A NOVEL COMBINATORIAL THERAPY WITH PULP STEM CELLS AND GRANULOCYTE COLONY-STIMULATING FACTOR FOR TOTAL PULP REGENERATION

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AUTORS

Koichiro Iohara,a Masashi Murakami,a Norio Takeuchi,a,b Yohei Osako,a Masataka Ito,c Ryo Ishizaka,a,d Shinji Utunomiya,e Hiroshi Nakamura,b Kenji Matsushita,f and Misako Nakashimaa

Departments of aDental Regenerative Medicine and

fOral Disease Research, Center of Advanced Medicine for Dental and Oral Diseases, National Center for Geriatrics and Gerontology, Research Institute, Obu, Japan;

Departments of bEndodontology and

dPediatric Dentistry, School of Dentistry, Aichi-gakuin University, Nagoya, Japan;

cDepartment of Developmental Anatomy and Regenerative Medicine, National Defense Medical College, Tokorozawa, Japan;

eDrug Safety Research Laboratories, Shin Nippon Biomedical Laboratories Ltd., Kagoshima, Japan

Corresponding author.

Correspondence: Misako Nakashima, D.D.S., Ph.D., Department of Oral Disease Research, National Center for Geriatrics and Gerontology, Research Institute, 35 Gengo, Morioka, Obu, Aichi 474-8522, Japan. Telephone: 81-562-44-5651, ext. 5065; Fax: 81-562-46-8684; E-Mail: pj.og.ggcn@okasim

Abstract

Treatment of deep caries with pulpitis is a major challenge in dentistry. Stem cell therapy represents a potential strategy to regenerate the dentin-pulp complex, enabling conservation and restoration of teeth. The objective of this study was to assess the efficacy and safety of pulp stem cell transplantation as a prelude for the impending clinical trials. Clinical-grade pulp stem cells were isolated and expanded according to good manufacturing practice conditions. The absence of contamination, abnormalities/aberrations in karyotype, and tumor formation after transplantation in an immunodeficient mouse ensured excellent quality control. After autologous transplantation of pulp stem cells with granulocyte-colony stimulating factor (G-CSF) in a dog pulpectomized tooth, regenerated pulp tissue including vasculature and innervation completely filled in the root canal, and regenerated dentin was formed in the coronal part and prevented microleakage up to day 180. Transplantation of pulp stem cells with G-CSF yielded a significantly larger amount of regenerated dentin-pulp complex compared with transplantation of G-CSF or stem cells alone. Also noteworthy was the reduction in the number of inflammatory cells and apoptotic cells and the significant increase in neurite outgrowth compared with results without G-CSF. The transplanted stem cells expressed angiogenic/neurotrophic factors. It is significant that G-CSF together with conditioned medium of pulp stem cells stimulated cell migration and neurite outgrowth, prevented cell death, and promoted immunosuppression in vitro. Furthermore, there was no evidence of toxicity or adverse events. In conclusion, the combinatorial trophic effects of pulp stem cells and G-CSF are of immediate utility for pulp/dentin regeneration, demonstrating the prerequisites of safety and efficacy critical for clinical applications.

Keywords: Autologous stem cell transplantation, G-CSF, Mesenchymal stem cells, Preclinical trials, Dog model, Stem cell culture, Tissue regeneration

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