title: Therapeutic interactions between mesenchymal stem cells for healing medication-related osteonecrosis of the jaw.
abstract: Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, including bone marrow, adipose, and mucosa. MSCs have the capacity for self-renewal and differentiation. Reports have been published on the systemic administration of MSCs leading to functional improvements by engraftment and differentiation, thus providing a new strategy to regenerate damaged tissues. Recently, it has become clear that MSCs possess immunomodulatory properties and can therefore be used to treat diseases. However, the therapeutic effect mechanisms of MSCs are yet to be determined. Here, we investigated these mechanisms using a medication-related osteonecrosis of the jaw (MRONJ)-like mouse model.
  
  
  
  To generate MRONJ-like characteristics, mice received intravenous zoledronate and dexamethasone two times a week. At 1 week after intravenous injection, maxillary first molars were extracted, and at 1 week after tooth extraction, MSCs were isolated from the bone marrow of the mice femurs and tibias. To compare "diseased MSCs" from MRONJ-like mice (d-MSCs) with "control MSCs" from untreated mice (c-MSCs), the isolated MSCs were analyzed by differentiation and colony-forming unit-fibroblast (CFU-F) assays and systemic transplantation of either d-MSCs or c-MSCs into MRONJ-like mice. Furthermore, we observed the exchange of cell contents among d-MSCs and c-MSCs during coculture with all combinations of each MSC type.
  
  
  
  d-MSCs were inferior to c-MSCs in differentiation and CFU-F assays. Moreover, the d-MSC-treated group did not show earlier healing in MRONJ-like mice. In cocultures with any combination, MSC pairs formed cell-cell contacts and exchanged cell contents. Interestingly, the exchange among c-MSCs and d-MSCs was more frequently observed than other pairs, and d-MSCs were distinguishable from c-MSCs.
  
  
  
  The interaction of c-MSCs and d-MSCs, including exchange of cell contents, contributes to the treatment potential of d-MSCs. This cellular behavior might be one therapeutic mechanism used by MSCs for MRONJ.
authors.affiliation: Section of Implant and Rehabilitative Dentistry, Division of Oral Rehabilitation, Faculty of Dental Science Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Matsuura
authors.affiliation: Section of Implant and Rehabilitative Dentistry, Division of Oral Rehabilitation, Faculty of Dental Science Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. atyuta@dent.kyushu-u.ac.jp.
authors.forename: Ikiru
authors.initials: I
authors.lastname: Atsuta
authors.affiliation: Section of Implant and Rehabilitative Dentistry, Division of Oral Rehabilitation, Faculty of Dental Science Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Ayukawa
authors.affiliation: Department of Molecular Cell and Oral Anatomy, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Yamaza
authors.affiliation: Section of Implant and Rehabilitative Dentistry, Division of Oral Rehabilitation, Faculty of Dental Science Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kondo
authors.affiliation: Section of Implant and Rehabilitative Dentistry, Division of Oral Rehabilitation, Faculty of Dental Science Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Section of Implant and Rehabilitative Dentistry, Division of Oral Rehabilitation, Faculty of Dental Science Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ueda
authors.affiliation: Section of Implant and Rehabilitative Dentistry, Division of Oral Rehabilitation, Faculty of Dental Science Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Wakana
authors.initials: W
authors.lastname: Oshiro
authors.affiliation: Section of Implant and Rehabilitative Dentistry, Division of Oral Rehabilitation, Faculty of Dental Science Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tsukiyama
authors.affiliation: Section of Implant and Rehabilitative Dentistry, Division of Oral Rehabilitation, Faculty of Dental Science Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Koyano
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D003114:Colony-Forming Units Assay / Q000379:methods; D005347:Fibroblasts / Q000166:cytology; D007568:Jaw / Q000166:cytology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010020:Osteonecrosis / Q000628:therapy*; D013234:Stem Cells / Q000166:cytology*; D014945:Wound Healing / Q000502:physiology*
keywords: Medication-related osteonecrosis of the jaw; Mesenchymal stem cell; Therapeutic mechanism