{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:51:08Z","timestamp":1791845468341,"version":"4.3.4"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2013,6,12]],"date-time":"2013-06-12T00:00:00Z","timestamp":1370995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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.<\/jats:p>","DOI":"10.5966\/sctm.2012-0132","type":"journal-article","created":{"date-parts":[[2013,6,13]],"date-time":"2013-06-13T03:02:27Z","timestamp":1371092547000},"page":"521-533","source":"Crossref","is-referenced-by-count":166,"title":["A Novel Combinatorial Therapy With Pulp Stem Cells and Granulocyte Colony-Stimulating Factor for Total Pulp Regeneration"],"prefix":"10.1093","volume":"2","author":[{"given":"Koichiro","family":"Iohara","sequence":"first","affiliation":[{"name":"Departments of Dental Regenerative Medicine, Center of Advanced Medicine for Dental and Oral Diseases, National Center for Geriatrics and Gerontology, Research Institute, Obu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Murakami","sequence":"additional","affiliation":[{"name":"Departments of Dental Regenerative Medicine, Center of Advanced Medicine for Dental and Oral Diseases, National Center for Geriatrics and Gerontology, Research Institute, Obu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Departments of Dental Regenerative Medicine, Center of Advanced Medicine for Dental and Oral Diseases, National Center for Geriatrics and Gerontology, Research Institute, Obu, Japan"},{"name":"Departments of Endodontology, School of Dentistry, Aichi-gakuin University, Nagoya, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Osako","sequence":"additional","affiliation":[{"name":"Departments of Dental Regenerative Medicine, Center of Advanced Medicine for Dental and Oral Diseases, National Center for Geriatrics and Gerontology, Research Institute, Obu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Developmental Anatomy and Regenerative Medicine, National Defense Medical College, Tokorozawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Ishizaka","sequence":"additional","affiliation":[{"name":"Departments of Dental Regenerative Medicine, Center of Advanced Medicine for Dental and Oral Diseases, National Center for Geriatrics and Gerontology, Research Institute, Obu, Japan"},{"name":"Departments of Pediatric Dentistry, School of Dentistry, Aichi-gakuin University, Nagoya, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Utunomiya","sequence":"additional","affiliation":[{"name":"Drug Safety Research Laboratories, Shin Nippon Biomedical Laboratories Ltd., Kagoshima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Departments of Endodontology, School of Dentistry, Aichi-gakuin University, Nagoya, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Departments of Oral Disease Research, Center of Advanced Medicine for Dental and Oral Diseases, National Center for Geriatrics and Gerontology, Research Institute, Obu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misako","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Departments of Dental Regenerative Medicine, Center of Advanced Medicine for Dental and Oral Diseases, National Center for Geriatrics and Gerontology, Research Institute, Obu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,6,12]]},"reference":[{"key":"2021122707321459400_ref1","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1016\/j.biomaterials.2011.11.056","article-title":"Regeneration of dental pulp following pulpectomy by fractionated stem\/progenitor cells from bone marrow and adipose tissue","volume":"33","author":"Ishizaka","year":"2012","journal-title":"Biomaterials"},{"key":"2021122707321459400_ref2","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1089\/ten.tea.2010.0615","article-title":"Complete pulp regeneration after pulpectomy by transplantation of CD105+ stem cells with stromal cell-derived factor-1","volume":"17","author":"Iohara","year":"2011","journal-title":"Tissue Eng Part A"},{"key":"2021122707321459400_ref3"},{"key":"2021122707321459400_ref4","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1634\/stemcells.2008-0393","article-title":"A novel stem cell source for vasculogenesis in ischemia: Subfraction of side population cells from dental pulp","volume":"26","author":"Iohara","year":"2008","journal-title":"Stem Cells"},{"key":"2021122707321459400_ref5","doi-asserted-by":"crossref","first-page":"3162","DOI":"10.1089\/scd.2012.0048","article-title":"Granulocyte-colony-stimulating factor stimulation of bone marrow mesenchymal stromal cells promotes CD34+ cell migration via a matrix metalloproteinase-2-dependent mechanism","volume":"21","author":"Ponte","year":"2012","journal-title":"Stem