, P I; Moutsopoulos, N et al. (2018) Task Force on Design and Analysis in Oral Health Research: Host-Microbiome Interactions in Dysbiosis. JDR Clin Trans Res 3:6-9
Serhan, Charles N (2017) Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. FASEB J 31:1273-1288
Freire, Marcelo O; Dalli, Jesmond; Serhan, Charles N et al. (2017) Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes. J Immunol 198:718-728
Manosudprasit, Aggasit; Kantarci, Alpdogan; Hasturk, Hatice et al. (2017) Spontaneous PMN apoptosis in type 2 diabetes and the impact of periodontitis. J Leukoc Biol 102:1431-1440
Damgaard, C; Kantarci, A; Holmstrup, P et al. (2017) Porphyromonas gingivalis-induced production of reactive oxygen species, tumor necrosis factor-?, interleukin-6, CXCL8 and CCL2 by neutrophils from localized aggressive periodontitis and healthy donors: modulating actions of red blood cells and resolvin E1 J Periodontal Res 52:246-254
Van Dyke, Thomas E (2017) Pro-resolving mediators in the regulation of periodontal disease. Mol Aspects Med 58:21-36
Papathanasiou, E; Trotman, C A; Scott, A R et al. (2017) Current and Emerging Treatments for Postsurgical Cleft Lip Scarring: Effectiveness and Mechanisms. J Dent Res 96:1370-1377

Showing the most recent 10 out of 17 publications