Systemic Transplantation of Human Adipose Tissue-Derived Mesenchymal Stem Cells for the Regeneration of Irradiation-Induced Salivary Gland Damage

Abstract

ObjectivesCell-based therapy has been reported to repair or restore damaged salivary gland (SG) tissue after irradiation. This study was aimed at determining whether systemic administration of human adipose-derived mesenchymal stem cells (hAdMSCs) can ameliorate radiation-induced SG damage.MethodshAdMSCs (1×106) were administered through a tail vein of C3H mice immediately after local irradiation, and then this infusion was repeated once a week for 3 consecutive weeks. At 12 weeks after irradiation, functional evaluations were conducted by measuring salivary flow rates (SFRs) and salivation lag times, and histopathologic and immunofluorescence histochemistry studies were performed to assay microstructural changes, apoptosis, and proliferation indices. The engraftment and in vivo differentiation of infused hAdMSCs were also investigated, and the transdifferentiation of hAdMSCs into amylase-producing SG epithelial cells (SGCs) was observed in vitro using a co-culture system.ResultsThe systemic administration of hAdMSCs exhibited improved SFRs at 12 weeks after irradiation. hAdMSC-transplanted SGs showed fewer damaged and atrophied acinar cells and higher mucin and amylase production levels than untreated irradiated SGs. Immunofluorescence TUNEL assays revealed fewer apoptotic cells in the hAdMSC group than in the untreated group. Infused hAdMSCs were detected in transplanted SGs at 4 weeks after irradiation and some cells were found to have differentiated into SGCs. In vitro, a low number of co-cultured hAdMSCs (13%–18%) were observed to transdifferentiate into SGCs.ConclusionThe findings of this study indicate that hAdMSCs have the potential to protect against irradiation-induced cell loss and to transdifferentiate into SGCs, and suggest that hAdMSC administration should be viewed as a candidate therapy for the treatment of radiation-induced SG damage.

Adipose mesenchymal stromal cells minimize and repair radiation-induced oral mucositis

“…aMSCs are promising for cellular therapies due to their prominent anti-inflammatory effects, enhancing IL-10 secretion, ease of isolation, high cell count after expansion, as well as their source abundance [73]. In radiation-induced normal tissue injury, aMSCs have shown significant repair of cutaneous radiation syndrome [79][80][81][82][83] and photo-aging [84], RT-induced acute salivary gland [85] and intestine injuries [70,[86][87][88], and chronic injuries induced by radiotherapy [80,89]. In addition, we have shown in a previous study that aMSCs are relatively resistant to ionizing radiation, a property that qualifies them to be a reliable cellular therapy candidate before and during RT [159].…”

“…In irradiated mice, systemically transplanted MSCs resulted in improvement of the saliva flow rate, lower salivary gland damage and atrophic acini and higher mucin and amylase production [85].…”

“…aMSCs have been investigated in many studies for cutaneous radiation syndrome [79][80][81][82][83] and photo-aging [84] with significant tissue repair. aMSCs systemic cell therapy led to significant restoration and improvement of acute salivary gland [85] and intestine injuries [70,[86][87][88] induced by ionizing radiation (IR). Furthermore, aMSCs have shown promise for successful cell therapy in chronic radiotherapy-induced injuries [80,89].…”

“…In addition, aMSCs systemic cell therapy has shown significant restoration and improvement of acute salivary gland [85] and intestine injuries [70,[86][87][88] induced by ionizing radiation (IR). Furthermore, aMSCs showed a promising potential of being a successful cell therapy option in chronic injuries induced by radiotherapy as well [80,89].…”

Wetting the whistle: neurotropic factor improves salivary function

“…This type of adenoviral approach has the potential to provide a more permanent treatment of this symptom; however, the expected duration of improvement following transgene delivery and other challenges associated with viral gene therapy remains unknown. Intriguingly, transplantation of salivary stem cells within bioengineered organs has also shown promise in rat and mouse models of xerostomia (13)(14)(15). However, this powerful approach remains years away from clinical implementation due to limited sources of human stem cells.…”