Cells Dev"},{"key":"2021122707321459400_ref6","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.jocn.2007.03.020","article-title":"Enhanced regeneration in spinal cord injury by concomitant treatment with granulocyte colony-stimulating factor and neuronal stem cells","volume":"15","author":"Pan","year":"2008","journal-title":"J Clin Neurosci"},{"key":"2021122707321459400_ref7","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1007\/s00701-009-0402-6","article-title":"Combination of bone marrow stromal cell transplantation with mobilization by granulocyte-colony stimulating factor promotes functional recovery after spinal cord transection","volume":"151","author":"Luo","year":"2009","journal-title":"Acta Neurochir (Wien)"},{"key":"2021122707321459400_ref8","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/1423-0127-16-75","article-title":"Escalated regeneration in sciatic nerve crush injury by the combined therapy of human amniotic fluid mesenchymal stem cells and fermented soybean extracts, natto","volume":"16","author":"Pan","year":"2009","journal-title":"J Biomed Sci"},{"key":"2021122707321459400_ref9","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1756-8722-5-19","article-title":"Clinical applications of mesenchymal stem cells","volume":"5","author":"Wang","year":"2012","journal-title":"J Hematol Oncol"},{"key":"2021122707321459400_ref10","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1634\/stemcells.2006-0161","article-title":"Side population cells isolated from porcine dental pulp tissue with self-renewal and multipotency for dentinogenesis, chondrogenesis, adipogenesis, and neurogenesis","volume":"24","author":"Iohara","year":"2006","journal-title":"Stem Cells"},{"key":"2021122707321459400_ref11","doi-asserted-by":"crossref","first-page":"F1626","DOI":"10.1152\/ajprenal.00339.2006","article-title":"Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury","volume":"292","author":"T\u00f6gel","year":"2007","journal-title":"Am J Phisiol Renal Physiol"},{"key":"2021122707321459400_ref12","doi-asserted-by":"crossref","first-page":"3197","DOI":"10.1096\/fj.06-6558com","article-title":"SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction","volume":"21","author":"Zhang","year":"2007","journal-title":"FASEB J"},{"key":"2021122707321459400_ref13","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1182\/blood.V68.1.162.162","article-title":"Purified colony-stimulating factors enhance the survival of humanneutrophils and eosinophils in vitro: A rapid and sensitive microassay for colony-stimulating factors","volume":"68","author":"Begley","year":"1986","journal-title":"Blood"},{"key":"2021122707321459400_ref14","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1002\/1097-0142(19900515)65:10<2185::AID-CNCR2820651005>3.0.CO;2-4","article-title":"The colony stimulating factors. Discovery, development, and clinical applications","volume":"65","author":"Metcalf","year":"1990","journal-title":"Cancer"},{"key":"2021122707321459400_ref15","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1161\/01.STR.0000208205.26253.96","article-title":"A novel neuroprotectant granulocyte-colony stimulating factor","volume":"37","author":"Solaroglu","year":"2006","journal-title":"Stroke"},{"key":"2021122707321459400_ref16","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1002\/mds.10385","article-title":"Severe forward flexion of the trunk in Parkinson's disease: Focal myopathy of the paraspinal muscles mimicking camptocormia","volume":"18","author":"Sch\u00e4bitz","year":"2003","journal-title":"Mov Disord"},{"key":"2021122707321459400_ref17","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1161\/01.CIR.0000142616.07367.66","article-title":"Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells","volume":"110","author":"Shyu","year":"2004","journal-title":"Circulation"},{"key":"2021122707321459400_ref18","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/sj.jcbfm.9600033","article-title":"G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice","volume":"25","author":"Gibson","year":"2005","journal-title":"J Cereb Blood Flow Metab"},{"key":"2021122707321459400_ref19","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/1471-2202-10-49","article-title":"Both systemic and local application of granulocyte-colony stimulating f actor (G-CSF) is neuroprotective after retinal ganglion cell axotomy","volume":"10","author":"Frank","year":"2009","journal-title":"BMC Neurosci"},{"key":"2021122707321459400_ref20","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1111\/j.1471-4159.2010.06659.x","article-title":"The hematopoietic factor granulocyte-colony stimulating