Dental and Craniofacial Stem Cell Biology

In Birmingham we have a longstanding research programme in pulp biology and regenerative endodontics which aims to exploit the innate repair ability of the dentine-pulp complex.   

Furthermore we have exciting new programmes of work studying the exosomes and secretomes derived from stem cells populations to identify optimal conditions for therapeutic application. This work is already yielding significant data for clinical application particularly in the area of neurogenesis and studies are also ongoing to assess secreted molecules for their roles in bone tissue engineering strategies as well their immunomodulatory properties. We are also exploring the use of ultrasound and photobiomodulatory therapies with a view to the development of novel therapeutic devices for clinical application.

Current projects and major research areas

Pulp Biology and Regenerative Endodontics

Staff: Cooper, Scheven, Shelton, Tomson

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 may be used to enable dentinogenic repair.

The mechanistic basis of dental materials such as calcium hydroxide in pulp capping regenerative therapies has long been studied and our recent work has now demonstrated that this restorative material along with others such as Mineral Trioxide Aggregate (MTA) and Biodentine, can locally release matrix-bound growth factors which beneficially modulate pulp cell responses. Indeed 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.

Craniofacial Tissue Regeneration and Engineering 

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 osteo-genic/-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.

pic 1-scaled(Above) Osteogenic differentiation in cultures of adipose-derived stem cells (ADSC), bone marrow mesenchymal stem cells (BMSC) and dental pulp stem cells (DPSC) showing various patterns and degrees of mineralisation.

Neurogenesis and neuronal repair

Staff: Scheven, Mead (PhD student 2012-2015)
Colaborators: Logan, Leadbeater

Our research group is evaluating the role and application of dental mesenchymal stem cells for neural repair. Our multi-disciplinary and collaborative 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. Current focus is 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. 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 therapy.

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(Above) Localisation of GFP-transfected DPSC within the vitreous body of the eye following cell transplantation

Theraputic Ultrasound

Staff: Walmsley, Scheven, Cooper, Shelton, Patel
External colaborators: Prof SR Ghorayeb (Hofstra University, NY, US)

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 and craniofacial repair, thereby promoting oral health and ultimately human health.

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(Above) CT scan of a tooth (left panel), and pressure and intensity plots of (45 kHz, 31 kPa) ultrasonic wave throughout the tooth including central pulp chamber (right panel).

(From: Ghorayeb, Patel, Walmsley, Scheven, J Ther Ultrasound 1:12, 2013)

Selected publications

  • 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.
  • Tomson PL, Lumley PJ, Alexander MY, Smith AJ, Cooper PR. Hepatocyte growth factor is sequestered in dentine matrix and promotes regeneration-associated events in dental pulp cells. Cytokine. 2013 Feb;61(2):622-9. doi: 10.1016/j.cyto.2012.11.009.
  • Smith JG, Smith AJ, Shelton RM, Cooper PR. Recruitment of dental pulp cells by dentine and pulp extracellular matrix components. Exp Cell Res. 2012 Nov 1;318(18):2397-406. doi: 10.1016/j.yexcr.2012.07.008.
  • Smith AJ, Scheven BA, Takahashi Y, Ferracane JL, Shelton RM, Cooper PR. Dentine as a bioactive extracellular matrix. Arch Oral Biol. 2012 Feb;57(2):109-21. doi: 10.1016/j.archoralbio.2011.07.008.
  • 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.
  • Mead B, Logan A, Berry M, Leadbeater W, Scheven BA (2014) Adult stem cell treatment for central vervous system injury. Current Tissue Engineering 3: 93-101B
  • 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.
  • B Mead, M Berry, A Logan, W Leadbeater, BA Scheven (2013) Intravitreally transplanted dental pulp stem cells promote neuroprotection and axon regeneration of retinal ganglion cells after optic nerve injury. Invest Opthamol Visual Sci 54:7544-56.
  • Upen US, Ghorayeb SR, Yamashita Y, Atanda F, Walmsley AD, Scheven BA (2015 in press) Ultrasound field characterization and bioeffects in multiwell culture plates. J Ther Ultrasound.

Current staff

Prof Paul Cooper

Dr Ben Scheven

Prof Damien Walmsley

Mr Upen Patel

Dr Dick Shelton

Dr Phil Tomson