Stem Cell Therapies for the Treatment of Radiation-Induced Normal Tissue Side Effects

Abstract

Significance: Targeted irradiation is an effective cancer therapy but damage inflicted to normal tissues surrounding the tumor may cause severe complications. While certain pharmacologic strategies can temper the adverse effects of irradiation, stem cell therapies provide unique opportunities for restoring functionality to the irradiated tissue bed. Recent Advances: Preclinical studies presented in this review provide encouraging proof of concept regarding the therapeutic potential of stem cells for treating the adverse side effects associated with radiotherapy in different organs. Early-stage clinical data for radiation-induced lung, bone, and skin complications are promising and highlight the importance of selecting the appropriate stem cell type to stimulate tissue regeneration. Critical Issues: While therapeutic efficacy has been demonstrated in a variety of animal models and human trials, a range of additional concerns regarding stem cell transplantation for ameliorating radiationinduced normal tissue sequelae remain. Safety issues regarding teratoma formation, disease progression, and genomic stability along with technical issues impacting disease targeting, immunorejection, and clinical scale-up are factors bearing on the eventual translation of stem cell therapies into routine clinical practice. Future Directions: Follow-up studies will need to identify the best possible stem cell types for the treatment of early and late radiation-induced normal tissue injury. Additional work should seek to optimize cellular dosing regimes, identify the best routes of administration, elucidate optimal transplantation windows for introducing cells into more receptive host tissues, and improve immune tolerance for longer-term engrafted cell survival into the irradiated microenvironment. Antioxid. Redox Signal. 21, 338-355.

Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain

“…Much of this work has also highlighted the importance of trophic support, particularly for the longer-term recovery from normal tissue injury (6,7,15). Although the mechanisms underlying the beneficial effects of stem cell transplantation are certain to be complex and multifaceted, present findings suggest that secreted MV likely play an important role in mediating trophic support derived from multipotent stem cells.…”

“…15), issues concerning ethics, immunorejection, and teratoma formation remain significant concerns. To circumvent some of these potential confounders and to establish a potentially novel therapeutic strategy for ameliorating radiation-induced cognitive dysfunction, MV were substituted for hNSC in cranial grafting procedures following head-only irradiation.…”

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].…”

“…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].…”

“…[71,89] aMSCs = adipose-derived mesenchymal stromal cell, bmMSC = bone marrow MSCs; BBB = blood brain barrier; BM = bone marrow; CNS = central nervous system; EPC = endothelial progenitor cells; GFAP = glial fibrillary acidic protein; hESC = human embryonic stem cell; hSC = human stem cells; hNSC = human neural stem cell, RT = radiation.…”