factor improves outcome in experimental spinal cord injury","volume":"113","author":"Pitzer","year":"2010","journal-title":"J Neurochem"},{"key":"2021122707321459400_ref21","doi-asserted-by":"crossref","first-page":"e29880","DOI":"10.1371\/journal.pone.0029880","article-title":"Granulocyte-colony stimulating factor (G-CSF) improves motor recovery in the rat impactor model for spinal cord injury","volume":"7","author":"Dittgen","year":"2012","journal-title":"PLoS One"},{"key":"2021122707321459400_ref22","doi-asserted-by":"crossref","first-page":"2572","DOI":"10.1161\/01.CIR.0000129770.93985.3E","article-title":"Acceleration of the healing process and myocardial regeneration may be important as a mechanism of improvement of cardiac function and remodeling by postinfarction granulocyte colony-stimulating factor treatment","volume":"109","author":"Minatoguchi","year":"2004","journal-title":"Circulation"},{"key":"2021122707321459400_ref23","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1096\/fj.03-0637fje","article-title":"Cytokine therapy prevents left ventricular remodeling and dysfunction after myocardial infarction through neovascularization","volume":"18","author":"Ohtsuka","year":"2004","journal-title":"FASEB J"},{"key":"2021122707321459400_ref24","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2739\/kurumemedj.52.89","article-title":"Vascular endothelial growth factor is involved in angioedema associated with eosinophilia","volume":"52","author":"Harada","year":"2005","journal-title":"Kurume Med J"},{"key":"2021122707321459400_ref25","first-page":"957","article-title":"Treatment with granulocyte-colony stimulating factor in patients with acute myocardial infarction. Evidence for a stimulation of neovascularization and improvement of myocardial perfusion","volume":"61","author":"Kuethe","year":"2006","journal-title":"Pharmazie"},{"key":"2021122707321459400_ref26","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1161\/01.ATV.0000190609.28293.17","article-title":"Therapeutic angiogenesis with intramuscular injection of low-dose recombinant granulocyte-colony stimulating factor","volume":"25","author":"Lee","year":"2005","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2021122707321459400_ref27","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1161\/01.STR.0000227299.62106.0e","article-title":"Developing granulocyte-colony stimulating factor for the treatment of stroke: Current status of clinical trials","volume":"37","author":"Sch\u00e4bitz","year":"2006","journal-title":"Stroke"},{"key":"2021122707321459400_ref28","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1503\/cmaj.051322","article-title":"Granulocyte colony-stimulating factor for acute ischemic stroke: A randomized controlled trial","volume":"174","author":"Shyu","year":"2006","journal-title":"CMAJ"},{"key":"2021122707321459400_ref29","doi-asserted-by":"crossref","first-page":"e23099","DOI":"10.1371\/journal.pone.0023099","article-title":"Mobilisation of hematopoietic CD34+ precursor cells in patients with acute stroke is safe: Results of an open-labeled nonrandomized phase I\/II trial","volume":"6","author":"Boy","year":"2011","journal-title":"PLoS One"},{"key":"2021122707321459400_ref30","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.bbrc.2009.03.003","article-title":"Potentiation of angiogenesis and regeneration by G-CSF after sciatic nerve crush injury","volume":"382","author":"Pan","year":"2009","journal-title":"Biochem Biophys Res Commun"},{"key":"2021122707321459400_ref31","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/1471-2202-12-61","article-title":"Granulocyte colony-stimulating factor increases the therapeutic efficacy of bone marrow mononuclear cell transplantation in cerebral ischemia in mice","volume":"12","author":"Zhang","year":"2011","journal-title":"BMC Neurosci"},{"key":"2021122707321459400_ref32","doi-asserted-by":"crossref","first-page":"689","DOI":"10.2217\/rme.09.44","article-title":"Ficoll-Paque versus Lymphoprep: A comparative study of two density gradient media for therapeutic bone marrow mononuclear cell preparations","volume":"4","author":"Yeo","year":"2009","journal-title":"Regen Med"},{"key":"2021122707321459400_ref33","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1172\/JCI23559","article-title":"The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis","volume":"115","author":"Schneider","year":"2005","journal-title":"J Clin Invest"},{"key":"2021122707321459400_ref34","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.neuroscience.2006.09.014","article-title":"Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat","volume":"143","author":"Solaroglu","year":"2006","journal-title":"Neuroscience"},{"key":"2021122707321459400_ref35","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.physbeh.2007.05.032","article-title":"Target