Dental and Craniofacial Stem Cell Biology

Staff: Cooper, Scheven, Shelton, Tomson, Camilleri

Our Pulp Biology and Regenerative Endodontics research programme aims to better understand the relationship between the tissue injury events which occur during disease and regenerative processes, focusing on stem / progenitor cells involved in the regenerative events along with matrix-mediated cellular signalling processes. The selection and isolation of stem cells with dentinogenic potentiality is now providing a tangible approach for clinical translation to develop new regenerative therapies.

This work is further facilitated through our studies on novel hydrogel technologies which can be used to enable de novo dentinogenesis events. The role played by materials such as hydraulic cements in vital pulp therapy and regenerative endodontic procedures on the local release matrix-bound growth factors which beneficially modulate pulp cell response is investigated. Our research on the role of calcium ion release and the interplay between cell proliferation antimicrobial characteristics has led to the understanding of the pathways to development of smart materials with specific properties.

Our work is making significant contributions at the cutting-edge of regenerative endodontic research by characterising novel growth factors in this process and determining their modes of action in fundamental tissue repair-associated processes such as cell proliferation, differentiation, angiogenesis, chemotaxis and mineralisation. We are also making significant in-roads into our understanding of the interactions between the inflammatory and tertiary dentinogenic responses. Research has identified several molecules that have pleiotropic effects and that the doses and temporal expression of these factors along with interaction with matrix molecules may be critical to their cellular signalling of inflammatory/immune or regenerative events in the diseased pulp.

Staff: Cooper, Shelton, Scheven

Our research in this area is aimed at obtaining a better understanding of the therapeutic potential of a range of stem cell-types and their role in craniofacial tissue regeneration. We are working with stem cells derived from bone marrow, adipose, dental pulp and, periodontal ligament tissues and are characterising their roles and responses in 2D and 3D standard culture and biomimetic environments.

Our aims include the identification and generation of conditions that can be used to better understand the role of these cell types in tissue repair. Our studies have compared the effect of cell sorting, cryopreservation and differentiation approaches on different stem cell types. Furthermore we are characterising the role of the secretomes and exosomes on osteogenic/-clastogenic, angiogenic and immune cell responses. Our findings have already highlighted that different stem cells cultured under different conditions in vitro may offer different therapeutic potential via the molecules they release. These findings may have significant therapeutic potential for tissue repair in dental diseases such as caries and periodontitis as well as in craniofacial bone regeneration following disease or trauma.

Staff: Scheven, Cooper, Walmsley

Past and current PhD students: Ben Mead, Arwa Al-Maswary, Nessma Sultan

Our research group is evaluating the role and application of dental mesenchymal stem cells for neural repair. The research uses specialised models to study the neurogenic cell differentiation potential of dental and mesenchymal stem cells as well as the role and effects of stem cell-derived trophic factors (secretome and exosomes) in neural injury and disease. Research focuses on the therapeutic use of DPSC in retinal & optic nerve injury following (head) trauma or neurodegenerative disease such as glaucoma.

We have obtained promising evidence that DPSC represent a potentially advantageous paracrine-mediated cell therapy for neuroprotection of retinal neuronal cells (retinal ganglion cells) and retinal nerve axon regeneration. Investigations are also undergoing to study the trophic effects of dental pulp stem cells in craniofacial (trigeminal) nerve regeneration as well as effects of low-intensity ultrasound on neuronal cells. Research is aiming to elucidate the precise trophic mechanisms of action by the stem cells and the development of a clinically suitable & translatable stem cell-based therapies.

Staff: Walmsley, Scheven, Shelton, Cooper

Ultrasound has various medical applications . Our research group is exploring the use of ultrasound as a non-invasive physical therapy for dental tissue healing and repair. The tooth is a hard mineralised structure with a living soft pulpal tissue core capable to respond to outside stimuli including physical forces. We study how ultrasound penetrates and travels in dental tissues and how it affects the reparative activities of the living cells within the core of the teeth. Our research has demonstrated that ultrasound in the low frequency range, generally used in dentistry for dental scaling, is able to stimulate both odontoblasts and dental pulp cells which are involved in dentine formation and repair.

The research represents a true multidisciplinary collaboration involving experts from physics, engineering, biology, biomaterials and dentistry. Mathematical simulation models are being developed to analyse low frequency & low intensity ultrasound transmission within dental tissues which will be compared with ultrasound-induced bio-effects in different experimental tooth models. Our studies also investigate whether ultrasound is able to activate and stimulate stem cells to support healing of dental and bone tissues.

The outcome of our studies is to exploit the development of a new ultrasound and non-invasive therapeutic devices that can be used in the clinic for dental, periodontal, bone and craniofacial repair, thereby promoting oral health and ultimately human health.

• FAPESP grant (The University of Birmingham and the University of Nottingham collaborative Research Program); 'Epigenetic regulation of osteogenic potential in mesenchymal stem cells derived from periodontal ligament' (2017-2020). Investigators: Dr G Wiench, Dr B Scheven, Dr D Andia.
• EPSCR Programme grant “Surgery enabled by ultrasonics (“Ultrasurge”) (2018-2023). Investigators: Prof D Walmsley, Dr B Scheven,  Dr D Shelton, Prof P Cooper.
• Rosetrees Trust grant. Development of a novel stem cell therapy for optic nerve damage (2013-2015). Investigators: Dr B Scheven, Dr W Leadbeater, Prof A Logan.

