title: Regeneration of dental-pulp-like tissue by chemotaxis-induced cell homing.
abstract: Tooth infections or injuries involving dental pulp are treated routinely by root canal therapy. Endodontically treated teeth are devitalized, susceptible to re-infections, fractures, and subsequent tooth loss. Here, we report regeneration of dental-pulp-like tissue by cell homing and without cell transplantation. Upon in vivo implantation of endodontically treated real-size, native human teeth in mouse dorsum for the tested 3 weeks, delivery of basic fibroblast growth factor and/or vascular endothelial growth factor (bFGF and/or VEGF) yielded re-cellularized and revascularized connective tissue that integrated to native dentinal wall in root canals. Further, combined delivery of bFGF, VEGF, or platelet-derived growth factor (PDGF) with a basal set of nerve growth factor (NGF) and bone morphogenetic protein-7 (BMP7) generated cellularized and vascularized tissues positive of VEGF antibody staining and apparent neo-dentin formation over the surface of native dentinal wall in some, but not all, endodontically treated teeth. Newly formed dental pulp tissue appeared dense with disconnected cells surrounded by extracellular matrix. Erythrocyte-filled blood vessels were present with endothelial-like cell lining. Reconstructed, multiple microscopic images showed complete fill of dental-pulp-like tissue in the entire root canal from root apex to pulp chamber with tissue integration to dentinal wall upon delivery of bFGF, VEGF, or PDGF with a basal set of NGF and BMP7. Quantitative ELISA showed that combinatory delivery of bFGF, VEGF, or PDGF with basal NGF and BMP7 elaborated von Willerbrand factor, dentin sialoprotein, and NGF. These findings represent the first demonstration of regenerated dental-pulp-like tissue in endodontically treated root canals of real-size, native human teeth. The present chemotaxis-based approach has potent cell homing effects for re-cellularization and revascularization in endodontically treated root canals in vivo, although in an ectopic model. Regeneration of dental pulp by cell homing, rather than cell delivery, may accelerate clinical translation.
authors.affiliation: Tissue Engineering and Regenerative Medicine Laboratory (TERML), Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Jin Y
authors.initials: JY
authors.lastname: Kim
authors.forename: Xuejun
authors.initials: X
authors.lastname: Xin
authors.forename: Eduardo K
authors.initials: EK
authors.lastname: Moioli
authors.forename: Jenny
authors.initials: J
authors.lastname: Chung
authors.forename: Chang Hun
authors.initials: CH
authors.lastname: Lee
authors.forename: Mo
authors.initials: M
authors.lastname: Chen
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Fu
authors.forename: Peter D
authors.initials: PD
authors.lastname: Koch
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Mao
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D003782:Dental Pulp / Q000166:cytology* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D020932:Nerve Growth Factor / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds / Q000737:chemistry; D019553:Tooth, Nonvital; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D014841:von Willebrand Factor / Q000378:metabolism; D000099311:Dentin Sialophosphoprotein
chemical_list: D055419:Bone Morphogenetic Protein 7; D016326:Extracellular Matrix Proteins; D016222:Fibroblast Growth Factor 2; D020932:Nerve Growth Factor; D010750:Phosphoproteins; D012795:Sialoglycoproteins; D042461:Vascular Endothelial Growth Factor A; D014841:von Willebrand Factor; D000099311:Dentin Sialophosphoprotein