Allogeneic multipotent mesenchymal stromal cell sheet transplantation promotes healthy healing of wounds caused by zoledronate and dexamethasone in canine mandibular bones

Abstract

IntroductionMany cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is an intractable disease, have been reported. Although a general intravenous injection of multipotent mesenchymal stromal cells (MSCs) may be effective for treating BRONJ, it has some severe problems. Therefore, our aim was to develop a treatment of locally administered MSCs. In this study, we investigated the effect of MSC sheet transplantation in the mandibular bone healing in beagle dogs, which were administered zoledronate and dexamethasone.MethodsMSCs isolated from subcutaneous fat were seeded onto temperature-responsive culture dishes to produce MSC sheets. Zoledronate and dexamethasone were administered to beagle dogs. Then, the parts of mandibular cortical bones were removed, and MSC sheets were transplanted to cover those bone defects (MSC sheet transplant side) or not (Control side). The specimens were evaluated in micro CT, histology, and immunohistochemistry.ResultsFour weeks after surgery, redness and swellings were observed in the mucosal wounds of the control sides of 2 of 3 dogs. In contrast, the mucosal wounds of the MSC sheet transplant sides of all dogs completely healed. Histological images showed some free sequestrums and many bacterial colonies, and Immunohistological analysis showed some cathepsin K-positive multinuclear cells detached from jaw bone surfaces in the control sides.ConclusionsMSC sheet transplantation promotes healthy healing of wounds caused by zoledronate and dexamethasone in canine mandibular bones. And the injured canine mandibular bones administered zoledronate and dexamethasone showed BRONJ-like findings.

Mesenchymal stromal cells administration for osteonecrosis of the jaw caused by bisphosphonate: report of two cases

“…However, it is not clear whether MSCs were expanded ex vivo as was the case here, a measure that increases MSCs number, which, theoretically, would favour bone healing. Furthermore, Kaibuchi et al demonstrated good results with allogeneic MSCs in a canine model of BRONJ [27].…”

Differentiation of equine induced pluripotent stem cells into mesenchymal lineage for therapeutic use

“…In this study, E-iPSCs were differentiated into MSCs for cell transplantation to treat musculoskeletal injuries in horses (Figure 8). MSCs are considered a safe cell-based therapy for horses due to their self-renewal and multi-lineage differentiation abilities and their low potential for teratoma formation compared to iPSCs, MSC transplantations, usually harvested from the bone marrow or umbilical cord, have been performed in humans, canines, and many other animals, including horses [27,28]. Until now, among these various cell types, bone marrow-derived mesenchymal stem cells have been the main resource for cell transplantation.…”

Cell therapy for medication-related osteonecrosis of the jaw: update on treatment strategies

“…In dentistry, Iwata et al (2018) conducted a clinical study in which periodontal ligament-derived MSC sheets were transplanted into 10 patients for periodontal reconstruction and observed significant improvements in radiographic bone height and various clinical findings. Since 2013, analysis of the use of cell sheet engineering as the optimal method of cell transplantation in the treatment of MRONJ has been carried out (Kaibuchi et al, 2016;Kaibuchi et al, 2019). In 1 study, after the administration of zoledronate and dexamethasone in Sprague-Dawley (SD) rats, the maxillary first molars were extracted to establish a rat model with MRONJlike lesions.…”