• Sultan N, Amin LE, Zaher AR, Grawish ME, and Scheven BA. Neurotrophic Effects of Dental Pulp Stem Cells on Trigeminal Neuronal Cells.  Scientific Reports 10, 19694 (2020)
• Petridis X, Beems BP, Tomson P, Scheven B, Giepmans B, Kuipers J, van der Sluis L, Harmsen MC (2018) Effect of dentin matrix components on the mineralization of human mesenchymal stromal cells. Tissue Eng Part A. 2018 Nov 16. doi:10.1089/ten.TEA.2018.0192.
• Marrelli Massimo, Codispoti Bruna, Shelton Richard M., Scheven Ben A., Cooper Paul R., Tatullo Marco, Paduano Francesco (2018) Dental Pulp Stem Cell Mechanoresponsiveness: Effects of Mechanical Stimuli on Dental Pulp Stem Cell Behavior. Frontiers in Physiology 9, 2018, 1685, DOI=10.3389/fphys.2018.01685   
• Gao Q, Cooper PR, Walmsley AD, Scheven BA (2017) Role of Piezo Channels in Ultrasound-stimulated Dental Stem Cells. Journal of Endodontics 43(7), pp. 1130-1136.
• Gao Q, Walmsley AD, Cooper PR, and Scheven BA (2016) Ultrasound Stimulation of Different Dental Stem Cell Populations: Role of Mitogen-activated Protein Kinase Signaling. Journal of  Endodontics 42(3), pp. 425-431.
• Mead B, Logan A, Berry M, Leadbeater W, Scheven BA. Dental pulp stem cells: A novel cell therapy for retinal and central nervous system repair (2017) Stem Cells 35(1):61-67
• Mead B, Hill LJ, Blanch RJ, Ward K, Logan A, Berry M, Leadbeater W, Scheven BA (2016) Mesenchymal stromal cell-mediated neuroprotection and functional preservation of retinal ganglion cells in a rodent model of glaucoma. Cytotherapy 18(4), pp. 487-496.
• B Mead, A Logan, M Berry, W Leadbeater, BA Scheven (2014) Paracrine-mediated neuroprotection and neuritogenesis of axotomised retinal ganglion cells by human dental pulp stem cells: comparison with human bone marrow and adipose-derived mesenchymal stem cells. PloS One 9: e109305.
• Cooper PR, Holder MJ, Smith AJ. Inflammation and regeneration in the dentin-pulp complex: a double-edged sword. J Endod. 2014 Apr;40(4 Suppl):S46-51. doi: 10.1016/j.joen.2014.01.021.
• Davies OG, Smith AJ, Cooper PR, Shelton RM, Scheven BA. The effects of cryopreservation on cells isolated from adipose, bone marrow and dental pulp tissues. Cryobiology. 2014 Oct;69(2):342-7. doi: 10.1016/j.cryobiol.2014.08.003. Epub 2014 Aug 12.
• Davies OG, Cooper PR, Shelton RM, Smith AJ, Scheven BA. A comparison of the in vitro mineralisation and dentinogenic potential of mesenchymal stem cells derived from adipose tissue, bone marrow and dental pulp. J Bone Miner Metab. 2014 Jul 6.
• Petridis X, Beems BP, Tomson PL, Scheven B, Giepmans BNG, Kuipers J, van der Sluis LWM, Harmsen MC. Effect of Dentin Matrix Components on the Mineralization of Human Mesenchymal Stromal Cells. Tissue Eng Part A. 2019 Aug;25(15-16):1104-1115
• Koutroulis A, Kuehne SA, Cooper PR, Camilleri J (2019) The role of calcium ion release on biocompatibility and antimicrobial properties of hydraulic cements. Sci Rep. 9(1): 19019.
• Mead B and Scheven BA (2015) Mesenchymal stem cell therapy for retinal ganglion cell neuroprotection and axon regeneration. Neural Regen Res. 10:371-373
• Mead B, Berry M, Logan A, Scott RA, Leadbeater W, Scheven BA (2015) Stem cell treatment of degenerative eye disease. Stem Cell Res 14:243-257.
• Mead B, Logan A, Berry M, Leadbeater W, Scheven BA (2014) Adult stem cell treatment for central vervous system injury. Current Tissue Engineering 3: 93-101
• B Mead, A Logan, M Berry, W Leadbeater, BA Scheven (2014) Dental pulp stem cells, a paracrine-mediated therapy for the retina. Neural Regen Research 9: 577-578. 
• Upen US, Ghorayeb SR,  Yamashita Y, Atanda F, Walmsley AD, Scheven BA (2015)  Ultrasound field characterization and bioeffects in multiwell culture plates. J Ther Ultrasound.
• SR Ghorayeb, U Patel, AD Walmsley, BA Scheven (2013) Biophysical characterisation of low-frequency ultrasound interaction with dental pulp stem cells. J Ther Ultrasound 1:12. 
• J Man, RM Shelton, G Landini, PR Cooper, BA Scheven (2012). Low intensity ultrasound stimulates osteoblast migration at different frequencies. J Bone Miner Metab 30: 602-607
• J Man, RM Shelton, PR Cooper, BAA Scheven (2012) Low-intensity low-frequency ultrasound promotes proliferation and differentiation of odontoblast-like cells. J Endod 38: 608-613.

Principal Investigators

• Professor Damien Walmsley

Postdocs

• Dr D Gupta (Ultrasurge)

Students

•  Arwa Al-Masary
• Nessma Sultan
• Jasper Natarajan
• Olga Yevlashevskaya
• Lisa Shriane
• Satnam Virdee