finding of pain nerve fibers: Neural growth mechanisms in the tooth pulp","volume":"92","author":"Fried","year":"2007","journal-title":"Physiol Behav"},{"key":"2021122707321459400_ref36","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1006\/exnr.1997.6523","article-title":"Effect of intermittent long-lasting electrical tooth stimulation on pulpal blood flow and immunocompetent cells: A hemodynamic and immunohistochemical study in young rat molars","volume":"146","author":"Fristad","year":"1997","journal-title":"Exp Neurol"},{"key":"2021122707321459400_ref37","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1177\/00220345930720031001","article-title":"Effect of sensory denervation on the response of rat molar pulp to exposure injury","volume":"72","author":"Byers","year":"1993","journal-title":"J Dent Res"},{"key":"2021122707321459400_ref38","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1046\/j.1365-201X.1996.69319000.x","article-title":"Local actions of acetylcholine on vasomotor regulation in rat incisor pulp","volume":"158","author":"Olgart","year":"1996","journal-title":"Acta Physiol Scand"},{"key":"2021122707321459400_ref39","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1097\/01.don.0000164138.49923.e5","article-title":"The application of tissue engineering to regeneration of pulp and dentin in endodontics","volume":"31","author":"Nakashima","year":"2005","journal-title":"J Endod"},{"key":"2021122707321459400_ref40","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/jemt.10007","article-title":"Three-dimensional wall structure and the innervation of dental pulp blood vessels","volume":"56","author":"Iijima","year":"2002","journal-title":"Microsc Res Tech"},{"key":"2021122707321459400_ref41","first-page":"121","article-title":"Quality assurance of clinical grade pulp stem cells manufactured in GMP-compliant facility","volume":"56","author":"Iohara","year":"2013","journal-title":"Jpn J Conser Dent"},{"key":"2021122707321459400_ref42","doi-asserted-by":"crossref","first-page":"503","DOI":"10.4061\/2010\/503593","article-title":"Culture and use of mesenchymal stromal cells in Phase I and II clinical trials","volume":"2010","author":"Philippe","year":"2010","journal-title":"Stem Cells Int"},{"key":"2021122707321459400_ref43","doi-asserted-by":"crossref","first-page":"180","DOI":"10.4049\/jimmunol.154.1.180","article-title":"Multiple defects in innate and adaptive immunologic function in NOD\/LtSz-scid mice","volume":"154","author":"Shultz","year":"1995","journal-title":"J Immunol"},{"key":"2021122707321459400_ref44","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1128\/jvi.71.1.465-470.1997","article-title":"Productive and lytic infection of human CD4+ type 1 helper T cells with macrophage-tropic human immunodeficiency virus type 1","volume":"71","author":"Tanaka","year":"1997","journal-title":"J Virol"},{"key":"2021122707321459400_ref45","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/sj.bmt.1702702","article-title":"Natural killer cell depletion by anti-asialo GM1 antiserum treatment enhances human hematopoietic stem cell engraftment in NOD\/Shi-scid mice","volume":"26","author":"Yoshino","year":"2000","journal-title":"Bone Marrow Transplant"},{"key":"2021122707321459400_ref46","doi-asserted-by":"crossref","first-page":"123","DOI":"10.2131\/jts.34.123","article-title":"Higher susceptibility of NOG mice to xenotransplanted tumors","volume":"34","author":"Machida","year":"2009","journal-title":"J Toxicol Sci"}],"container-title":["Stem Cells Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.5966%2Fsctm.2012-0132","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.5966%2Fsctm.2012-0132","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/2\/7\/521\/41885262\/stcltm_2_7_521.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stcltm\/article-pdf\/2\/7\/521\/41885262\/stcltm_2_7_521.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T09:08:59Z","timestamp":1715504939000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stcltm\/article\/2\/7\/521-533\/6385690"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,6,12]]},"references-count":46,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2013,6,12]]},"published-print":{"date-parts":[[2013,7,1]]}},"URL":"https:\/\/doi.org\/10.5966\/sctm.2012-0132","relation":{},"ISSN":["2157-6564","2157-6580"],"issn-type":[{"value":"2157-6564","type":"print"},{"value":"2157-6580","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,7,1]]},"published":{"date-parts":[[2013,6,12]]}}}